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Sample records for synthesis molecular pharmacology

  1. Selective antagonists at group I metabotropic glutamate receptors: synthesis and molecular pharmacology of 4-aryl-3-isoxazolol amino acids

    DEFF Research Database (Denmark)

    Kromann, Hasse; Sløk, Frank A; Stensbøl, Tine B

    2002-01-01

    Homologation of (S)-glutamic acid (Glu, 1) and Glu analogues has previously provided ligands with activity at metabotropic Glu receptors (mGluRs). The homologue of ibotenic acid (7), 2-amino-3-(3-hydroxy-5-isoxazolyl)propionic acid (HIBO, 8), and the 4-phenyl derivative of 8, compound 9a, are bot...... antagonists at group I mGluRs. Here we report the synthesis and molecular pharmacology of HIBO analogues 9b-h containing different 4-aryl substituents. All of these compounds possess antagonist activity at group I mGluRs but are inactive at group II and III mGluRs....

  2. Tetrazolyl isoxazole amino acids as ionotropic glutamate receptor antagonists: synthesis, modelling and molecular pharmacology

    DEFF Research Database (Denmark)

    Frølund, Bente; Greenwood, Jeremy R; Holm, Mai Marie

    2005-01-01

    and 1b were pharmacologically characterized in receptor binding assays, and electrophysiologically on homomeric AMPA receptors (GluR1-4), homomeric (GluR5 and GluR6) and heteromeric (GluR6/KA2) kainic acid receptors, using two-electrode voltage-clamped Xenopus laevis oocytes expressing these receptors...

  3. Annulated heterocyclic bioisosteres of norarecoline. Synthesis and molecular pharmacology at five recombinant human muscarinic acetylcholine receptors

    DEFF Research Database (Denmark)

    Bräuner-Osborne, Hans; Ebert, B; Brann, M R

    1995-01-01

    = 0.011 microM), and 4d (IC50 = 0.0008 microM). Pharmacological effects (EC50 or Ki values) and intrinsic activities (per cent of maximal carbachol responses) were determined using five recombinant human mAChRs (m1-m5) and the functional assay, receptor selection and amplification technology (R...... inhibitors of the binding of tritiated quinuclidinyl benzilate (QNB), pirenzepine (PZ), and oxotremorine-M (Oxo-M) to tissue membrane preparations. In the [3H]-Oxo-M binding assay, receptor affinities in the low nanomolar range were measured for 4a (IC50 = 0.010 microM), 4b (IC50 = 0.003 microM), 4c (IC50...

  4. Synthesis, pharmacological evaluation and molecular docking studies of pyrimidinedione based DPP-4 inhibitors as antidiabetic agents

    Science.gov (United States)

    Jha, Vibhu; Bhadoriya, Kamlendra Singh

    2018-04-01

    Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of newly developed antidiabetic drugs that bock DPP-4. DPP-4 is responsible for degradation of incretins harmones such as GLP-1 (Glucagon like Peptide) and GIP (Gastric inhibitory polypeptide) that maintain blood-glucose level. Pyrimidinedione based compounds were designed and synthesized for DPP-4 inhibitory activity. These heterocycles were designed by taking Alogliptin as a reference DPP-4 inhibitors and synthesized as N-methylated and N-benzylated pyrimidinediones. These compounds were subjected to DPP-4 assay, five out of nine synthesized compounds have shown in vitro DPP-4 inhibitory activity in significant range. Further, molecular docking studies of these compounds were performed on DPP-4 subunit and compared with natural DPP-4 inhibitors like Flavone, Resveratrol, Quercetin, Diprotin A. Docking studies have led to the conclusion that there are some identical amino acid interactions as Tyr 666 and Tyr 662, seen in both synthesized compounds and natural DPP-4 inhibitors. This study completely gives a good scope for further derivatisation and optimization of synthesized compounds to get clinical candidate as DPP-4 inhibitor for antidiabetic activity.

  5. Flurbiprofen–antioxidant mutual prodrugs as safer nonsteroidal anti-inflammatory drugs: synthesis, pharmacological investigation, and computational molecular modeling

    Directory of Open Access Journals (Sweden)

    Ashraf Z

    2016-07-01

    prodrugs at all times of assessment. The results of ulcerogenic activity showed that all prodrugs produced less GI irritation than flurbiprofen. Molecular docking and simulation studies were carried out with cyclooxygenase (COX-1 and COX-2 proteins, and it was observed that our prodrugs have more potential to selectively bind to COX-2 than to COX-1. It is concluded that the synthesized prodrugs have promising pharmacological activities with reduced GI adverse effects than the parent drug. Keywords: flurbiprofen prodrugs, natural antioxidants, molecular docking, molecular dynamic simulation, pharmacological investigation, NSAIDs

  6. Flurbiprofen–antioxidant mutual prodrugs as safer nonsteroidal anti-inflammatory drugs: synthesis, pharmacological investigation, and computational molecular modeling

    Science.gov (United States)

    Ashraf, Zaman; Alamgeer; Kanwal, Munazza; Hassan, Mubashir; Abdullah, Sahar; Waheed, Mamuna; Ahsan, Haseeb; Kim, Song Ja

    2016-01-01

    Flurbiprofen–antioxidant mutual prodrugs were synthesized to reduce the gastrointestinal (GI) effects associated with flurbiprofen. For reducing the GI toxicity, the free carboxylic group (–COOH) was temporarily masked by esterification with phenolic –OH of natural antioxidants vanillin, thymol, umbelliferone, and sesamol. The in vitro hydrolysis of synthesized prodrugs showed that they were stable in buffer solution at pH 1.2, indicating their stability in the stomach. The synthesized prodrugs undergo significant hydrolysis in 80% human plasma and thus release free flurbiprofen. The minimum reversion was observed at pH 1.2, suggesting that prodrugs are less irritating to the stomach than flurbiprofen. The anti-inflammatory, analgesic, antipyretic, and ulcerogenic activities of prodrugs were evaluated. All the synthesized prodrugs significantly (Pflurbiprofen showed 69% inhibition. Antipyretic activity was investigated using brewer’s yeast-induced pyrexia model, and significant (Pflurbiprofen. Molecular docking and simulation studies were carried out with cyclooxygenase (COX-1 and COX-2) proteins, and it was observed that our prodrugs have more potential to selectively bind to COX-2 than to COX-1. It is concluded that the synthesized prodrugs have promising pharmacological activities with reduced GI adverse effects than the parent drug. PMID:27555750

  7. Flurbiprofen-antioxidant mutual prodrugs as safer nonsteroidal anti-inflammatory drugs: synthesis, pharmacological investigation, and computational molecular modeling.

    Science.gov (United States)

    Ashraf, Zaman; Alamgeer; Kanwal, Munazza; Hassan, Mubashir; Abdullah, Sahar; Waheed, Mamuna; Ahsan, Haseeb; Kim, Song Ja

    2016-01-01

    Flurbiprofen-antioxidant mutual prodrugs were synthesized to reduce the gastrointestinal (GI) effects associated with flurbiprofen. For reducing the GI toxicity, the free carboxylic group (-COOH) was temporarily masked by esterification with phenolic -OH of natural antioxidants vanillin, thymol, umbelliferone, and sesamol. The in vitro hydrolysis of synthesized prodrugs showed that they were stable in buffer solution at pH 1.2, indicating their stability in the stomach. The synthesized prodrugs undergo significant hydrolysis in 80% human plasma and thus release free flurbiprofen. The minimum reversion was observed at pH 1.2, suggesting that prodrugs are less irritating to the stomach than flurbiprofen. The anti-inflammatory, analgesic, antipyretic, and ulcerogenic activities of prodrugs were evaluated. All the synthesized prodrugs significantly (Pflurbiprofen showed 69% inhibition. Antipyretic activity was investigated using brewer's yeast-induced pyrexia model, and significant (Pflurbiprofen. Molecular docking and simulation studies were carried out with cyclooxygenase (COX-1 and COX-2) proteins, and it was observed that our prodrugs have more potential to selectively bind to COX-2 than to COX-1. It is concluded that the synthesized prodrugs have promising pharmacological activities with reduced GI adverse effects than the parent drug.

  8. Molecular Docking Study, Green Synthesis and Pharmacological Evaluation of 1,3,4-thiadiazole Derivatives as Potential Antiepileptic Agents

    Czech Academy of Sciences Publication Activity Database

    Sahoo, B. M.; Dinda, S. C.; Kumar, B. V. V. R.; Panda, J. R.; Brahmkshatriya, Pathik

    2013-01-01

    Roč. 13, č. 14 (2013), s. 2076-2081 ISSN 1389-5575 Institutional support: RVO:61388963 Keywords : antiepileptic activity * docking study * epilepsy * green synthesis * neurotoxicity * thiadiazole Subject RIV: CC - Organic Chemistry Impact factor: 3.186, year: 2013

  9. Multipotent MAO and cholinesterase inhibitors for the treatment of Alzheimer's disease: synthesis, pharmacological analysis and molecular modeling of heterocyclic substituted alkyl and cycloalkyl propargyl amine.

    Science.gov (United States)

    Samadi, Abdelouahid; de los Ríos, Cristóbal; Bolea, Irene; Chioua, Mourad; Iriepa, Isabel; Moraleda, Ignacio; Bartolini, Manuela; Andrisano, Vincenza; Gálvez, Enrique; Valderas, Carolina; Unzeta, Mercedes; Marco-Contelles, José

    2012-06-01

    The synthesis, pharmacological evaluation and molecular modeling of heterocyclic substituted alkyl and cycloalkyl propargyl amines 1-7 of type I, and 9-12 of type II, designed as multipotent inhibitors able to simultaneously inhibit monoamine oxidases (MAO-A/B) as well as cholinesterase (AChE/BuChE) enzymes, as potential drugs for the treatment of Alzheimer's disease, are described. Indole derivatives 1-7 of type I are well known MAO inhibitors whose capacity to inhibit AChE and BuChE was here investigated for the first time. As a result, compound 7 was identified as a MAO-B inhibitor (IC(50) = 31 ± 2 nM) and a moderately selective eqBuChE inhibitor (IC(50) = 4.7 ± 0.2 μM). Conversely, the new and readily available 5-amino-7-(prop-2-yn-1-yl)-6,7,8,9-tetrahydropyrido[2,3-b][1,6]naphthyridine derivatives 9-13 of type II are poor MAO inhibitors, but showed AChE selective inhibition, compound 12 being the most attractive as it acts as a non-competitive inhibitor on EeAChE (IC(50) = 25 ± 3 nM, K(i) = 65 nM). The ability of this compound to interact with the AChE peripheral binding site was confirmed by kinetic studies and by molecular modeling investigation. Studies on human ChEs confirmed that 12 is a selective AChE inhibitor with inhibitory potency in the submicromolar range. Moreover, in agreement with its mode of action, 12 was shown to be able to inhibit Aβ aggregation induced by hAChE by 30.6%. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  10. Systems Pharmacology in Small Molecular Drug Discovery

    Directory of Open Access Journals (Sweden)

    Wei Zhou

    2016-02-01

    Full Text Available Drug discovery is a risky, costly and time-consuming process depending on multidisciplinary methods to create safe and effective medicines. Although considerable progress has been made by high-throughput screening methods in drug design, the cost of developing contemporary approved drugs did not match that in the past decade. The major reason is the late-stage clinical failures in Phases II and III because of the complicated interactions between drug-specific, human body and environmental aspects affecting the safety and efficacy of a drug. There is a growing hope that systems-level consideration may provide a new perspective to overcome such current difficulties of drug discovery and development. The systems pharmacology method emerged as a holistic approach and has attracted more and more attention recently. The applications of systems pharmacology not only provide the pharmacodynamic evaluation and target identification of drug molecules, but also give a systems-level of understanding the interaction mechanism between drugs and complex disease. Therefore, the present review is an attempt to introduce how holistic systems pharmacology that integrated in silico ADME/T (i.e., absorption, distribution, metabolism, excretion and toxicity, target fishing and network pharmacology facilitates the discovery of small molecular drugs at the system level.

  11. Dual functional cholinesterase and MAO inhibitors for the treatment of Alzheimer's disease: synthesis, pharmacological analysis and molecular modeling of homoisoflavonoid derivatives.

    Science.gov (United States)

    Wang, Yali; Sun, Yang; Guo, Yueyan; Wang, Zechen; Huang, Ling; Li, Xingshu

    2016-01-01

    Because of the complexity of Alzheimer's disease (AD), the multi-target-directed ligand (MTDL) strategy is expected to provide superior effects for the treatment of AD, instead of the classic one-drug-one-target strategy. In this context, we focused on the design, synthesis and evaluation of homoisoflavonoid derivatives as dual acetyl cholinesterase (AChE) and monoamine oxidase (MAO-B) inhibitors. Among all the synthesized compounds, compound 10 provided a desired balance of AChE and hMAO-B inhibition activities, with IC50 value of 3.94 and 3.44 μM, respectively. Further studies revealed that compound 10 was a mixed-type inhibitor of AChE and an irreversible inhibitor of hMAO-B, which was also confirmed by molecular modeling studies. Taken together, the data indicated that 10 was a promising dual functional agent for the treatment of AD.

  12. Molecular Pharmacology of CXCR4 inhibition

    DEFF Research Database (Denmark)

    Steen, Anne; Rosenkilde, Mette Marie

    2012-01-01

    pharmacology of well-known CXCR4 antagonists in order to augment the potency and affinity and to increase the specificity of future CXCR4-targeting compounds. In this chapter, binding modes of CXCR4 antagonists that have been shown to mobilize stem cells are discussed. In addition, comparisons between results...

  13. Synthesis of Tetracyclic Diterpenoids with Pharmacologic Relevance

    Czech Academy of Sciences Publication Activity Database

    Šíša, Miroslav; Vaněk, Tomáš

    2016-01-01

    Roč. 22, č. 12 (2016), s. 1767-1807 ISSN 1381-6128 R&D Projects: GA MŠk(CZ) LD15006 Institutional support: RVO:61389030 Keywords : Diterpenoids * synthesis * biological activity Subject RIV: CE - Biochemistry Impact factor: 2.611, year: 2016

  14. Structural Exploration of Quinazolin-4(3H)-ones as Anticonvulsants: Rational Design, Synthesis, Pharmacological Evaluation, and Molecular Docking Studies.

    Science.gov (United States)

    Ugale, Vinod G; Bari, Sanjay B

    2016-11-01

    Anticonvulsants effective against multiple seizures are of wide interest as antiepileptic drugs, especially if active against pharmaco-resistant seizures. Herein, we synthesized 16 different, rationally designed 2-((6,7-dimethoxy-4-oxo-2-phenylquinazolin-3(4H)-yl)amino)-N-(substituted phenyl)acetamides and screened for anticonvulsant activities through in vivo experiments. Compound 4d emerged as prototype with excellent anti-seizure action in mice against electroshock, chemically induced and pharmaco-resistant 6-Hz seizure models with no symptoms of neurotoxicity and hepatotoxicity (ED 50  = 23.5 mg/kg, MES, mice, i.p.; ED 50  = 32.6 mg/kg, scPTZ, mice, i.p.; ED 50  = 45.2 mg/kg, 6-Hz, mice, i.p.; TD 50  = 325.9 mg/kg, mice, i.p.). In addition, investigation of compound 4l in mice for its pharmacological profile proved it as safer anticonvulsant, devoid of the side effects such as motor dysfunction and hepatotoxicity of classical antiepileptic drugs (ED 50  = 26.1 mg/kg, MES, mice, i.p.; ED 50  = 79.4 mg/kg, scPTZ, mice, i.p.; TD 50  = 361.2 mg/kg, mice, i.p.). We also predicted physiochemical and pharmacokinetic properties of structurally optimized quinazolin-4(3H)-ones by a computational protocol. A combination of in vivo anticonvulsant profile, ex vivo toxicity, and in silico studies suggested that the synthesized compounds may be useful as broad-spectrum anti-seizure drug candidates with favorable pharmacokinetic parameters. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. VPAC receptors: structure, molecular pharmacology and interaction with accessory proteins.

    Science.gov (United States)

    Couvineau, Alain; Laburthe, Marc

    2012-05-01

    The vasoactive intestinal peptide (VIP) is a neuropeptide with wide distribution in both central and peripheral nervous systems, where it plays important regulatory role in many physiological processes. VIP displays a large biological functions including regulation of exocrine secretions, hormone release, fetal development, immune responses, etc. VIP appears to exert beneficial effect in neuro-degenerative and inflammatory diseases. The mechanism of action of VIP implicates two subtypes of receptors (VPAC1 and VPAC2), which are members of class B receptors belonging to the super-family of GPCR. This article reviews the current knowledge regarding the structure and molecular pharmacology of VPAC receptors. The structure-function relationship of VPAC1 receptor has been extensively studied, allowing to understand the molecular basis for receptor affinity, specificity, desensitization and coupling to adenylyl cyclase. Those studies have clearly demonstrated the crucial role of the N-terminal ectodomain (N-ted) of VPAC1 receptor in VIP recognition. By using different approaches including directed mutagenesis, photoaffinity labelling, NMR, molecular modelling and molecular dynamic simulation, it has been shown that the VIP molecule interacts with the N-ted of VPAC1 receptor, which is itself structured as a 'Sushi' domain. VPAC1 receptor also interacts with a few accessory proteins that play a role in cell signalling of receptors. Recent advances in the structural characterization of VPAC receptor and more generally of class B GPCRs will lead to the design of new molecules, which could have considerable interest for the treatment of inflammatory and neuro-degenerative diseases. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  16. Alternative Radioligands for Investigating the Molecular Pharmacology of Melatonin Receptors.

    Science.gov (United States)

    Legros, Céline; Brasseur, Chantal; Delagrange, Philippe; Ducrot, Pierre; Nosjean, Olivier; Boutin, Jean A

    2016-03-01

    Melatonin exerts a variety of physiologic activities that are mainly relayed through the melatonin receptors MT1 and MT2 Low expressions of these receptors in tissues have led to widespread experimental use of the agonist 2-[(125)I]-iodomelatonin as a substitute for melatonin. We describe three iodinated ligands: 2-(2-[(2-iodo-4,5-dimethoxyphenyl)methyl]-4,5-dimethoxy phenyl) (DIV880) and (2-iodo-N-2-[5-methoxy-2-(naphthalen-1-yl)-1H-pyrrolo[3,2-b]pyridine-3-yl])acetamide (S70254), which are specific ligands at MT2 receptors, and N-[2-(5-methoxy-1H-indol-3-yl)ethyl]iodoacetamide (SD6), an analog of 2-[(125)I]-iodomelatonin with slightly different characteristics. Here, we further characterized these new ligands with regards to their molecular pharmacology. We performed binding experiments, saturation assays, association/dissociation rate measurements, and autoradiography using sheep and rat tissues and recombinant cell lines. Our results showed that [(125)I]-S70254 is receptor, and can be used with both cells and tissue. This radioligand can be used in autoradiography. Similarly, DIV880, a partial agonist [43% of melatonin on guanosine 5'-3-O-(thio)triphosphate binding assay], selective for MT2, can be used as a tool to selectively describe the pharmacology of this receptor in tissue samples. The molecular pharmacology of both human melatonin receptors MT1 and MT2, using a series of 24 ligands at these receptors and the new radioligands, did not lead to noticeable variations in the profiles. For the first time, we described radiolabeled tools that are specific for one of the melatonin receptors (MT2). These tools are amenable to binding experiments and to autoradiography using sheep or rat tissues. These specific tools will permit better understanding of the role and implication in physiopathologic processes of the melatonin receptors. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  17. Low-molecular-weight heparins: pharmacologic profile and product differentiation.

    Science.gov (United States)

    Fareed, J; Jeske, W; Hoppensteadt, D; Clarizio, R; Walenga, J M

    1998-09-10

    The interchangeability of low-molecular-weight heparins (LMWHs) has been the subject of discussion since these products were first introduced for the prophylaxis of deep vein thrombosis. Experimental evidence now exists to show that LMWHs differ from each other in a number of characteristics. Products have been differentiated on the basis of molecular weight and biologic properties, but only limited information derived from the clinical setting is available. Potency has been described on the basis of anti-Factor Xa activity, but at equivalent anti-Xa activities, the anti-Factor IIa activity of different products shows marked variations. At the relatively small doses used for the management of postsurgical deep vein thrombosis, the effect of these interproduct differences may be relatively minor, but as LMWHs are developed for therapeutic use at much higher doses, such differences may become clinically important. Variations in safety and efficacy reported in clinical trials of LMWHs may reflect the known differences in their molecular composition and pharmacologic properties.

  18. Molecular Regulation of Histamine Synthesis

    Directory of Open Access Journals (Sweden)

    Hua Huang

    2018-06-01

    Full Text Available Histamine is a critical mediator of IgE/mast cell-mediated anaphylaxis, a neurotransmitter and a regulator of gastric acid secretion. Histamine is a monoamine synthesized from the amino acid histidine through a reaction catalyzed by the enzyme histidine decarboxylase (HDC, which removes carboxyl group from histidine. Despite the importance of histamine, transcriptional regulation of HDC gene expression in mammals is still poorly understood. In this review, we focus on discussing advances in the understanding of molecular regulation of mammalian histamine synthesis.

  19. Synthesis and pharmacology of 3-hydroxy-delta2-isoxazoline-cyclopentane analogues of glutamic acid

    DEFF Research Database (Denmark)

    Conti, P; De Amici, M; Bräuner-Osborne, Hans

    2002-01-01

    The synthesis and pharmacology of two potential glutamic acid receptor ligands are described. Preparation of the bicyclic 3-hydroxy-delta2-isoxazoline-cyclopentane derivatives (+/-)-7 and (+/-)-8 was accomplished via 1,3-dipolar cycloaddition of bromonitrile oxide to suitably protected 1-amino......-cyclopent-3-enecarboxylic acids. Their structure was established using a combination of 1H NMR spectroscopy and molecular mechanics calculations carried out on the intermediate cycloadducts (+/-)-11 and (+/-)-12. Amino acid derivatives (+/-)-7 and (+/-)-8 were assayed at ionotropic and metabotropic glutamic...... acid receptor subtypes and their activity compared with that of trans-ACPD and cis-ACPD. The results show that the replacement of the omega-carboxylic group of the model compounds with the 3-hydroxy-delta2-isoxazoline moiety abolishes or reduces drastically the activity at the metabotropic glutamate...

  20. Synthesis and preliminary pharmacological evaluation of asymmetric chloroquine analogues.

    Science.gov (United States)

    Witiak, D T; Grattan, D A; Heaslip, R J; Rahwan, R G

    1981-06-01

    Asymmetric chloroquine analogues (1-4) were prepared of known absolute configuration in order to assess stereochemical influences on selected biological activities. Since chloroquine has been shown to possess spasmolytic properties, analogues 1-4 were tested for similar pharmacological effects on smooth-muscle contraction. The (S)- and (R)-chlorochloroquine enantiomers (1 and 2, respectively) were more potent antispasmodics than the less lipophilic (S)- and (R)-hydroxychloroquines (3 and 4, respectively) when tested against KCl- or acetylcholine-induced contractions of the isolated mouse ileum. A membrane stabilizing mechanism of action for the chloroquine analogues is proposed since neither cellular toxicity nor calcium antagonism plays a role in the spasmolytic action of these compounds. Although compounds 1-4 also inhibited PGF2 alpha-induced contractions of the ileum, 1 was significantly more potent than 2; the latter in turn was equipotent to 3 and 4. It is tentatively proposed that 1 may possess stereoselective affinity for the PGF2 alpha receptor in the ileum. This observation may be further exploited to obtain more selective profiles of biological activity through molecular manipulation.

  1. Design, synthesis, pharmacological evaluation, QSAR analysis, molecular modeling and ADMET of novel donepezil-indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer's disease.

    Science.gov (United States)

    Bautista-Aguilera, Oscar M; Esteban, Gerard; Bolea, Irene; Nikolic, Katarina; Agbaba, Danica; Moraleda, Ignacio; Iriepa, Isabel; Samadi, Abdelouahid; Soriano, Elena; Unzeta, Mercedes; Marco-Contelles, José

    2014-03-21

    The design, synthesis, and pharmacological evaluation of donepezil-indolyl based amines 7-10, amides 12-16, and carboxylic acid derivatives 5 and 11, as multipotent ASS234 analogs, able to inhibit simultaneously cholinesterase (ChE) and monoamine oxidase (MAO) enzymes for the potential treatment of Alzheimer's disease (AD), is reported. Theoretical studies using 3D-Quantitative Structure-Activity Relationship (3D-QSAR) was used to define 3D-pharmacophores for inhibition of MAO A/B, AChE, and BuChE enzymes. We found that, in general, and for the same substituent, amines are more potent ChE inhibitors (see compounds 12, 13 versus 7 and 8) or equipotent (see compounds 14, 15 versus 9 and 10) than the corresponding amides, showing a clear EeAChE inhibition selectivity. For the MAO inhibition, amides were not active, and among the amines, compound 14 was totally MAO A selective, while amines 15 and 16 were quite MAO A selective. Carboxylic acid derivatives 5 and 11 showed a multipotent moderate selective profile as EeACE and MAO A inhibitors. Propargylamine 15 [N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)prop-2-yn-1-amine] resulted in the most potent hMAO A (IC50 = 5.5 ± 1.4 nM) and moderately potent hMAO B (IC50 = 150 ± 31 nM), EeAChE (IC50 = 190 ± 10 nM), and eqBuChE (IC50 = 830 ± 160 nM) inhibitor. However, the analogous N-allyl and the N-morpholine derivatives 16 and 14 deserve also attention as they show an attractive multipotent profile. To sum up, donepezil-indolyl hybrid 15 is a promising drug for further development for the potential prevention and treatment of AD. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  2. GABA uptake inhibitors. Design, molecular pharmacology and therapeutic aspects

    DEFF Research Database (Denmark)

    Krogsgaard-Larsen, P; Frølund, B; Frydenvang, Karla Andrea

    2000-01-01

    demonstrated that neuronal and glial GABA transport mechanisms have dissimilar substrate specificities. With GABA transport mechanisms as pharmacological targets, strategies for pharmacological interventions with the purpose of stimulating GABA neurotransmission seem to be (1) effective blockade of neuronal......, tiagabine (49) containing (R)-nipecotic acid (24) as the GABA transport carrier-recognizing structure element, is now marketed as an antiepileptic agent....

  3. Molecular pharmacology of promiscuous seven transmembrane receptors sensing organic nutrients.

    Science.gov (United States)

    Wellendorph, Petrine; Johansen, Lars Dan; Bräuner-Osborne, Hans

    2009-09-01

    A number of highly promiscuous seven transmembrane (7TM) receptors have been cloned and characterized within the last few years. It is noteworthy that many of these receptors are activated broadly by amino acids, proteolytic degradation products, carbohydrates, or free fatty acids and are expressed in taste tissue, the gastrointestinal tract, endocrine glands, adipose tissue, and/or kidney. These receptors thus hold the potential to act as sensors of food intake, regulating, for example, release of incretin hormones from the gut, insulin/glucagon from the pancreas, and leptin from adipose tissue. The promiscuous tendency in ligand recognition of these receptors is in contrast to the typical specific interaction with one physiological agonist seen for most receptors, which challenges the classic "lock-and-key" concept. We here review the molecular mechanisms of nutrient sensing of the calcium-sensing receptor, the G protein-coupled receptor family C, group 6, subtype A (GPRC6A), and the taste1 receptor T1R1/T1R3, which are sensing L-alpha-amino acids, the carbohydrate-sensing T1R2/T1R3 receptor, the proteolytic degradation product sensor GPR93 (also termed GPR92), and the free fatty acid (FFA) sensing receptors FFA1, FFA2, FFA3, GPR84, and GPR120. The involvement of the individual receptors in sensing of food intake has been validated to different degrees because of limited availability of specific pharmacological tools and/or receptor knockout mice. However, as a group, the receptors represent potential drug targets, to treat, for example, type II diabetes by mimicking food intake by potent agonists or positive allosteric modulators. The ligand-receptor interactions of the promiscuous receptors of organic nutrients thus remain an interesting subject of emerging functional importance.

  4. Stereodivergent synthesis with a programmable molecular machine

    Science.gov (United States)

    Kassem, Salma; Lee, Alan T. L.; Leigh, David A.; Marcos, Vanesa; Palmer, Leoni I.; Pisano, Simone

    2017-09-01

    It has been convincingly argued that molecular machines that manipulate individual atoms, or highly reactive clusters of atoms, with Ångström precision are unlikely to be realized. However, biological molecular machines routinely position rather less reactive substrates in order to direct chemical reaction sequences, from sequence-specific synthesis by the ribosome to polyketide synthases, where tethered molecules are passed from active site to active site in multi-enzyme complexes. Artificial molecular machines have been developed for tasks that include sequence-specific oligomer synthesis and the switching of product chirality, a photo-responsive host molecule has been described that is able to mechanically twist a bound molecular guest, and molecular fragments have been selectively transported in either direction between sites on a molecular platform through a ratchet mechanism. Here we detail an artificial molecular machine that moves a substrate between different activating sites to achieve different product outcomes from chemical synthesis. This molecular robot can be programmed to stereoselectively produce, in a sequential one-pot operation, an excess of any one of four possible diastereoisomers from the addition of a thiol and an alkene to an α,β-unsaturated aldehyde in a tandem reaction process. The stereodivergent synthesis includes diastereoisomers that cannot be selectively synthesized through conventional iminium-enamine organocatalysis. We anticipate that future generations of programmable molecular machines may have significant roles in chemical synthesis and molecular manufacturing.

  5. Solid-phase synthesis of complex and pharmacologically interesting heterocycles

    DEFF Research Database (Denmark)

    Nielsen, Thomas Eiland

    2009-01-01

    Efficient routes for the creation of heterocycles continue to be one of the primary goals for solid-phase synthesis. Recent advances in this field rely most notably on transition-metal-catalysis and N-acyliminium chemistry to mediate a range of cyclization processes for the generation of compounds...... with significant structural complexity and diversity. This review describes some of the most systematic solid-phase approaches that are potentially suited for pharmaceutical applications, that is, the methods described are useful for the synthesis of compound collections, and exhibit tunable stereochemistry...

  6. [From Purkinje's pharmacologic observations to molecular drug interactions].

    Science.gov (United States)

    Kvĕtina, J

    1998-11-01

    The 650th anniversary of the foundation of Charles University (7 April 1348) in Prague has initiated a number of historical surveys of the subjects which has been taught at the University for a longer period of time. The disciplines connected with pharmacotherapy were being developed in an empirical conception at the University from the second half of the 14th century but the beginnings of experimental drug research date as late as the mid-19th century. The present survey of the history of "the sciences of medicaments" therefore attempts to outline in short entries the developmental stages of pharmaceutical and pharmacological investigations in the territory of Bohemia and Moravia in about recent 150 years. The arrangement of data is chronological; in the part covering the second half of the 20th century the research of a predominantly exploratory character (universities and academic institutions and their representatives) and research aimed primarily to innovate medicaments (research institutions of pharmaceutical industry and clinical pharmacology and some of their representatives) are treated separately.

  7. Synthesis, characterization and pharmacological evaluation of amide prodrugs of Flurbiprofen

    International Nuclear Information System (INIS)

    Mishra, Ashutosh; Veerasamy, Ravichandran; Jain, Prateek Kumar; Dixit, Vinod Kumar; Agrawal, Ram Kishor

    2008-01-01

    Flurbiprofen (FB) suffers from the general side effects of NSAIDs, owing to presence of free carboxylic acid group. The study was aimed to retard the adverse effects of gastrointestinal origin. Ten prodrugs of FB were synthesized by amidation with ethyl esters of amino acids, namely, glycine, L-phenylalanine, L-tryptophan, L-valine, L-isoleucine, L-alanine, L-leucine, L-glutamic acid, L-aspartic acid and β alanine. Purified synthesized prodrugs were characterized by m.p., TLC, solubility, partition coefficients, elemental analyses, UV, FTIR, NMR and MS. Synthesized prodrugs were subjected for bioavailability studies, analgesic, anti-inflammatory activities and ulcerogenic index. Marked reduction of ulcerogenic index and comparable analgesic, antiinflammatory activities were obtained in all cases as compared to FB. Among synthesized prodrugs AR-9, AR-10 and AR-2 showing excellent pharmacological response and encouraging hydrolysis rate both in (Simulated Intestinal Fluid) SIF and in 80% human plasma. Prodrugs with increased aliphatic side chain length or introduction of aromatic substituent resulted in enhanced partition coefficient but diminished dissolution and hydrolysis rate. Such prodrugs can be considered for sustained release purpose. (author)

  8. Synthesis, characterization and pharmacological evaluation of amide prodrugs of Flurbiprofen

    Energy Technology Data Exchange (ETDEWEB)

    Mishra, Ashutosh; Veerasamy, Ravichandran; Jain, Prateek Kumar; Dixit, Vinod Kumar; Agrawal, Ram Kishor [Dr. H. S. Gour Vishwavidyalaya, Sagar (India). Dept. of Pharmaceutical Sciences. Pharmaceutical Chemistry Research Lab.]. E-mail: dragrawal2001@yahoo.co.in

    2008-07-01

    Flurbiprofen (FB) suffers from the general side effects of NSAIDs, owing to presence of free carboxylic acid group. The study was aimed to retard the adverse effects of gastrointestinal origin. Ten prodrugs of FB were synthesized by amidation with ethyl esters of amino acids, namely, glycine, L-phenylalanine, L-tryptophan, L-valine, L-isoleucine, L-alanine, L-leucine, L-glutamic acid, L-aspartic acid and {beta} alanine. Purified synthesized prodrugs were characterized by m.p., TLC, solubility, partition coefficients, elemental analyses, UV, FTIR, NMR and MS. Synthesized prodrugs were subjected for bioavailability studies, analgesic, anti-inflammatory activities and ulcerogenic index. Marked reduction of ulcerogenic index and comparable analgesic, antiinflammatory activities were obtained in all cases as compared to FB. Among synthesized prodrugs AR-9, AR-10 and AR-2 showing excellent pharmacological response and encouraging hydrolysis rate both in (Simulated Intestinal Fluid) SIF and in 80% human plasma. Prodrugs with increased aliphatic side chain length or introduction of aromatic substituent resulted in enhanced partition coefficient but diminished dissolution and hydrolysis rate. Such prodrugs can be considered for sustained release purpose. (author)

  9. Synthesis and pharmacological activity evaluation of arctigenin monoester derivatives.

    Science.gov (United States)

    Chen, Qiulian; Yang, Limin; Han, Mei; Cai, Enbo; Zhao, Yan

    2016-12-01

    Arctigenin (ARG), a nature medicine with many pharmacological activities, was poorly soluble in water and placed restriction on practical usage. Six novel arctigenin monoester derivatives were obtained from the reflux reaction with arctigenin, carboxylic acids (crotonic acid, furoic acid, 2-naphthalene acid and indol-3-acetic acid), EDCI and DMAP in dichloromethane at 60°C for 4-6h and their properties on nitrite scavenging assay were investigated in vitro. Based on the results, the one of the most effective derivatives, arctigenin β-indolylacetate (ARG6), was selected to study anti-tumor activity in vivo at doses of 20 and 40mg/kg. The results showed that comparison with ARG group, ARG6 exhibited more anti-tumor activity in H22 tumor-bearing mice. Furthermore, ARG6 exhibited less damage to the liver, kidney, spleen and thymus when compared with those in positive group. Biochemical parameters of ALT, AST, BUN and Cre showed ARG6 had little toxicity to mice as well. ARG6 significantly improved serum cytokine levels of IL-2, IL-6, IFN-γ and TNF-α, and decreased VEGF compared with ARG. Moreover, H & E staining, TUNEL assay and immunohistochemical of tumor issues also indicated that ARG6 exhibited anti-tumor activity in vivo. In brief, the present study provide a method to improve ARG anti-tumor activity and provide a reference for new anti-tumor agent. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  10. Synthesis of Neoclerodane Diterpenes and Their Pharmacological Effects

    Science.gov (United States)

    Lovell, Kimberly M.; Prevatt-Smith, Katherine M.; Lozama, Anthony; Prisinzano, Thomas E.

    Salvinorin A is a neoclerodane diterpene that has been shown to be an agonist at kappa opioid receptors. Its unique structure makes it an attractive target for synthetic organic chemists due to its seven chiral centers and diterpene scaffold. This molecule is also interesting to pharmacologists because it is a non-serotonergic hallucinogen, and the first opioid ligand discovered that lacks a basic nitrogen. There have been several total synthesis approaches to salvinorin A, and these will be detailed within this chapter. Additionally, research efforts have concentrated on structure modification of the salvinorin A scaffold through semi-synthetic methods. Most modifications have focused on the manipulation of the acetate at C-2 and the furan ring. However, chemistry has also been developed to generate analogs at the C-1 ketone, the C-4 methyl ester, and the C-17 lactone. The synthetic methodologies developed for the salvinorin A scaffold will be described, as well as specific analogs with interesting biological activities.

  11. Design, synthesis, and pharmacological characterization of polyamine toxin derivatives

    DEFF Research Database (Denmark)

    Jensen, Lars S; Bølcho, Ulrik; Egebjerg, Jan

    2006-01-01

    for memory formation and are involved in neurodegenerative diseases. Previous studies have demonstrated that modification of the polyamine moiety of philanthotoxins can lead to very potent and highly selective ligands for the AMPA receptor, as exemplified with philanthotoxin-56. Much less attention has been......Polyamine toxins, such as philanthotoxins, are low-molecular-weight compounds isolated from spiders and wasps, which modulate ligand-gated ion channels in the nervous system. Philanthotoxins bind to the pore-forming region of AMPA receptors, a subtype of glutamate receptors which are important...... paid to the importance of the aromatic head group of philanthotoxins, but herein we demonstrate that modification of this moiety leads to a significant improvement in potency relative to philanthotoxin-56 at cloned AMPA receptors. Interestingly, the incorporation of an adamantane moiety is particularly...

  12. Synthesis, characterization, antimicrobial activity and molecular ...

    African Journals Online (AJOL)

    Synthesis, characterization, antimicrobial activity and molecular docking studies of combined pyrazol-barbituric acid pharmacophores. Assem Barakat, Bandar M. Al-Qahtani, Abdullah M. Al-Majid, M. Ali Mohammed Rafi Shaik, Mohamed H.M. Al-Agamy, Abdul Wadood ...

  13. Molecular Mechanism for Various Pharmacological Activities of NSAIDS

    Directory of Open Access Journals (Sweden)

    Tohru Mizushima

    2010-05-01

    Full Text Available The anti-inflammatory action of non-steroidal anti-inflammatory drugs (NSAIDs is mediated through their inhibitory effects on cyclooxygenase (COX activity. On the other hand, NSAID use is often associated with gastrointestinal complications. The inhibition of COX by NSAIDs is not the sole explanation for the gastrointestinal side effects of NSAIDs. Furthermore, recent epidemiological studies have revealed that prolonged NSAID use reduces the risk of cancer and Alzheimer’s disease (AD and a COX-independent unknown mechanism is suggested to be involved in these activities of NSAIDs. In this article, I review our recent work on the COX-independent mechanism involved in NSAID-induced gastric lesions and anti-tumor and anti-AD activities of NSAIDs. Using DNA microarray analysis, we found that NSAIDs affect expression of various genes in a COX-independent manner. We found that membrane permeabilization activity of NSAIDs and resulting NSAID-induced apoptosis are involved in NSAID-induced gastric lesions. On the other hand, induction of expression of tight junction-related genes and endoplasmic reticulum chaperones were suggested to be involved in anti-tumor and anti-AD, respectively, activities of NSAIDs. These results suggest that NSAIDs affect expression of various genes in a COX-independent manner, which is involved in various pharmacological activities of NSAIDs.

  14. Rational design, synthesis, and pharmacological evaluation of 2-azanorbornane-3-exo,5-endo-dicarboxylic acid

    DEFF Research Database (Denmark)

    Bunch, Lennart; Liljefors, Tommy; Greenwood, Jeremy R

    2003-01-01

    conformationally restricted (S)-glutamic acid (Glu) analogue intended as a mimic of the folded Glu conformation. The synthesis of 1 was completed in its racemic form in eight steps from commercially available starting materials. As a key step, the first facially selective hydroboration of a 5-methylidene[2......The design and synthesis of conformationally restricted analogues of alpha-amino acids is an often used strategy in medicinal chemistry research. Here we present the rational design, synthesis, and pharmacological evaluation of 2-azanorbornane-3-exo,5-endo-dicarboxylic acid (1), a novel...... studies on native 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) (IC(50) > 300 microM, [(3)H]AMPA) or kainic acid (IC(50) > 160 microM, [(3)H]kainic acid) receptors nor in binding studies on the cloned iGluR5,6 subtypes (IC(50) > 300 microM, [(3)H]kainic acid)....

  15. Molecular pharmacology of promiscuous seven transmembrane receptors sensing organic nutrients

    DEFF Research Database (Denmark)

    Wellendorph, Petrine; Johansen, Lars Dan; Bräuner-Osborne, Hans

    2009-01-01

    drug targets, to treat, for example, type II diabetes by mimicking food intake by potent agonists or positive allosteric modulators. The ligand-receptor interactions of the promiscuous receptors of organic nutrients thus remain an interesting subject of emerging functional importance....... in taste tissue, the gastrointestinal tract, endocrine glands, adipose tissue, and/or kidney. These receptors thus hold the potential to act as sensors of food intake, regulating, for example, release of incretin hormones from the gut, insulin/glucagon from the pancreas, and leptin from adipose tissue....... The promiscuous tendency in ligand recognition of these receptors is in contrast to the typical specific interaction with one physiological agonist seen for most receptors, which challenges the classic "lock-and-key" concept. We here review the molecular mechanisms of nutrient sensing of the calcium...

  16. Clinical, molecular, and pharmacological aspects of FMR1 related disorders.

    Science.gov (United States)

    Pugin, A; Faundes, V; Santa María, L; Curotto, B; Aliaga, S; Salas, I; Soto, P; Bravo, P; Peña, M I; Alliende, M A

    2017-05-01

    Fragile X syndrome, the most common inherited cause of intellectual disability, is associated with a broad spectrum of disorders across different generations of a single family. This study reviews the clinical manifestations of fragile X-associated disorders as well as the spectrum of mutations of the fragile X mental retardation 1 gene (FMR1) and the neurobiology of the fragile X mental retardation protein (FMRP), and also provides an overview of the potential therapeutic targets and genetic counselling. This disorder is caused by expansion of the CGG repeat (>200 repeats) in the 5 prime untranslated region of FMR1, resulting in a deficit or absence of FMRP. FMRP is an RNA-binding protein that regulates the translation of several genes that are important in synaptic plasticity and dendritic maturation. It is believed that CGG repeat expansions in the premutation range (55 to 200 repeats) elicit an increase in mRNA levels of FMR1, which may cause neuronal toxicity. These changes manifest clinically as developmental problems such as autism and learning disabilities as well as neurodegenerative diseases including fragile X-associated tremor/ataxia syndrome (FXTAS). Advances in identifying the molecular basis of fragile X syndrome may help us understand the causes of neuropsychiatric disorders, and they will probably contribute to development of new and specific treatments. Copyright © 2014 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  17. Synthesis and Pharmacological Evaluation of Selective Histone Deacetylase 6 Inhibitors in Melanoma Models

    Czech Academy of Sciences Publication Activity Database

    Tavares, M. T.; Shen, S.; Knox, T.; Hadley, M.; Kutil, Zsofia; Bařinka, Cyril; Villagra, A.; Kozikowski, A. P.

    2017-01-01

    Roč. 8, č. 10 (2017), s. 1031-1036 ISSN 1948-5875 R&D Projects: GA ČR GA15-19640S; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:86652036 Keywords : HDAC6 inhibitors * nexturastat A * melanoma Subject RIV: FR - Pharmacology ; Medidal Chemistry OBOR OECD: Biochemistry and molecular biology Impact factor: 3.746, year: 2016

  18. Molecular catchers for pharmacologically active substances in wastewaters, a theoretical study

    International Nuclear Information System (INIS)

    Salazar Valencia, P J; Pérez Merchancano, S T; Bolívar Marinez, L E; Paredes, H

    2016-01-01

    A basic and pressing need in the treatment of residual waste waters for urban and rural centers is the removal of pharmacological active residues from them, these resides are originated in a wide array of domestic, agricultural and industrial sources and can't be removed in the residual waters treatment plants by conventional methods, the result is the incorporation of them into the ecosystem altering the physiology and behavior of living organisms. Among the most active pharmacological substances found in very high concentration in residual waters is paracetamol, an analgesic of very wide excessive use due to its ease of access and low cost [1]. No pharmacological substance is entirely absorbed by the human organism and therefore a wide family of molecular residues is excreted by the urinary tract. In this work we have used the AM1 (Austin Model 1), PM3 (Parametric Method 3) and ZINDO/CI semiempirical methods, from the NDO (Neglect Differential Overlap) family [2] to study and observe the structural, electronic and optical characteristics of paracetamol while immersed in different basic and acidic aqueous environments, either alone or interacting with lignosulphonates. We have previously found that lignosulphonates, a lignin derivatives of wide industrial applications, can be engineered as a binding and flocculant agent and acts as molecular catchers therefore showing the potential to be used as a mean to filter and eliminate molecular residues from the residual waters [3]. (paper)

  19. Molecularly Imprinted Polymer Synthesis Using RAFT Polymerisation

    International Nuclear Information System (INIS)

    Cormack, P.A.G.; Faizatul Shimal Mehamod; Faizatul Shimal Mehamod

    2013-01-01

    In this paper, the synthesis and characterisation of caffeine-imprinted polymers are described. The polymers were prepared in monolithic form via both reversible addition-fragmentation chain-transfer (RAFT) polymerisation and conventional free radical polymerisation, using methacrylic acid and ethylene glycol dimethacrylate as the functional monomer and crosslinking agent, respectively. The potential benefits in applying RAFT polymerisation techniques towards the synthesis of molecularly imprinted polymers (MIPs) are explored and elucidated. The pore structures of the polymers produced were characterised by nitrogen sorption porosimetry and the molecular recognition properties of representative products were evaluated in high-performance liquid chromatography (HPLC) mode. Molecular imprinting effects were confirmed by analysing the relative retentions of analytes on imprinted and non-imprinted HPLC stationary phases. It was found that a caffeine-imprinted polymer synthesised by RAFT polymerisation was superior to a polymer prepared using a conventional synthetic approach; the imprinting factor and column efficiency were found to be higher for the former material. (author)

  20. Pharmacological inhibition of eicosanoid synthesis and hyperalgesia in yeast-injected rat paws

    International Nuclear Information System (INIS)

    Opas, E.E.; Dallob, A.; Herold, E.; Luell, S.; Humes, J.L.

    1986-01-01

    Brewer's yeast caused an inflammation characterized by edema and hyperalgesia when injected into the hindpaw of a rat. These events were temporally distinct and each was associated with increases of specific arachidonic and oxygenation products. As determined by radioimmunoassay (RIA) on whole paw lipid extracts, the 5-lipoxygenase (5-LO) products, leukotrienes C 4 and D 4 and 5-hydroxyeicosatetraendic acid (5-HETE) were synthesized concurrently with the onset of edema (maximal at 15 minutes after yeast injection). The hyperalgesic phase of the inflammation (3-4 hr after yeast injection) was associated with increased tissue levels of the cyclooxygenase (CO) products, prostaglandin E 2 and thromboxane B 2 (TXB 2 ) as well as increases in levels of the 5-LO products, leukotriene B 4 (LTB 4 ) and 5-HETE. Pharmacological agents modulated the synthesis of eicosanoids and suppressed the hyperalgesic response

  1. Molecular Pharmacology of VEGF-A Isoforms: Binding and Signalling at VEGFR2.

    Science.gov (United States)

    Peach, Chloe J; Mignone, Viviane W; Arruda, Maria Augusta; Alcobia, Diana C; Hill, Stephen J; Kilpatrick, Laura E; Woolard, Jeanette

    2018-04-23

    Vascular endothelial growth factor-A (VEGF-A) is a key mediator of angiogenesis, signalling via the class IV tyrosine kinase receptor family of VEGF Receptors (VEGFRs). Although VEGF-A ligands bind to both VEGFR1 and VEGFR2, they primarily signal via VEGFR2 leading to endothelial cell proliferation, survival, migration and vascular permeability. Distinct VEGF-A isoforms result from alternative splicing of the Vegfa gene at exon 8, resulting in VEGF xxx a or VEGF xxx b isoforms. Alternative splicing events at exons 5⁻7, in addition to recently identified posttranslational read-through events, produce VEGF-A isoforms that differ in their bioavailability and interaction with the co-receptor Neuropilin-1. This review explores the molecular pharmacology of VEGF-A isoforms at VEGFR2 in respect to ligand binding and downstream signalling. To understand how VEGF-A isoforms have distinct signalling despite similar affinities for VEGFR2, this review re-evaluates the typical classification of these isoforms relative to the prototypical, “pro-angiogenic” VEGF 165 a. We also examine the molecular mechanisms underpinning the regulation of VEGF-A isoform signalling and the importance of interactions with other membrane and extracellular matrix proteins. As approved therapeutics targeting the VEGF-A/VEGFR signalling axis largely lack long-term efficacy, understanding these isoform-specific mechanisms could aid future drug discovery efforts targeting VEGF receptor pharmacology.

  2. Integration of pharmacology, molecular pathology, and population data science to support precision gastrointestinal oncology.

    Science.gov (United States)

    Ogino, Shuji; Jhun, Iny; Mata, Douglas A; Soong, Thing Rinda; Hamada, Tsuyoshi; Liu, Li; Nishihara, Reiko; Giannakis, Marios; Cao, Yin; Manson, JoAnn E; Nowak, Jonathan A; Chan, Andrew T

    2017-01-01

    Precision medicine has a goal of customizing disease prevention and treatment strategies. Under the precision medicine paradigm, each patient has unique pathologic processes resulting from cellular genomic, epigenomic, proteomic, and metabolomic alterations, which are influenced by pharmacological, environmental, microbial, dietary, and lifestyle factors. Hence, to realize the promise of precision medicine, multi-level research methods that can comprehensively analyze many of these variables are needed. In order to address this gap, the integrative field of molecular pathology and population data science (i.e., molecular pathological epidemiology) has been developed to enable such multi-level analyses, especially in gastrointestinal cancer research. Further integration of pharmacology can improve our understanding of drug effects, and inform decision-making of drug use at both the individual and population levels. Such integrative research demonstrated potential benefits of aspirin in colorectal carcinoma with PIK3CA mutations, providing the basis for new clinical trials. Evidence also suggests that HPGD (15-PDGH) expression levels in normal colon and the germline rs6983267 polymorphism that relates to tumor CTNNB1 (β-catenin)/ WNT signaling status may predict the efficacy of aspirin for cancer chemoprevention. As immune checkpoint blockade targeting the CD274 (PD-L1)/ PDCD1 (PD-1) pathway for microsatellite instability-high (or mismatch repair-deficient) metastatic gastrointestinal or other tumors has become standard of care, potential modifying effects of dietary, lifestyle, microbial, and environmental factors on immunotherapy need to be studied to further optimize treatment strategies. With its broad applicability, our integrative approach can provide insights into the interactive role of medications, exposures, and molecular pathology, and guide the development of precision medicine.

  3. Molecular, pharmacological, and signaling properties of octopamine receptors from honeybee (Apis mellifera) brain.

    Science.gov (United States)

    Balfanz, Sabine; Jordan, Nadine; Langenstück, Teresa; Breuer, Johanna; Bergmeier, Vera; Baumann, Arnd

    2014-04-01

    G protein-coupled receptors are important regulators of cellular signaling processes. Within the large family of rhodopsin-like receptors, those binding to biogenic amines form a discrete subgroup. Activation of biogenic amine receptors leads to transient changes of intracellular Ca²⁺-([Ca²⁺](i)) or 3',5'-cyclic adenosine monophosphate ([cAMP](i)) concentrations. Both second messengers modulate cellular signaling processes and thereby contribute to long-lasting behavioral effects in an organism. In vivo pharmacology has helped to reveal the functional effects of different biogenic amines in honeybees. The phenolamine octopamine is an important modulator of behavior. Binding of octopamine to its receptors causes elevation of [Ca²⁺](i) or [cAMP](i). To date, only one honeybee octopamine receptor that induces Ca²⁺ signals has been molecularly and pharmacologically characterized. Here, we examined the pharmacological properties of four additional honeybee octopamine receptors. When heterologously expressed, all receptors induced cAMP production after binding to octopamine with EC₅₀(s) in the nanomolar range. Receptor activity was most efficiently blocked by mianserin, a substance with antidepressant activity in vertebrates. The rank order of inhibitory potency for potential receptor antagonists was very similar on all four honeybee receptors with mianserin > cyproheptadine > metoclopramide > chlorpromazine > phentolamine. The subroot of octopamine receptors activating adenylyl cyclases is the largest that has so far been characterized in arthropods, and it should now be possible to unravel the contribution of individual receptors to the physiology and behavior of honeybees. © 2013 International Society for Neurochemistry.

  4. Molecular mechanisms of resistance to Rituximab and pharmacologic strategies for its circumvention.

    Science.gov (United States)

    Stolz, Claudia; Schuler, Martin

    2009-06-01

    The introduction of Rituximab has greatly improved therapeutic options for patients with B-cell non-Hodgkin lymphoma (B-NHL). However, a substantial fraction of patients with aggressive B-NHL fails first-line therapy, and most patients with relapsing indolent B-NHL eventually acquire Rituximab resistance. Molecular understanding of the underlying mechanisms facilitates the development of pharmacologic strategies to overcome resistance. Rituximab exerts its activity on CD20-expressing B-cells by indirect and direct effector mechanisms. Indirect mechanisms are complement-dependent cytotoxicity (CDC), and antibody-dependent cell-mediated cytotoxicity (ADCC). Direct activities, such as growth inhibition, induction of apoptosis and chemosensitisation, have been reported, but are less defined. Moreover, the relative contribution of CDC, ADCC and direct mechanisms to the activity of Rituximab in vivo is unclear. Down-regulation of CD20 and expression of complement inhibitors have been described as escape mechanisms in B-NHL. Recent reports suggest that deregulated phosphoinositide-3-kinase (PI3K)/Akt, mitogen-activated kinases (MAPK) and nuclear-factor kappaB (NF-kappaB), as well as up-regulation of anti-apoptotic proteins may determine the efficacy of Rituximab to kill B-NHL cells in vitro and in vivo. The latter signalling pathways are attractive targets for pharmacologic modulation of resistance to Rituximab. With the advent of new inhibitors and antibodies, rationally designed clinical trials addressing Rituximab resistance are feasible.

  5. Molecular Cloning and Pharmacological Properties of an Acidic PLA2 from Bothrops pauloensis Snake Venom

    Directory of Open Access Journals (Sweden)

    Francis Barbosa Ferreira

    2013-12-01

    Full Text Available In this work, we describe the molecular cloning and pharmacological properties of an acidic phospholipase A2 (PLA2 isolated from Bothrops pauloensis snake venom. This enzyme, denominated BpPLA2-TXI, was purified by four chromatographic steps and represents 2.4% of the total snake venom protein content. BpPLA2-TXI is a monomeric protein with a molecular mass of 13.6 kDa, as demonstrated by Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF analysis and its theoretical isoelectric point was 4.98. BpPLA2-TXI was catalytically active and showed some pharmacological effects such as inhibition of platelet aggregation induced by collagen or ADP and also induced edema and myotoxicity. BpPLA2-TXI displayed low cytotoxicity on TG-180 (CCRF S 180 II and Ovarian Carcinoma (OVCAR-3, whereas no cytotoxicity was found in regard to MEF (Mouse Embryonic Fibroblast and Sarcoma 180 (TIB-66. The N-terminal sequence of forty-eight amino acid residues was determined by Edman degradation. In addition, the complete primary structure of 122 amino acids was deduced by cDNA from the total RNA of the venom gland using specific primers, and it was significantly similar to other acidic D49 PLA2s. The phylogenetic analyses showed that BpPLA2-TXI forms a group with other acidic D49 PLA2s from the gender Bothrops, which are characterized by a catalytic activity associated with anti-platelet effects.

  6. Molecular Cloning and Pharmacological Properties of an Acidic PLA2 from Bothrops pauloensis Snake Venom

    Science.gov (United States)

    Ferreira, Francis Barbosa; Gomes, Mário Sérgio Rocha; Naves de Souza, Dayane Lorena; Gimenes, Sarah Natalie Cirilo; Castanheira, Letícia Eulalio; Borges, Márcia Helena; Rodrigues, Renata Santos; Yoneyama, Kelly Aparecida Geraldo; Homsi Brandeburgo, Maria Inês; Rodrigues, Veridiana M.

    2013-01-01

    In this work, we describe the molecular cloning and pharmacological properties of an acidic phospholipase A2 (PLA2) isolated from Bothrops pauloensis snake venom. This enzyme, denominated BpPLA2-TXI, was purified by four chromatographic steps and represents 2.4% of the total snake venom protein content. BpPLA2-TXI is a monomeric protein with a molecular mass of 13.6 kDa, as demonstrated by Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) analysis and its theoretical isoelectric point was 4.98. BpPLA2-TXI was catalytically active and showed some pharmacological effects such as inhibition of platelet aggregation induced by collagen or ADP and also induced edema and myotoxicity. BpPLA2-TXI displayed low cytotoxicity on TG-180 (CCRF S 180 II) and Ovarian Carcinoma (OVCAR-3), whereas no cytotoxicity was found in regard to MEF (Mouse Embryonic Fibroblast) and Sarcoma 180 (TIB-66). The N-terminal sequence of forty-eight amino acid residues was determined by Edman degradation. In addition, the complete primary structure of 122 amino acids was deduced by cDNA from the total RNA of the venom gland using specific primers, and it was significantly similar to other acidic D49 PLA2s. The phylogenetic analyses showed that BpPLA2-TXI forms a group with other acidic D49 PLA2s from the gender Bothrops, which are characterized by a catalytic activity associated with anti-platelet effects. PMID:24304676

  7. Anesthetic pharmacology

    National Research Council Canada - National Science Library

    Evers, Alex S; Maze, M; Kharasch, Evan D

    2011-01-01

    ...: Section 1 introduces the principles of drug action, Section 2 presents the molecular, cellular and integrated physiology of the target organ/functional system and Section 3 reviews the pharmacology...

  8. Molecular clips based on propanediurea : synthesis and physical properties

    NARCIS (Netherlands)

    Jansen, Robertus Johannes

    2002-01-01

    This thesis describes the synthesis and physical properties of a series of molecular clips derived from the concave molecule propanediurea. These molecular clips are cavity-containing receptors that can bind a variety of aromatic guests. This binding is a result of hydrogen bonding and pi-pi

  9. The synthesis and pharmacological evaluation of (±-2,3-seco-fentanyl analogues

    Directory of Open Access Journals (Sweden)

    LJ. DOSEN-MICOVIC

    2004-11-01

    Full Text Available An efficient, five-step synthetic approach to various acyclic 1,3-diamines has been developed and applied to the preparation of a novel class of open-chained fentanyl analogues. The acyclic derivatives 5.1–5.5 (all new compounds were synthesized with the aim of estimating the significance of the piperidine ring for the opioid analgesic activity of anilido-piperidines. The starting b-keto-amide 1.1, prepared by the aminolysis of methyl acetoacetate with methylphenethylamine, (93 % yield, was successively reacted with NaH and BuLi, to form the highly reactive a,g-dienolate anion 1.1a. Regio and chemoselective g-alkylation of the dienolate with various primary and secondary alkyl halides furnished the b-keto-amides 1.2–1.5 (76–91 %. Reductive amination of the keto-amides 1.1–1.5 with aniline and Zn powder in acetic acid, via the enamine intermediates 2.1–2.5, afforded the b-anilino amides 3.1–3.5 (74–85 %. After reductive deoxygenation of the tertiary amide group, using in situ generated diborane, the corresponding 1,3-diamines 4.1–4.5 were obtained (87–97 %. The synthesis of (±-2,3-seco-fentanyls 5.1–5.5 was completed by N-acylation of the diamines 4.1–4.5 with propionyl chloride, followed by precipitation of the monooxalate salts (86–95 %. The parent compound, 2,3-seco-fentanyl 5.1, was found to be a 40 times less potent narcotic analgesic than fentanyl but still 5–6 times more active than morphine in rats, while i-Pr derivative 5.3 was inactive. Apart from the pharmacological significance, the general procedure described herein may afford various functionalized, 1,3-diamines as potential complexing agents and building blocks for the synthesis of aza-crown ethers.

  10. Anti-inflammatory agents of the carbamoylmethyl ester class: synthesis, characterization, and pharmacological evaluation

    Directory of Open Access Journals (Sweden)

    Sadek B

    2013-03-01

    Full Text Available Bassem Sadek,1 Amar Mansuor Hamruoni,2 Abdu Adem1 1Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, 2Department of Pharmaceutical Sciences, College of Pharmacy, Al Ain University of Science and Technology, Al-Ain, United Arab Emirates Abstract: In this study, target compounds 5–12 were synthesized via acid amine coupling of ibuprofen and naproxen with methyl ester derivatives of amino acids, namely, l-proline, sarcosine, l-tyrosine, and l-glutamic acid. When tested for anti-inflammatory activity using the acute carrageenan-induced hind paw method in rats, compounds 5–12 showed significantly greater anti-inflammatory activity, in the range of 40.64%–87.82%, compared with a placebo control group (P < 0.001. Among the newly synthesized compounds 5–12, naproxen derivatives 9–12 with anti-inflammatory activity ranging between 66.99% and 87.82% showed significantly higher (P < 0.05 potency than ibuprofen derivatives 5–8 with inhibition in the range of 22.03%–52.91% and control groups of ibuprofen (76.34% or naproxen (75.59%, P < 0.05. Moreover, derivatives 9–12 derived from naproxen, in particular compounds 9 and 10 which achieved 83.91% and 87.82% inhibition of inflammation, respectively, showed significantly (P < 0.05 higher potency than naproxen derivatives 11 and 12. Notably, among naproxen derivatives 9–12, the gastric ulcerogenicity for 9 (ulcer index 11.73 and 10 (ulcer index 12.30 was found to be significantly lower (P < 0.05 than that of the active ibuprofen and naproxen control groups with ulcer indices of 22.87 and 24.13, respectively. On the other hand, naproxen derivatives 9–11 showed significant inhibition (P < 0.05 of prostaglandin E2 synthesis when compared with the active control group receiving indomethacin, suggesting a correlation between the observed low ulcerogenicity and effect on prostaglandin E2 synthesis for compounds 9 and 10. However

  11. Impure but not inactive: Behavioral pharmacology of dibenzylpiperazine, a common by-product of benzylpiperazine synthesis.

    Science.gov (United States)

    Dolan, Sean B; Shetty, Ritu A; Forster, Michael J; Gatch, Michael B

    2018-06-01

    Substituted piperazines comprise a substantial proportion of the novel psychoactive substance market. Among the most widely abused piperazine compounds are meta-chlorophenylpiperazine (mCPP), tri-fluoromethylphenylpiperazine (TFMPP), and, especially, benzylpiperazine (BZP), which are commonly incorporated, either alone or in combination, in illicit "party pills" or "ecstasy" formulations. Illicit synthesis of BZP often results in production of an impure by-product dibenzylpiperazine (DBZP), which frequently appears alongside BZP in these formulations; however, despite its ubiquity, little information exists regarding the abuse liability of DBZP. The current study aimed to evaluate the abuse-related behavioral pharmacology of DBZP. DBZP, mCPP, and TFMPP were tested in parallel in mice in locomotor activity and conditioned place preference assays, and in a drug discrimination assay with rats trained to discriminate either methamphetamine, cocaine, (±)-3,4-methylenedioxymethamphetamine (MDMA), or -2,5-dimethoxy-4-methylamphetamine(DOM). Each of the compounds tested produced dose-dependent decreases in locomotor activity. DBZP substituted fully for methamphetamine, produced subthreshold drug-appropriate responding for cocaine and MDMA, and failed to substitute for DOM. Conversely, TFMPP and mCPP only produced subthreshold drug-appropriate responding for methamphetamine and MDMA, respectively, and both compounds failed to substitute for cocaine or DOM. None of the compounds tested produced a place preference. DBZP produced convulsions in rats at the highest dose tested. These data indicate that DBZP is more similar to BZP, albeit with lower potency and efficacy, than its serotonergic piperazine counterparts, and is a behaviorally-active compound with some abuse liability and potential for adverse health effects.

  12. Synthesis, Pharmacological Profile and Docking Studies of New Sulfonamides Designed as Phosphodiesterase-4 Inhibitors.

    Directory of Open Access Journals (Sweden)

    Isabelle Karine da Costa Nunes

    Full Text Available Prior investigations showed that increased levels of cyclic AMP down-regulate lung inflammatory changes, stimulating the interest in phosphodiesterase (PDE4 as therapeutic target. Here, we described the synthesis, pharmacological profile and docking properties of a novel sulfonamide series (5 and 6a-k designed as PDE4 inhibitors. Compounds were screened for their selectivity against the four isoforms of human PDE4 using an IMAP fluorescence polarized protocol. The effect on allergen- or LPS-induced lung inflammation and airway hyper-reactivity (AHR was studied in A/J mice, while the xylazine/ketamine-induced anesthesia test was employed as a behavioral correlate of emesis in rodents. As compared to rolipram, the most promising screened compound, 6a (LASSBio-448 presented a better inhibitory index concerning PDE4D/PDE4A or PDE4D/PDE4B. Accordingly, docking analyses of the putative interactions of LASSBio-448 revealed similar poses in the active site of PDE4A and PDE4C, but slight unlike orientations in PDE4B and PDE4D. LASSBio-448 (100 mg/kg, oral, 1 h before provocation, inhibited allergen-induced eosinophil accumulation in BAL fluid and lung tissue samples. Under an interventional approach, LASSBio-448 reversed ongoing lung eosinophilic infiltration, mucus exacerbation, peribronchiolar fibrosis and AHR by allergen provocation, in a mechanism clearly associated with blockade of pro-inflammatory mediators such as IL-4, IL-5, IL-13 and eotaxin-2. LASSBio-448 (2.5 and 10 mg/kg also prevented inflammation and AHR induced by LPS. Finally, the sulfonamide derivative was shown to be less pro-emetic than rolipram and cilomilast in the assay employed. These findings suggest that LASSBio-448 is a new PDE4 inhibitor with marked potential to prevent and reverse pivotal pathological features of diseases characterized by lung inflammation, such as asthma.

  13. Molecular, biophysical, and pharmacological properties of calcium-activated chloride channels.

    Science.gov (United States)

    Kamaleddin, Mohammad Amin

    2018-02-01

    Calcium-activated chloride channels (CaCCs) are a family of anionic transmembrane ion channels. They are mainly responsible for the movement of Cl - and other anions across the biological membranes, and they are widely expressed in different tissues. Since the Cl - flow into or out of the cell plays a crucial role in hyperpolarizing or depolarizing the cells, respectively, the impact of intracellular Ca 2+ concentration on these channels is attracting a lot of attentions. After summarizing the molecular, biophysical, and pharmacological properties of CaCCs, the role of CaCCs in normal cellular functions will be discussed, and I will emphasize how dysregulation of CaCCs in pathological conditions can account for different diseases. A better understanding of CaCCs and a pivotal regulatory role of Ca 2+ can shed more light on the therapeutic strategies for different neurological disorders that arise from chloride dysregulation, such as asthma, cystic fibrosis, and neuropathic pain. © 2017 Wiley Periodicals, Inc.

  14. Synthesis and Characterisation of Aluminophosphate Molecular Sieves

    Energy Technology Data Exchange (ETDEWEB)

    Halvorsen, E.N.

    1996-02-01

    Catalysts are very important in petrochemical processes. One of the properties that make crystalline, microporous materials attractive for catalytic purposes is their well-defined structure and ability to act as shape selective catalysts. This doctoral thesis presents the synthesis and characterization of a number of crystalline, microporous aluminophosphates and silicoaluminophosphates. 99 refs., 50 figs., 12 tabs.

  15. Synthesis, structure-activity relationship, and pharmacological profile of analogs of the ASIC-3 inhibitor A-317567.

    Science.gov (United States)

    Kuduk, Scott D; Di Marco, Christina N; Bodmer-Narkevitch, Vera; Cook, Sean P; Cato, Matthew J; Jovanovska, Aneta; Urban, Mark O; Leitl, Michael; Sain, Nova; Liang, Annie; Spencer, Robert H; Kane, Stefanie A; Hartman, George D; Bilodeau, Mark T

    2010-01-20

    The synthesis, structure-activity relationship (SAR), and pharmacological evaluation of analogs of the acid-sensing ion channel (ASIC) inhibitor A-317567 are reported. It was found that the compound with an acetylenic linkage was the most potent ASIC-3 channel blocker. This compound reversed mechanical hypersensitivity in the rat iodoacetate model of osteoarthritis pain, although sedation was noted. Sedation was also observed in ASIC-3 knockout mice, questioning whether sedation and antinociception are mediated via a non-ASIC-3 specific mechanism.

  16. Synthesis of Novel Hydrocarbon Soluble Multifunctional Anionic Initiators: Tools for Synthesis of Novel Dendrimer and Molecular Brush Polymer Architectures

    Science.gov (United States)

    2015-02-09

    Synthesis of Novel Dendrimer and Molecular Brush Polymer Architectures. Research Area:7.4 The views, opinions and/or findings contained in this report...journals: Final Report: Synthesis of Novel Hydrocarbon Soluble Multifunctional Anionic Initiators: Tools for Synthesis of Novel Dendrimer and Molecular

  17. Synthesis, biological evaluation and molecular docking studies of ...

    African Journals Online (AJOL)

    Synthesis, biological evaluation and molecular docking studies of Mannich bases derived from 1, 3, 4-oxadiazole- 2-thiones as potential urease inhibitors. ... Mannich bases (5-17) were subjected to in silico screening as urease inhibitors, using crystal structure of urease (Protein Data Bank ID: 5FSE) as a model enzyme.

  18. Synthesis and molecular docking of new hydrazones derived from ...

    African Journals Online (AJOL)

    Synthesis and molecular docking of new hydrazones derived from ethyl isonipecotate and their biological activities. A Munir, Aziz-ur Rehman, M.A. Abbasi, S.Z. Siddiqui, A Nasir, S.G. Khan, S Rasool, S.A.A. Shah ...

  19. Novel 1-hydroxyazole bioisosteres of glutamic acid. Synthesis, protolytic properties, and pharmacology

    DEFF Research Database (Denmark)

    Stensbøl, Tine B; Uhlmann, Peter; Morel, Sandrine

    2002-01-01

    A number of 1-hydroxyazole derivatives were synthesized as bioisosteres of (S)-glutamic acid (Glu) and as analogues of the AMPA receptor agonist (R,S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA, 3b). All compounds were subjected to in vitro pharmacological studies, including ...

  20. Solid-supported synthesis: From pharmacologically relevant heterocycles to biologically active surfaces

    DEFF Research Database (Denmark)

    Komnatnyy, Vitaly V.

    for solid-phase synthesis, methods for on - and off-bead screening of combinatorial libraries and their applic ation to various biological targets. The first part of the thesis is dedicated to the development of methodology for the synthesis of structurally diverse heterocyclic scaffolds via N...... methods for the controlled organo-functionalization of titanium, one of the most prominent materials in medicinal device industry, have been suggested . Initial acidic and oxidative treatment s of the metal surface genera te reactive hydroxyl moieties , which are subsequently modified with synthetically...... versatile amine -containing reagents. Subsequent applications in antimicrobial peptide synthesis, metal -catalysis, release from the surface, and polymer grafti ng, are also presented....

  1. [Ginseng prescription rules and molecular mechanism in treating coronary heart disease based on data mining and integrative pharmacology].

    Science.gov (United States)

    Li, Sen; Tang, Shi-Huan; Liu, Jin-Ling; Su, Jin; He, Fu-Yuan

    2018-04-01

    The ancient dragon Materia Medica, Compendium of Materia Medica and other works recorded that the main effect of ginseng is tonifying qi. It is reported that the main active ingredient of ginseng is ginsenoside. Modern studies have found that ginseng mono saponins are effective for cardiovascular related diseases. This paper preliminary clarified the efficacy of traditional ginseng-nourishing qi and cardiovascular disease through the traditional Chinese medicine (TCM) inheritance auxiliary platform and integration platform of association of pharmacology. With the help of TCM inheritance auxiliary platform-analysis of "Chinese medicine database", Chinese medicine treatment of modern diseases that ginseng rules, so the traditional effect associated with modern medicine and pharmacology; application integration platform enrichment analysis on the target of drug and gene function, metabolic pathway, to further explore the molecular mechanism of ginseng in the treatment of coronary heart disease, aimed at mining the molecular mechanism of ginseng in the treatment of coronary heart disease. Chinese medicine containing ginseng 307 prescriptions, 87 kinds of disease indications, western medicine disease Chinese medicine therapy for ginseng main coronary heart disease; analysis of molecular mechanism of ginseng pharmacology integration platform for the treatment of coronary heart disease. Ginsenosides(Ra₁, Ra₂, Rb₁, Rb₂, Rg₁, Ro) bind these targets, PRKAA1, PRKAA2, NDUFA4, COX5B, UQCRC1, affect chemokines, non-alcoholic fatty liver, gonadotropin, carbon metabolism, glucose metabolism and other pathways to treat coronary heart disease indirectly. The molecular mechanism of Panax ginseng's multi-component, multi-target and synergistic action is preliminarily elucidated in this paper. Copyright© by the Chinese Pharmaceutical Association.

  2. Molecular cloning and pharmacology of functionally distinct isoforms of the human histamine H(3) receptor

    DEFF Research Database (Denmark)

    Wellendorph, Petrine; Goodman, M W; Burstein, E S

    2002-01-01

    The pharmacology of histamine H(3) receptors suggests the presence of distinct receptor isoforms or subtypes. We herein describe multiple, functionally distinct, alternatively spliced isoforms of the human H(3) receptor. Combinatorial splicing at three different sites creates at least six distinct...... receptor isoforms, of which isoforms 1, 2, and 4, encode functional proteins. Detailed pharmacology on isoforms 1 (unspliced receptor), and 2 (which has an 80 amino acid deletion within the third intracellular loop of the protein) revealed that both isoforms displayed robust responses to a series of known...... revealed a rank order of potency at both isoforms of clobenpropit>iodophenpropit>thioperamide, and these drugs are fivefold less potent at isoform 2 than isoform 1. To further explore the pharmacology of H(3) receptor function, we screened 150 clinically relevant neuropsychiatric drugs for H(3) receptor...

  3. Synthesis and pharmacology of N-alkylated derivatives of the excitotoxin ibotenic acid

    DEFF Research Database (Denmark)

    Madsen, U; Dumpis, M A; Bräuner-Osborne, Hans

    1998-01-01

    Three amino-alkylated derivatives of the naturally occurring excitatory amino acid (EAA) receptor agonist ibotenic acid (Ibo) have been synthesized and tested pharmacologically. N-Methyl-Ibo (1a) and N-ethyl-Ibo (1b) were shown to be agonists at NMDA receptors (EC50 = 140 and 320 micro......-c and the potent NMDA agonist 2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid (AMAA) in order to elucidate the observed structure-activity data....

  4. On the Molecular Pharmacology of Resveratrol on Oxidative Burst Inhibition in Professional Phagocytes

    Czech Academy of Sciences Publication Activity Database

    Nosáľ, R.; Drábiková, K.; Jančinová, V.; Perečko, T.; Ambrožová, Gabriela; Číž, Milan; Lojek, Antonín; Pekarová, Michaela; Šmidrkal, J.; Harmatha, Juraj

    2014-01-01

    Roč. 2014, Jan 28 (2014), 706269/1-706269/9 ISSN 1942-0900 Institutional support: RVO:61388963 ; RVO:68081707 Keywords : resveratrol * oxidative burst * human neutrophils Subject RIV: FR - Pharmacology ; Medidal Chemistry Impact factor: 3.516, year: 2014 http://www.hindawi.com/journals/omcl/2014/706269/

  5. Synthesis and pharmacological characterization of novel inverse agonists acting on the viral-encoded chemokine receptor US28.

    Science.gov (United States)

    Hulshof, Janneke W; Vischer, Henry F; Verheij, Mark H P; Fratantoni, Silvina A; Smit, Martine J; de Esch, Iwan J P; Leurs, Rob

    2006-11-01

    G-protein coupled receptors encoded by viruses represent an unexplored class of potential drug targets. In this study, we describe the synthesis and pharmacological characterization of the first class of inverse agonists acting on the HCMV-encoded receptor US28. It is shown that replacement of the 4-hydroxy group of lead compound 1 with a methylamine group results in a significant 6-fold increase in affinity. Interestingly, increasing the rigidity of the spacer by the introduction of a double bond also leads to a significant increase in binding affinity compared to 1. These novel inverse agonists serve as valuable tools to elucidate the role of constitutive signaling in the pathogenesis of viral infection and may have therapeutic potential as leads for new antiviral drugs.

  6. Dual Nicotinic Acetylcholine Receptor α4β2 Antagonists/α7 Agonists: Synthesis, Docking Studies, and Pharmacological Evaluation of Tetrahydroisoquinolines and Tetrahydroisoquinolinium Salts

    DEFF Research Database (Denmark)

    Crestey, François; Jensen, Anders A; Soerensen, Christian

    2018-01-01

    We describe the synthesis of tetrahydroisoquinolines and tetrahydroisoquinolinium salts together with their pharmacological properties at various nicotinic acetylcholine receptors. In general, the compounds were α4β2 nAChR antagonists, with the tetrahydroisoquinolinium salts being more potent than...

  7. Synthesis and pharmacological evaluation of DHβE analogs as neuronal nicotinic acetylcholine receptor antagonists

    DEFF Research Database (Denmark)

    Jepsen, Tue H.; Jensen, Anders A.; Lund, Mads Henrik

    2014-01-01

    Dihydro-β-erythroidine (DHβE) is a member of the Erythrina family of alkaloids and a potent competitive antagonist of the α4β2-subtype of the nicotinic acetylcholine receptors (nAChRs). Guided by an X-ray structure of DHβE in complex with an ACh binding protein, we detail the design, synthesis...

  8. Molecular and clinical pharmacology of intranasal corticosteroids: clinical and therapeutic implications.

    Science.gov (United States)

    Derendorf, H; Meltzer, E O

    2008-10-01

    Intranasal corticosteroids (INSs) are effective treatments for allergic rhinitis, rhinosinusitis, and nasal polyposis. In recent years, increased understanding of corticosteroid and glucocorticoid receptor pharmacology has enabled the development of molecules designed specifically to achieve potent, localized activity with minimal risk of systemic exposure. Pharmacologic potency studies using affinity and other assessments have produced similar rank orders of potency, with the most potent being mometasone furoate, fluticasone propionate, and its modification, fluticasone furoate. The furoate and propionate ester side chains render these agents highly lipophilic, which may facilitate their absorption through nasal mucosa and uptake across phospholipid cell membranes. These compounds demonstrate negligible systemic absorption. Systemic absorption rates are higher among the older corticosteroids (flunisolide, beclomethasone dipropionate, triamcinolone acetonide, and budesonide), which have bioavailabilities in the range of 34-49%. Studies, including 1-year studies with mometasone furoate, fluticasone propionate, and budesonide that evaluated potential systemic effects of INSs in children have generally found no adverse effects on hypothalamic-pituitary-adrenal axis function or growth. Clinical data suggest no significant differences in efficacy between the INSs. Theoretically, newer agents with lower systemic availability may be preferable, and may come closer to the pharmacokinetic/pharmacologic criteria for the ideal therapeutic choice.

  9. Non-pharmacological interventions for reducing aggression and violence in serious mental illness: A systematic review and narrative synthesis.

    Science.gov (United States)

    Rampling, J; Furtado, V; Winsper, C; Marwaha, S; Lucca, G; Livanou, M; Singh, S P

    2016-04-01

    For people with mental illness that are violent, a range of interventions have been adopted with the aim of reducing violence outcomes. Many of these interventions have been borrowed from other (offender) populations and their evidence base in a Serious Mental Illness (SMI) population is uncertain. To aggregate the evidence base for non-pharmacological interventions in reducing violence amongst adults with SMI and PD (Personality Disorder), and to assess the efficacy of these interventions. We chose to focus on distinct interventions rather than on holistic service models where any element responsible for therapeutic change would be difficult to isolate. We performed a systematic review and narrative synthesis of non-pharmacological interventions intended to reduce violence in a SMI population and in patients with a primary diagnosis of PD. Five online databases were searched alongside a manual search of seven relevant journals, and expert opinion was sourced. Eligibility of all returned articles was independently assessed by two authors, and quality of studies was appraised via the Cochrane Collaboration Tool for Assessing Risk of Bias. We included 23 studies of diverse psychological and practical interventions, with a range of experimental and quasi-experimental study designs that included 7 Randomised Controlled Trials (RCTs). The majority were studies of Mentally Disordered Offenders. The stronger evidence existed for patients with a SMI diagnosis receiving Cognitive Behavioural Therapy or modified Reasoning & Rehabilitation (R&R). For patients with a primary diagnosis of PD, a modified version of R&R appeared tolerable and Enhanced Thinking Skills showed some promise in improving attitudes over the short-term, but studies of Dialectical Behaviour Therapy in this population were compromised by high risk of experimental bias. Little evidence could be found for non-pharmacological, non-psychological interventions. The evidence for non-pharmacological

  10. Molecular and Physiological Factors of Neuroprotection in Hypoxia-tolerant Models: Pharmacological Clues for the Treatment of Stroke

    Directory of Open Access Journals (Sweden)

    Thomas I. Nathaniel

    2015-01-01

    Full Text Available The naked mole-rat possesses several unique physiological and molecular features that underlie their remarkably and exceptional resistance to tissue hypoxia. Elevated pattern of Epo, an erythropoietin (Epo factor; c-fos; vascular endothelial growth factor (VEGF; and hypoxia-inducible factors (HIF-1α contribute to the adaptive strategy to cope with hypoxic stress. Moreover, the naked mole-rat has a lower metabolic rate than any other eutherian mammal of comparable size that has been studied. The ability to actively reduce metabolic rate represents a strategy widely used in the face of decreased tissue oxygen availability. Understanding the different molecular and physiological factors that induce metabolic suppression could guide the development of pharmacological agents for the clinical management of stroke patient.

  11. Synthesis of novel chalcone derivatives by conventional and microwave irradiation methods and their pharmacological activities

    Directory of Open Access Journals (Sweden)

    Mohammed Rayees Ahmad

    2016-09-01

    Full Text Available Chalcones are abundant in edible plants and are considered to be the precursors of flavonoids and isoflavonoids. Chalcones belong to an important class of flavonoids, which may be prepared by Claisen–Schmidt condensation. They possess a wide range of biological activities and industrial applications. The cytotoxicity against tumour cell lines may be the result of disruption of the cell cycle, inhibition of angiogenesis, interference with p53-MDM2 interaction, mitochondrial uncoupling or induction of apoptosis. Chalcones are synthesized by conventional and microwave assisted synthesis methods. By microwave assisted synthesis, a considerable increase in the reaction rate has been observed and that too, with better yields. The compounds have been screened for cytotoxic activity and antioxidant activity.

  12. Benzoheterocyclic amodiaquine analogues with potent antiplasmodial activity: synthesis and pharmacological evaluation.

    Science.gov (United States)

    Ongarora, Dennis S B; Gut, Jiri; Rosenthal, Philip J; Masimirembwa, Collen M; Chibale, Kelly

    2012-08-01

    The synthesis and evaluation of antiplasmodial activity of benzothiazole, benzimidazole, benzoxazole and pyridine analogues of amodiaquine is hereby reported. Benzothiazole and benzoxazole analogues with a protonatable tertiary nitrogen atom possessed excellent activity against the W2 and K1 chloroquine resistant strains of Plasmodium falciparum, with IC(50)s ranging from 7 to 22 nM. Copyright © 2012 Elsevier Ltd. All rights reserved.

  13. The Molecular Industrial Revolution: Automated Synthesis of Small Molecules.

    Science.gov (United States)

    Trobe, Melanie; Burke, Martin D

    2018-04-09

    Today we are poised for a transition from the highly customized crafting of specific molecular targets by hand to the increasingly general and automated assembly of different types of molecules with the push of a button. Creating machines that are capable of making many different types of small molecules on demand, akin to that which has been achieved on the macroscale with 3D printers, is challenging. Yet important progress is being made toward this objective with two complementary approaches: 1) Automation of customized synthesis routes to different targets by machines that enable the use of many reactions and starting materials, and 2) automation of generalized platforms that make many different targets using common coupling chemistry and building blocks. Continued progress in these directions has the potential to shift the bottleneck in molecular innovation from synthesis to imagination, and thereby help drive a new industrial revolution on the molecular scale. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. A Comprehensive Review of Punica granatum (Pomegranate) Properties in Toxicological, Pharmacological, Cellular and Molecular Biology Researches

    Science.gov (United States)

    Rahimi, Hamid Reza; Arastoo, Mohammad; Ostad, Seyed Nasser

    2012-01-01

    Punica granatum (Pg), commonly known as pomegranate (Pg), is a member of the monogeneric family, Punicaceae, and is mainly found in Iran which is considered to be its primary centre of origin. Pg and its chemical components possess various pharmacological and toxicological properties including antioxidant, anti-inflammatory (by inhibiting pro-inflammatory cytokines), anti-cancer and anti-angiogenesis activities. They also show inhibitory effects on invasion/motility, cell cycle, apoptosis, and vital enzymes such as cyclooxygenase (COX), lipooxygenase (LOX), cytochrome P450 (CYP450), phospholipase A2 (PLA2), ornithine decarboxylase (ODC), carbonic anhydrase (CA), 17beta-hydroxysteroid dehydrogenase (17β-HSDs) and serine protease (SP). Furthermore, they can stimulate cell differentiation and possess anti-mutagenic effects. Pg can also interfere with several signaling pathways including PI3K/AKT, mTOR, PI3K, Bcl-X, Bax, Bad, MAPK, ERK1/2, P38, JNK, and caspase. However, the exact mechanisms for its pharmacological and toxicological properties remain to be unclear and need further evaluation. These properties strongly suggest a wide range use of Pg for clinical applications. This review will discuss the areas for which Pg has shown therapeutic properties in different mechanisms. PMID:24250463

  15. Dihydroazulene Photochromism:Synthesis, Molecular Electronics and Hammett Correlations

    DEFF Research Database (Denmark)

    Broman, Søren Lindbæk

    This thesis describes the development of a versatile synthetic protocol for preparation of a large selection of dihydroazulenes (DHAs) with both electron withdrawing and donating groups. By UV-Vis and NMR spectroscopies and even in a single-molecule junction, their ability to undergo a light...... will be discussed in detail. The second chapter describes the design and synthesis of DHA/VHFs intended for use in molecular electronics and their solution and single-molecule junction switching properties. By the expansion of the recently reported procedure for functionalization of this system by Suzuki cross...

  16. Alpha- and beta-adrenoceptors in hypertension: molecular biology and pharmacological studies

    NARCIS (Netherlands)

    Michel, M. C.; Philipp, T.; Brodde, O. E.

    1992-01-01

    Recent years have witnessed astonishing progress in our understanding of the molecular basis of adrenoceptor structure, function and regulation and revealed an unexpected heterogeneity of adrenoceptors demonstrating the existence of at least 11 subtypes. This paper discusses the implications of

  17. Molecular Basis of Cardiac Delayed Rectifier Potassium Channel Function and Pharmacology.

    Science.gov (United States)

    Wu, Wei; Sanguinetti, Michael C

    2016-06-01

    Human cardiomyocytes express 3 distinct types of delayed rectifier potassium channels. Human ether-a-go-go-related gene (hERG) channels conduct the rapidly activating current IKr; KCNQ1/KCNE1 channels conduct the slowly activating current IKs; and Kv1.5 channels conduct an ultrarapid activating current IKur. Here the authors provide a general overview of the mechanistic and structural basis of ion selectivity, gating, and pharmacology of the 3 types of cardiac delayed rectifier potassium ion channels. Most blockers bind to S6 residues that line the central cavity of the channel, whereas activators interact with the channel at 4 symmetric binding sites outside the cavity. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Molecular pharmacology of 4-substituted glutamic acid analogues at ionotropic and metabotropic excitatory amino acid receptors

    DEFF Research Database (Denmark)

    Bräuner-Osborne, Hans; Nielsen, B; Stensbøl, T B

    1997-01-01

    (subtypes 1alpha and 2), respectively, whereas (S)-4-methyleneglutamic acid showed high but rather non-selective affinity for the (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA), kainic acid, NMDA and mGlu receptors (subtypes 1alpha and 2). Although none of the compounds were specific......The pharmacology of (2S,4R)-4-methylglutamic acid, (2S,4S)-4-methylglutamic acid and (S)- and (R)-4-methyleneglutamic acids (obtained in high chemical and enantiomeric purity from racemic 4-methyleneglutamic acid by chiral HPLC using a Crownpak CR(+) column), was examined in binding experiments...... using rat brain ionotropic glutamate receptors, and in functional assays using cloned metabotropic glutamate (mGlu) receptors. As a notable result of these studies, (2S,4R)-4-methylglutamic acid and (2S,4S)-4-methylglutamic acid were shown to be selective for kainic acid receptors and mGlu receptors...

  19. Synthesis, three-dimensional structure, conformation and correct chemical shift assignment determination of pharmaceutical molecules by NMR and molecular modeling

    Energy Technology Data Exchange (ETDEWEB)

    Azeredo, Sirlene O.F. de; Sales, Edijane M.; Figueroa-Villar, José D., E-mail: jdfv2009@gmail.com [Instituto Militar de Engenharia (IME), Rio de Janeiro, RJ (Brazil). Grupo de Ressonância Magnética Nuclear e Química Medicinal

    2017-07-01

    This work includes the synthesis of phenanthrenequinone guanylhydrazone and phenanthro[9,10-e][1,2,4]triazin-3-amine to be tested as intercalate with DNA for treatment of cancer. The other synthesized product, 2-[(4-chlorophenylamino)methylene]malononitrile, was designed for future determination of its activity against leishmaniasis. A common problem about some articles on the literature is that some previously published compounds display error of their molecular structures. In this article it is shown the application of several procedures of nuclear magnetic resonance (NMR) to determine the complete molecular structure and the non questionable chemical shift assignment of the synthesized compounds, and also their analysis by molecular modeling to confirm the NMR results. To determine the capacity of pharmacological compounds to interact with biological targets is determined by docking. This work is to motivate the application of NMR and molecular modeling on organic synthesis, being a process that is very important for the study of the prepared compounds as interactions with biological targets by NMR. (author)

  20. Synthesis, three-dimensional structure, conformation and correct chemical shift assignment determination of pharmaceutical molecules by NMR and molecular modeling

    International Nuclear Information System (INIS)

    Azeredo, Sirlene O.F. de; Sales, Edijane M.; Figueroa-Villar, José D.

    2017-01-01

    This work includes the synthesis of phenanthrenequinone guanylhydrazone and phenanthro[9,10-e][1,2,4]triazin-3-amine to be tested as intercalate with DNA for treatment of cancer. The other synthesized product, 2-[(4-chlorophenylamino)methylene]malononitrile, was designed for future determination of its activity against leishmaniasis. A common problem about some articles on the literature is that some previously published compounds display error of their molecular structures. In this article it is shown the application of several procedures of nuclear magnetic resonance (NMR) to determine the complete molecular structure and the non questionable chemical shift assignment of the synthesized compounds, and also their analysis by molecular modeling to confirm the NMR results. To determine the capacity of pharmacological compounds to interact with biological targets is determined by docking. This work is to motivate the application of NMR and molecular modeling on organic synthesis, being a process that is very important for the study of the prepared compounds as interactions with biological targets by NMR. (author)

  1. The synthesis and preliminary pharmacological evaluation of the racemic cis and trans 3-alkylfentanyl analogues

    Directory of Open Access Journals (Sweden)

    LJ. DOSEN-MICOVIC

    2004-07-01

    Full Text Available A general, five step method for the synthesis of 3-alkylfentanyl analogues (i.e., cis and trans 3-alkyl-4-anilidopiperidines 6.1–6.6 has been developed. The starting N-phenethyl-4-piperidone 1 was first converted into the cyclohexylimine derivative 2, a-deprotonated with butyllithium and the resulting imine anion efficiently monoalkylated with primary and secondary alkyl halides. After mild acid hydrolysis, the obtained 3-alkyl-4-piperidones 3.1–3.6 were isolated in good yields (79–85 %, then condensed with aniline to form imines 4.1–4.6. Subsequent reduction of the imines (LiAlH4/THF yielded cis/trans mixtures of 3-alkyl-4-anilinopiperidines 5.1–5.6. Quantitative separation of the diastereoisomers by column chromatography of Al2O3 gave pure cis 5.1–5.6 (29–51 % yield and trans 5.1–5.6 (19–27 % yield, with the cis/trans ratio in the range 7/3–6/4. The synthesis was concluded by N-acylation of the purified 5.1–5.6, with propionyl chloride, to afford cis and trans 3-alkyl-4-anilidopiperidines 6.1–6.6 (~95 % yield, as monooxalate salts. No enatioseparation was attempted at any stage. The relative cis/trans stereochemistry was provisionally assigned from the 1H-NMR spectra. Of the twelve synthesized 3-alkylfentanyls, ten compounds (two known and eight novel derivatives, all as the monooxalate salts were preliminarily tested as analgesics in rats, comparing the potency to fentanyl. Except for the known (±-cis-3-Me fentanyl 6.1cis, (8 × fentanyl, and the novel (±-cis-3-Et fentanyl 6.2cis, (1.5 × fentanyl, all of the others were less active than fentanyl or inactive. Some tentative conclusions on the structure-activity relationship (SAR in this series of derivatives have been made.

  2. Synthesis and pharmacology of 3-isoxazolol amino acids as selective antagonists at group I metabotropic glutamic acid receptors

    DEFF Research Database (Denmark)

    Madsen, U; Bräuner-Osborne, H; Frydenvang, Karla Andrea

    2001-01-01

    Using ibotenic acid (2) as a lead, two series of 3-isoxazolol amino acid ligands for (S)-glutamic acid (Glu, 1) receptors have been developed. Whereas analogues of (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid [AMPA, (RS)-3] interact selectively with ionotropic Glu receptors (i......GluRs), the few analogues of (RS)-2-amino-3-(3-hydroxy-5-isoxazolyl)propionic acid [HIBO, (RS)-4] so far known typically interact with iGluRs as well as metabotropic Glu receptors (mGluRs). We here report the synthesis and pharmacology of a series of 4-substituted analogues of HIBO. The hexyl analogue 9 was shown...... to originate in (S)-11 (EC(50) = 395 microM, K(b) = 86 and 90 microM, respectively). Compound 9, administered icv, but not sc, was shown to protect mice against convulsions induced by N-methyl-D-aspartic acid (NMDA). Compounds 9 and 11 were resolved using chiral HPLC, and the configurational assignments...

  3. Synthesis and Pharmacology of Halogenated δ-Opioid-Selective [D-Ala2]Deltorphin II Peptide Analogues

    Science.gov (United States)

    Pescatore, Robyn; Marrone, Gina F.; Sedberry, Seth; Vinton, Daniel; Finkelstein, Netanel; Katlowitz, Yitzchak E.; Pasternak, Gavril W.; Wilson, Krista R.; Majumdar, Susruta

    2015-01-01

    Deltorphins are naturally occurring peptides produced by the skin of the giant monkey frog (Phyllomedusa bicolor). They are δ-opioid receptor-selective agonists. Herein, we report the design and synthesis of a peptide, Tyr-D-Ala-(pI)Phe-Glu-Ile-Ile-Gly-NH2 3 (GATE3-8), based on the [D-Ala2]deltorphin II template, which is δ-selective in in vitro radioligand binding assays over the μ- and κ-opioid receptors. It is a full agonist in [35S]GTPγS functional assays and analgesic when administered supraspinally to mice. Analgesia of 3 (GATE3-8) is blocked by the selective δ receptor antagonist naltrindole, indicating that the analgesic action of 3 is mediated by the δ-opioid receptor. We have established a radioligand in which 125I isincorporated into 3 (GATE3-8). The radioligand has a KD of 0.1 nM in Chinese hamster ovary (CHO) cells expressing the δ receptor. Additionally, a series of peptides based on 3 (GATE3-8) was synthesized by incorporating various halogens in the para position on the aromatic ring of Phe3. The peptides were characterized for binding affinity at the μ-, δ-, and κ-opioid receptors, which showed a linear correlation between binding affinity and the size of the halogen substituent. These peptides may be interesting tools for probing δ-opioid receptor pharmacology. PMID:25844930

  4. Synthesis and pharmacology of halogenated δ-opioid-selective [d-Ala(2)]deltorphin II peptide analogues.

    Science.gov (United States)

    Pescatore, Robyn; Marrone, Gina F; Sedberry, Seth; Vinton, Daniel; Finkelstein, Netanel; Katlowitz, Yitzchak E; Pasternak, Gavril W; Wilson, Krista R; Majumdar, Susruta

    2015-06-17

    Deltorphins are naturally occurring peptides produced by the skin of the giant monkey frog (Phyllomedusa bicolor). They are δ-opioid receptor-selective agonists. Herein, we report the design and synthesis of a peptide, Tyr-d-Ala-(pI)Phe-Glu-Ile-Ile-Gly-NH2 3 (GATE3-8), based on the [d-Ala(2)]deltorphin II template, which is δ-selective in in vitro radioligand binding assays over the μ- and κ-opioid receptors. It is a full agonist in [(35)S]GTPγS functional assays and analgesic when administered supraspinally to mice. Analgesia of 3 (GATE3-8) is blocked by the selective δ receptor antagonist naltrindole, indicating that the analgesic action of 3 is mediated by the δ-opioid receptor. We have established a radioligand in which (125)I is incorporated into 3 (GATE3-8). The radioligand has a KD of 0.1 nM in Chinese hamster ovary (CHO) cells expressing the δ receptor. Additionally, a series of peptides based on 3 (GATE3-8) was synthesized by incorporating various halogens in the para position on the aromatic ring of Phe(3). The peptides were characterized for binding affinity at the μ-, δ-, and κ-opioid receptors, which showed a linear correlation between binding affinity and the size of the halogen substituent. These peptides may be interesting tools for probing δ-opioid receptor pharmacology.

  5. Design, synthesis, conformational and molecular docking study of some novel acyl hydrazone based molecular hybrids as antimalarial and antimicrobial agents.

    Science.gov (United States)

    Kumar, Parvin; Kadyan, Kulbir; Duhan, Meenakshi; Sindhu, Jayant; Singh, Vineeta; Saharan, Baljeet Singh

    2017-11-14

    Acyl hydrazones are an important class of heterocyclic compounds promising pharmacological characteristics. Malaria is a life-threatening mosquito-borne blood disease caused by a plasmodium parasite. In some places, malaria can be treated and controlled with early diagnosis. However, some countries lack the resources to do this effectively. The present work involves the design and synthesis of some novel acyl hydrazone based molecular hybrids of 1,4-dihydropyridine and pyrazole (5a-g). These molecular hybrids were synthesised by condensation of 1,4-dihydropyridin-4-yl-phenoxyacetohydrazides with differently substituted pyrazole carbaldehyde. The final compound (5) showed two conformations (the major, E, s-cis and the minor, E, s-trans) as revealed by NMR spectral data and further supported by the energy calculations (MOPAC2016 using PM7 method). All the synthesised compounds were screened for their in vitro antimalarial activities against chloroquine-sensitive malaria parasite Plasmodium falciparum (3D7) and antimicrobial activity against Gram positive bacteria i.e. Bacillus cereus, Gram negative bacteria i.e. Escherichia coli and antifungal activity against one yeast i.e. Aspergillus niger. All these compounds were found more potent than chloroquine and clotrimazole, the standard drugs. In vitro antiplasmodial IC 50 value of the most potent compound 5d was found to be 4.40 nM which is even less than all the three reference drugs chloroquine (18.7 nM), pyrimethamine (11 nM) and artimisinin (6 nM). In silico binding study of compound 5d with plasmodial cysteine protease falcipain-2 indicated the inhibition of falcipain-2 as the probable reason for the antimalarial potency of compound 5d. All the compounds had shown good to excellent antimicrobial and antifungal activities.

  6. Molecular mechanism of reduction in pregnenolone synthesis by cigarette smoke

    International Nuclear Information System (INIS)

    Bose, Mahuya; Whittal, Randy M.; Gairola, C. Gary; Bose, Himangshu S.

    2008-01-01

    Steroidogenic acute regulatory protein (StAR) facilitates the movement of cholesterol from the outer to inner mitochondrial membrane for the synthesis of pregnenolone. Here, we investigated the molecular mechanism of the reduction of pregnenolone synthesis by cigarette smoke condensate (CSC). Pre-exposure or post-exposure of cells with CSC led to reduced pregnenolone synthesis, in a fashion similar to its effect on isolated mitochondria. However, there was no difference in the expression of 30 kDa StAR in cells treated with moderately concentrated CSC by either regimen. The active form of 37 kDa StAR is degraded easily suggesting that the continuous presence of CSC reduces StAR expression. Mitochondrial import of 35 S-methionine-labeled StAR followed by extraction of the StAR-mitochondrial complex with 1% digitonin showed similarly sized complexes in the CSC-treated and untreated mitochondria. Further analysis by sucrose density gradient centrifugation showed a specific complex, 'complex 2', in the untreated mitochondria but absent in the CSC-treated mitochondria. Mass spectrometric analysis revealed that complex 2 is the outer mitochondrial protein, VDAC1. Knockdown of VDAC1 expression by siRNA followed by co-transfection with StAR resulted in a lack of pregnenolone synthesis and 37 kDa StAR expression with reduced expression of the intermediate, 32 kDa StAR. Taken together, these results suggest that in the absence of VDAC1, active StAR expression is reduced indicating that VDAC1 expression is essential for StAR activity. In the absence of VDAC1-StAR interaction, cholesterol cannot be transported into mitochondria; thus the interaction with VDAC1 is a mandatory step for initiating steroidogenesis

  7. Current dichotomy between traditional molecular biological and omic research in cancer biology and pharmacology.

    Science.gov (United States)

    Reinhold, William C

    2015-12-10

    There is currently a split within the cancer research community between traditional molecular biological hypothesis-driven and the more recent "omic" forms or research. While the molecular biological approach employs the tried and true single alteration-single response formulations of experimentation, the omic employs broad-based assay or sample collection approaches that generate large volumes of data. How to integrate the benefits of these two approaches in an efficient and productive fashion remains an outstanding issue. Ideally, one would merge the understandability, exactness, simplicity, and testability of the molecular biological approach, with the larger amounts of data, simultaneous consideration of multiple alterations, consideration of genes both of known interest along with the novel, cross-sample comparisons among cell lines and patient samples, and consideration of directed questions while simultaneously gaining exposure to the novel provided by the omic approach. While at the current time integration of the two disciplines remains problematic, attempts to do so are ongoing, and will be necessary for the understanding of the large cell line screens including the Developmental Therapeutics Program's NCI-60, the Broad Institute's Cancer Cell Line Encyclopedia, and the Wellcome Trust Sanger Institute's Cancer Genome Project, as well as the the Cancer Genome Atlas clinical samples project. Going forward there is significant benefit to be had from the integration of the molecular biological and the omic forms or research, with the desired goal being improved translational understanding and application.

  8. Cockroach GABAB receptor subtypes: molecular characterization, pharmacological properties and tissue distribution.

    Science.gov (United States)

    Blankenburg, S; Balfanz, S; Hayashi, Y; Shigenobu, S; Miura, T; Baumann, O; Baumann, A; Blenau, W

    2015-01-01

    γ-aminobutyric acid (GABA) is the predominant inhibitory neurotransmitter in the central nervous system (CNS). Its effects are mediated by either ionotropic GABAA receptors or metabotropic GABAB receptors. GABAB receptors regulate, via Gi/o G-proteins, ion channels, and adenylyl cyclases. In humans, GABAB receptor subtypes are involved in the etiology of neurologic and psychiatric disorders. In arthropods, however, these members of the G-protein-coupled receptor family are only inadequately characterized. Interestingly, physiological data have revealed important functions of GABAB receptors in the American cockroach, Periplaneta americana. We have cloned cDNAs coding for putative GABAB receptor subtypes 1 and 2 of P. americana (PeaGB1 and PeaGB2). When both receptor proteins are co-expressed in mammalian cells, activation of the receptor heteromer with GABA leads to a dose-dependent decrease in cAMP production. The pharmacological profile differs from that of mammalian and Drosophila GABAB receptors. Western blot analyses with polyclonal antibodies have revealed the expression of PeaGB1 and PeaGB2 in the CNS of the American cockroach. In addition to the widespread distribution in the brain, PeaGB1 is expressed in salivary glands and male accessory glands. Notably, PeaGB1-like immunoreactivity has been detected in the GABAergic salivary neuron 2, suggesting that GABAB receptors act as autoreceptors in this neuron. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. Pharmacological Activities and Synthesis of Esculetin and Its Derivatives: A Mini-Review

    Directory of Open Access Journals (Sweden)

    Chengyuan Liang

    2017-03-01

    Full Text Available Esculetin, synonymous with 6,7-dihydroxycoumarin, is the main active ingredient of the traditional Chinese medicine Cortex Fraxini. The twig skin or trunk bark of Cortex Fraxini are used by herb doctors as a mild, bitter liver and gallbladder meridians’ nontoxic drug as well as dietary supplement. Recently, with a variety of novel esculetin derivatives being reported, the molecular mechanism research as well as clinical application of Cortex Fraxini and esculetin are becoming more attractive. This mini-review will consolidate what is known about the biological activities, the mechanism of esculetin and its synthetic derivatives over the past decade in addition to providing a brief synopsis of the properties of esculetin.

  10. Comparison of combinatorial clustering methods on pharmacological data sets represented by machine learning-selected real molecular descriptors.

    Science.gov (United States)

    Rivera-Borroto, Oscar Miguel; Marrero-Ponce, Yovani; García-de la Vega, José Manuel; Grau-Ábalo, Ricardo del Corazón

    2011-12-27

    Cluster algorithms play an important role in diversity related tasks of modern chemoinformatics, with the widest applications being in pharmaceutical industry drug discovery programs. The performance of these grouping strategies depends on various factors such as molecular representation, mathematical method, algorithmical technique, and statistical distribution of data. For this reason, introduction and comparison of new methods are necessary in order to find the model that best fits the problem at hand. Earlier comparative studies report on Ward's algorithm using fingerprints for molecular description as generally superior in this field. However, problems still remain, i.e., other types of numerical descriptions have been little exploited, current descriptors selection strategy is trial and error-driven, and no previous comparative studies considering a broader domain of the combinatorial methods in grouping chemoinformatic data sets have been conducted. In this work, a comparison between combinatorial methods is performed,with five of them being novel in cheminformatics. The experiments are carried out using eight data sets that are well established and validated in the medical chemistry literature. Each drug data set was represented by real molecular descriptors selected by machine learning techniques, which are consistent with the neighborhood principle. Statistical analysis of the results demonstrates that pharmacological activities of the eight data sets can be modeled with a few of families with 2D and 3D molecular descriptors, avoiding classification problems associated with the presence of nonrelevant features. Three out of five of the proposed cluster algorithms show superior performance over most classical algorithms and are similar (or slightly superior in the most optimistic sense) to Ward's algorithm. The usefulness of these algorithms is also assessed in a comparative experiment to potent QSAR and machine learning classifiers, where they perform

  11. SYNTHESIS AND CHARACTERIZATION OF NEW STABILIZERS WITH OPTIMAL MOLECULAR WEIGHT

    Institute of Scientific and Technical Information of China (English)

    Jiang-qing Pan

    2001-01-01

    Over 2 × l08 tons of polymers are produced every year, and a large portion of polymers faces the degradation problem. There are many effective methods to protect polymers against degradation and the addition of stabilizers to polymer remains the most convenient and effective way of enhancing polymer life and performance. In this article, a series of effective stabilizers with optimal molecular weight (MW), including common, monomeric and polymeric stabilizers (antioxidant and light stabilizer) were synthesized using isocyanation, controlled isocyanation, hydrosilylation, epoxide addition, macroreaction of stabilizing functional compounds and polymerization of monomeric stabilizers. The sructure and performance of these new stabilizers were characterized by using IR, NMR, MS, UV-spectra, XPS and elemental analysis. The current development of stabilizer synthesis was also reviewed.``

  12. Heat Shock Proteins and Autophagy Pathways in Neuroprotection: from Molecular Bases to Pharmacological Interventions

    Directory of Open Access Journals (Sweden)

    Botond Penke

    2018-01-01

    Full Text Available Neurodegenerative diseases (NDDs such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease (HD, amyotrophic lateral sclerosis, and prion diseases are all characterized by the accumulation of protein aggregates (amyloids into inclusions and/or plaques. The ubiquitous presence of amyloids in NDDs suggests the involvement of disturbed protein homeostasis (proteostasis in the underlying pathomechanisms. This review summarizes specific mechanisms that maintain proteostasis, including molecular chaperons, the ubiquitin-proteasome system (UPS, endoplasmic reticulum associated degradation (ERAD, and different autophagic pathways (chaperon mediated-, micro-, and macro-autophagy. The role of heat shock proteins (Hsps in cellular quality control and degradation of pathogenic proteins is reviewed. Finally, putative therapeutic strategies for efficient removal of cytotoxic proteins from neurons and design of new therapeutic targets against the progression of NDDs are discussed.

  13. Molecular pharmacology of cell receptors for cardiac glycosides, opiates, ACTH and ion channel modulators

    Energy Technology Data Exchange (ETDEWEB)

    Hnatowich, M R

    1986-01-01

    The influence of light and oxygen on molecular interactions between the artificial food dye, erythrosine (ERY), and (/sup 3/H)ouabain ((/sup 3/H)OUA) binding sites on (Na/sup +/ + K/sup +/)-ATPase in rat brain and guinea pig heart was investigated. Putative endogenous digitalis-like factors (DLF's) were studied in four in vitro assays for cardiac glycosides. (/sup 3/H)Etorphine binding was characterized in rat brain homogenates, depleted of opioids, from animals acutely and chronically treated with morphine and naloxone, and either unstressed or cold-restraint-stressed. Binding sites for the ion channel modulators (/sup 3/H)verapamil ((/sup 3/H)VER) and (/sup 3/H) phencyclidine ((/sup 3/H)PCP) were characterized in rat brain.

  14. Synthesis, Molecular Modelling and Biological Evaluation of Novel Heterodimeric, Multiple Ligands Targeting Cholinesterases and Amyloid Beta

    Directory of Open Access Journals (Sweden)

    Michalina Hebda

    2016-03-01

    Full Text Available Cholinesterases and amyloid beta are one of the major biological targets in the search for a new and efficacious treatment of Alzheimer’s disease. The study describes synthesis and pharmacological evaluation of new compounds designed as dual binding site acetylcholinesterase inhibitors. Among the synthesized compounds, two deserve special attention—compounds 42 and 13. The former is a saccharin derivative and the most potent and selective acetylcholinesterase inhibitor (EeAChE IC50 = 70 nM. Isoindoline-1,3-dione derivative 13 displays balanced inhibitory potency against acetyl- and butyrylcholinesterase (BuChE (EeAChE IC50 = 0.76 μM, EqBuChE IC50 = 0.618 μM, and it inhibits amyloid beta aggregation (35.8% at 10 μM. Kinetic studies show that the developed compounds act as mixed or non-competitive acetylcholinesterase inhibitors. According to molecular modelling studies, they are able to interact with both catalytic and peripheral active sites of the acetylcholinesterase. Their ability to cross the blood-brain barrier (BBB was confirmed in vitro in the parallel artificial membrane permeability BBB assay. These compounds can be used as a solid starting point for further development of novel multifunctional ligands as potential anti-Alzheimer’s agents.

  15. The botulinum toxin as a therapeutic agent: molecular and pharmacological insights

    Directory of Open Access Journals (Sweden)

    Kukreja R

    2015-12-01

    Full Text Available Roshan Kukreja,1 Bal Ram Singh2 1Department of Chemistry and Biochemistry, University of Massachusetts, 2Botulinum Research Center, Institute of Advanced Sciences, Dartmouth, MA, USA Abstract: Botulinum neurotoxins (BoNTs, the most potent toxins known to mankind, are metalloproteases that act on nerve–muscle junctions to block exocytosis through a very specific and exclusive endopeptidase activity against soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE proteins of presynaptic vesicle fusion machinery. This very ability of the toxins to produce flaccid muscle paralysis through chemical denervation has been put to good use, and these potentially lethal toxins have been licensed to treat an ever expanding list of medical disorders and more popularly in the field of esthetic medicine. In most cases, therapeutic BoNT preparations are high-molecular-weight protein complexes consisting of BoNT, complexing proteins, and excipients. There is at least one isolated BoNT, which is free of complexing proteins in the market (Xeomin®. Each commercially available BoNT formulation is unique, differing mainly in molecular size and composition of complexing proteins, biological activity, and antigenicity. BoNT serotype A is marketed as Botox®, Dysport®, and Xeomin®, while BoNT type B is commercially available as Myobloc®. Nerve terminal intoxication by BoNTs is completely reversible, and the duration of therapeutic effects of BoNTs varies for different serotypes. Depending on the target tissue, BoNTs can block the cholinergic neuromuscular or cholinergic autonomic innervation of exocrine glands and smooth muscles. Therapeutic BoNTs exhibit a high safety and very limited adverse effects profile. Despite their established efficacy, the greatest concern with the use of therapeutic BoNTs is their propensity to elicit immunogenic reactions that might render the patient unresponsive to subsequent treatments, particularly in chronic

  16. New Radioligands for Describing the Molecular Pharmacology of MT1 and MT2 Melatonin Receptors

    Directory of Open Access Journals (Sweden)

    Olivier Nosjean

    2013-04-01

    Full Text Available Melatonin receptors have been studied for several decades. The low expression of the receptors in tissues led the scientific community to find a substitute for the natural hormone melatonin, the agonist 2-[125I]-iodomelatonin. Using the agonist, several hundreds of studies were conducted, including the discovery of agonists and antagonists for the receptors and minute details about their molecular behavior. Recently, we attempted to expand the panel of radioligands available for studying the melatonin receptors by using the newly discovered compounds SD6, DIV880, and S70254. These compounds were characterized for their affinities to the hMT1 and hMT2 recombinant receptors and their functionality in the classical GTPS system. SD6 is a full agonist, equilibrated between the receptor isoforms, whereas S70254 and DIV880 are only partial MT2 agonists, with Ki in the low nanomolar range while they have no affinity to MT1 receptors. These new tools will hopefully allow for additions to the current body of information on the native localization of the receptor isoforms in tissues.

  17. Synthesis, pharmacological activity evaluation and molecular modeling of new polynuclear heterocyclic compounds containing benzimidazole derivatives.

    Science.gov (United States)

    Bassyouni, Fatma A; Saleh, Tamer S; ElHefnawi, Mahmoud M; Abd El-Moez, Sherein I; El-Senousy, Waled M; Abdel-Rehim, Mohamed E

    2012-12-01

    Novel heterocyclic compounds containing benzimidazole derivatives were synthesized from 2-(1H-benzimidazol-2-yl) acetonitrile (1) and arylhydrazononitrile derivative 2 was obtained via coupling of 1 with 4-methyl phenyldiazonium salt, which was then reacted with hydroxylamine hydrochloride to give amidooxime derivative 3. This product was cyclized into the corresponding oxadiazole derivative 4 upon reflux in acetic anhydride. Compound 4 was refluxed in DMF in the presence of triethylamine to give the corresponding 5-(1H-benzimidazol-2-yl)-2-p-tolyl-2H-1,2,3-triazol-4-amine 6. Treatment of compound 6 with ethyl chloroformate afforded 2,6-dihydro-2-(4-methylphenyl)-1,2,3-triazolo[4",5"-4',5']pyrimido[1,6-a]benzimidazole-5(4H)-one (8). 1,2-bis(2-cyanomethyl-1H-benzimidazol-1-yl)ethane-1,2-dione (10) was synthesized via the condensation reaction of 2-(1H-benzimidazol-2-yl) acetonitrile (1) and diethyloxalate. The reactivity of compound 10 towards some diamine reagents was studied. The in vitro antimicrobial activity of the synthesized compounds was investigated against several pathogenic bacterial strains such as Escherichia coli O157, Salmonella typhimurium, E. coli O119, S. paratyphi, Pseudomonas aeruginosa, Staphylococcus aureus, Listeria monocytogenes and Bacillus cereus. The results of MIC revealed that compounds 12a-c showed the most effective antimicrobial activity against tested strains. On the other hand, compounds 12a, b exhibited high activity against rotavirus Wa strain while compounds 12b, c exhibited high activity against adenovirus type 7. In silico target prediction, docking and validation of the compounds 12a-c were performed. The dialkylglycine decarboxylase bacterial enzyme was predicted as a potential bacterial target receptor using pharmacophore-based correspondence with previous leads; giving the highest normalized scores and a high correlation docking score with mean inhibition concentrations. A novel binding mechanism was predicted after docking using the MOE software and its validation.

  18. Synthesis and pharmacological evaluation of a new series of radiolabeled ligands for 5-HT7 receptor PET neuroimaging

    International Nuclear Information System (INIS)

    Colomb, Julie; Becker, Guillaume; Forcellini, Elsa; Meyer, Sandra; Buisson, Lauriane; Zimmer, Luc; Billard, Thierry

    2014-01-01

    Introduction: The brain serotonin-7 receptor (5-HT 7 ) is the most recently discovered serotonin receptor. It is targeted by several drug-candidates in psychopharmacology and neuropharmacology. In these fields, positron emission tomography (PET) is a molecular imaging modality offering great promise for accelerating the development process from preclinical discovery to clinical phases. We recently described fluorinated 5-HT 7 radioligands, inspired by the structure of SB269970, the prototypical 5-HT 7 antagonist. Although these results were promising, it appeared that the radiotracer-candidates suffered, among other drawbacks, from too low a 5-HT 7 receptor affinity. Methods: In the present study, seven structural analogs of SB269970 were synthesized using design strategies aiming to improve their radiopharmacological properties. Their 5-HT 7 binding properties were investigated by cellular functional assay. The nitro-precursors of the analogs were radiolabeled by [ 18 F-]nucleophilic substitution, and in vitro autoradiography was performed in rat brain, followed by in vivo microPET. Result: The chemical and radiochemical purity of the fluorine radiotracers was > 99% with specific activity in the 40–129 GBq/μmol range. The seven derivatives presented heterogeneous binding affinities toward 5-HT 7 and 5-HT 1A receptors. While [ 18 F]2F3P3 had promising characteristics in vitro, it showed poor brain penetration in vivo, partially reversed after pharmacological inhibition of P-glycoprotein. Conclusions: These results indicated that, while chemical modification of these series improved several radiotracer-candidates in terms of 5-HT 7 receptor affinity and specificity toward 5-HT 1A receptors, other physicochemical modulations would be required in order to increase brain penetration

  19. Solid-phase synthesis of molecularly imprinted nanoparticles.

    Science.gov (United States)

    Canfarotta, Francesco; Poma, Alessandro; Guerreiro, Antonio; Piletsky, Sergey

    2016-03-01

    Molecularly imprinted polymers (MIPs) are synthetic materials, generally based on acrylic or methacrylic monomers, that are polymerized in the presence of a specific target molecule called the 'template' and capable of rebinding selectively to this target molecule. They have the potential to be low-cost and robust alternatives to biomolecules such as antibodies and receptors. When prepared by traditional synthetic methods (i.e., with free template in solution), their usefulness has been limited by high binding site heterogeneity, the presence of residual template and the fact that the production methods are complex and difficult to standardize. To overcome some of these limitations, we developed a method for the synthesis of MIP nanoparticles (nanoMIPs) using an innovative solid-phase approach, which relies on the covalent immobilization of the template molecules onto the surface of a solid support (glass beads). The obtained nanoMIPs are virtually free of template and demonstrate high affinity for the target molecule (e.g., melamine and trypsin in our published work). Because of an affinity separation step performed on the solid phase after polymerization, poor binders and unproductive polymer are removed, so the final product has more uniform binding characteristics. The overall protocol, starting from the immobilization of the template onto the solid phase and including the purification and characterization of the nanoparticles, takes up to 1 week.

  20. Pharmacological Classification and Activity Evaluation of Furan and Thiophene Amide Derivatives Applying Semi-Empirical ab initio Molecular Modeling Methods

    Directory of Open Access Journals (Sweden)

    Leszek Bober

    2012-05-01

    Full Text Available Pharmacological and physicochemical classification of the furan and thiophene amide derivatives by multiple regression analysis and partial least square (PLS based on semi-empirical ab initio molecular modeling studies and high-performance liquid chromatography (HPLC retention data is proposed. Structural parameters obtained from the PCM (Polarizable Continuum Model method and the literature values of biological activity (antiproliferative for the A431 cells expressed as LD50 of the examined furan and thiophene derivatives was used to search for relationships. It was tested how variable molecular modeling conditions considered together, with or without HPLC retention data, allow evaluation of the structural recognition of furan and thiophene derivatives with respect to their pharmacological properties.

  1. Utilization of molecular species of diglycerides in the synthesis of lecithin

    NARCIS (Netherlands)

    Mudd, J.B.; Golde, L.M.G. van; Deenen, L.L.M. van

    1969-01-01

    1. 1. The synthesis of lecithin by rat liver microsomes was measured in the presence of [14C]CDP-choline and three molecular species of diglycerides derived from rat liver lecithin containing four, two and one double bond. The rate of synthesis of lecithin was the same regardless of the fatty acid

  2. Synthesis of one-dimensional metal-containing insulated molecular wire with versatile properties directed toward molecular electronics materials.

    Science.gov (United States)

    Masai, Hiroshi; Terao, Jun; Seki, Shu; Nakashima, Shigeto; Kiguchi, Manabu; Okoshi, Kento; Fujihara, Tetsuaki; Tsuji, Yasushi

    2014-02-05

    We report, herein, the design, synthesis, and properties of new materials directed toward molecular electronics. A transition metal-containing insulated molecular wire was synthesized through the coordination polymerization of a Ru(II) porphyrin with an insulated bridging ligand of well-defined structure. The wire displayed not only high linearity and rigidity, but also high intramolecular charge mobility. Owing to the unique properties of the coordination bond, the interconversion between the monomer and polymer states was realized under a carbon monoxide atmosphere or UV irradiation. The results demonstrated a high potential of the metal-containing insulated molecular wire for applications in molecular electronics.

  3. Quaternary Alkylammonium Conjugates of Steroids: Synthesis, Molecular Structure, and Biological Studies

    Directory of Open Access Journals (Sweden)

    Bogumił Brycki

    2015-11-01

    Full Text Available The methods of synthesis as well as physical, spectroscopic (1H-NMR, 13C-NMR, and FT-IR, ESI-MS, and biological properties of quaternary and dimeric quaternary alkylammonium conjugates of steroids are presented. The results were contrasted with theoretical calculations (PM5 methods and potential pharmacological properties (PASS. Alkylammonium sterols exhibit a broad spectrum of antimicrobial activity comparable to squalamine.

  4. An evidence-based update on the pharmacological activities and possible molecular targets of Lycium barbarum polysaccharides

    Directory of Open Access Journals (Sweden)

    Cheng J

    2014-12-01

    Full Text Available Jiang Cheng,1,2 Zhi-Wei Zhou,2 Hui-Ping Sheng,3 Lan-Jie He,4 Xue-Wen Fan,1 Zhi-Xu He,5 Tao Sun,6 Xueji Zhang,7 Ruan Jin Zhao,8 Ling Gu,9 Chuanhai Cao,2 Shu-Feng Zhou2,5 1Department of Neurology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China; 2Department of Pharmaceutical Science, College of Pharmacy, University of South Florida, Tampa, FL, USA; 3Department of Infectious Diseases, 4Department of Endocrinology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 5Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, 6Key Laboratory of Craniocerebral Diseases of Ningxia Hui Autonomous Region, Ningxia Medical University, Yinchuan, Ningxia, 7Research Center for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, People’s Republic of China; 8Center for Traditional Chinese Medicine, Sarasota, FL, USA; 9School of Biology and Chemistry, University of Pu’er, Pu’er, Yunnan, People’s Republic of China Abstract: Lycium barbarum berries, also named wolfberry, Fructus lycii, and Goji berries, have been used in the People’s Republic of China and other Asian countries for more than 2,000 years as a traditional medicinal herb and food supplement. L. barbarum polysaccharides (LBPs are the primary active components of L. barbarum berries and have been reported to possess a wide array of pharmacological activities. Herein, we update our knowledge on the main pharmacological activities and possible molecular targets of LBPs. Several clinical studies in healthy subjects show that consumption of wolfberry juice improves general wellbeing and immune functions. LBPs are reported to have antioxidative and antiaging properties in different models. LBPs show antitumor activities against various types of

  5. Review of the Chemistry and Pharmacology of 7-Methyljugulone ...

    African Journals Online (AJOL)

    Review of the Chemistry and Pharmacology of 7-Methyljugulone. ... Methods: The chemical and pharmacological data were retrieved from the well-known scientific websites such as Pubmed, Google Scholar, Reaxys, Scirus, Scopus, ... Keywords: 7-methyljugulone; biosynthesis; in vitro synthesis; pharmacology

  6. Synthesis and Characterization of Magnesium Substituted Aluminophosphate Molecular Sieves with AEL Structure

    Institute of Scientific and Technical Information of China (English)

    Benjing Xu; Ling Qian; Xinmei Liu; Chunmin Song; Zifeng Yan

    2004-01-01

    MAPO-11 molecular sieves were synthesized by hydrothermal methods. The influence of precursor of magnesium, Mg/Al ratio, synthesis temperature, synthesis time and the type of template on the formation and properties of MAPO-11 molecular sieves was examined. The samples were characterized by the techniques of X-ray diffraction (XRD), scanning electron microscopy (SEM), thermogravimetric/differential thermogravimetric analysis (TG-DGA), etc. The results show that the shape and size of crystal were influenced by the precursor of Mg, the Mg/Al ratio and the type of template, and the TG-DGA analysis shows that MAPO-11 molecular sieves as-synthesized have poor thermal stability.

  7. Synthesis and in vitro pharmacology at AMPA and kainate preferring glutamate receptors of 4-heteroarylmethylidene glutamate analogues

    DEFF Research Database (Denmark)

    Valgeirsson, Jon; Christensen, Jeppe K; Kristensen, Anders S

    2003-01-01

    affinity for the GluR2 subtype of AMPA receptors. As an attempt to develop new pharmacological tools for studies of GluR5 receptors, (S)-E-4-(2-thiazolylmethylene)glutamic acid (4a) was designed as a structural hybrid between 1 and 3. 4a was shown to be a potent GluR5 agonist and a high affinity ligand...

  8. Stereochemistry and molecular pharmacology of (S)-thio-ATPA, a new potent and selective GluR5 agonist

    DEFF Research Database (Denmark)

    Stensbøl, T B; Jensen, H S; Nielsen, B

    2001-01-01

    )-Glu) receptors (EC(50)=14 microM), comparable in potency with ATPA (EC(50)=34 microM). Recent findings, that (S)-ATPA is a potent (EC(50)=0.48 microM) and selective agonist at homomerically expressed ionotropic GluR5, prompted us to resolve thio-ATPA using chiral chromatography and pharmacologically characterize...

  9. Synthesis of Heteroaromatic Compounds by Oxidative Aromatization Using an Activated Carbon/Molecular Oxygen System

    Directory of Open Access Journals (Sweden)

    Masahiko Hayashi

    2009-08-01

    Full Text Available A variety of heteroaromatic compounds, such as substituted pyridines, pyrazoles, indoles, 2-substituted imidazoles, 2-substituted imidazoles, 2-arylbenzazoles and pyrimidin-2(1H-ones are synthesized by oxidative aromatization using the activated carbon and molecular oxygen system. Mechanistic study focused on the role of activated carbon in the synthesis of 2-arylbenzazoles is also discussed. In the final section, we will disclose the efficient synthesis of substituted 9,10-anthracenes via oxidative aromatization.

  10. Optimisation of the synthesis of vancomycin-selective molecularly imprinted polymer nanoparticles using automatic photoreactor

    OpenAIRE

    Muzyka, Kateryna; Karim, Khalku; Guerreiro, Antonio; Poma, Alessandro; Piletsky, Sergey

    2014-01-01

    A novel optimized protocol for solid-state synthesis of molecularly imprinted polymer nanoparticles (nanoMIPs) with specificity for antibiotic vancomycin is described. The experimental objective was optimization of the synthesis parameters (factors) affecting the yield of obtained nanoparticles which have been synthesized using the first prototype of an automated solid-phase synthesizer. Applications of experimental design (or design of experiments) in optimization of nanoMIP yield were carri...

  11. A Biomedical Investigation of the Hepatoprotective Effect of Radix salviae miltiorrhizae and Network Pharmacology-Based Prediction of the Active Compounds and Molecular Targets

    Directory of Open Access Journals (Sweden)

    Ming Hong

    2017-03-01

    Full Text Available Radix salviae miltiorrhizae (Danshen in Chinese, a classic traditional Chinese medicine (TCM herb, has been used for centuries to treat liver diseases. In this study, the preventive and curative potential of Danshen aqueous extract on acute/chronic alcoholic liver disease (ALD and non-alcoholic fatty liver disease (NAFLD was studied. The in vivo results indicated that Danshen could alleviate hepatic inflammation, fatty degeneration, and haptic fibrogenesis in ALD and NAFLD models. In the aspect of mechanism of action, the significant reduction in MDA levels in both ALD and NAFLD models implies the decreased levels of oxidative stress by Danshen. However, Danshen treatment could not activate the internal enzymatic antioxidant system in ALD and NAFLD models. To further explore the hepatoprotective mechanism of Danshen, an in silico-based network pharmacology approach was employed in the present study. The pharmacological network analysis result revealed that six potential active ingredients such as tanshinone iia, salvianolic acid b, and Danshensu may contribute to the hepatoprotective effects of Danshen on ALD and NAFLD. The action mechanism may relate with regulating the intracellular molecular targets such as PPARα, CYP1A2, and MMP2 for regulation of lipid metabolism, antioxidant and anti-fibrogenesis by these potential active ingredients. Our studies suggest that the combination of network pharmacology strategy with in vivo experimental study may provide a forceful tool for exploring the mechanism of action of traditional Chinese medicine (TCM herb and developing novel bioactive ingredients.

  12. Rational Design, Synthesis and Pharmacological Evaluation of the (2R)- and (2S)-Stereoisomers of 3-(2-Carboxypyrrolidinyl)-2-methyl Acetic Acid as Ligands for the Ionotropic Glutamate Receptors

    DEFF Research Database (Denmark)

    Rasmussen, Julie; Storgaard, Morten; Pickering, Darryl S

    2011-01-01

    In this paper we describe the rational design, synthesis and pharmacological evaluation of two new stereoisomeric (S)-glutamate (Glu) analogues. The rational design was based on hybrid structures of the natural product kainic acid, a synthetic analogue CPAA and the high-affinity Glu analogue SYM...

  13. Synthesis of molecular complexes for small molecule activation

    International Nuclear Information System (INIS)

    Andrez, Julie

    2016-01-01

    The redox chemistry of f-elements is drawing the attention of inorganic chemists due to their unusual reaction pathways. Notably low-valent f-element complexes have been shown to be able to activate small molecules such as CO_2 and N_2 in mild conditions. Compared to d-block metals, f-elements present a coordination chemistry dominated by electrostatic interactions and steric constraints. Molecular complexes of f-elements could thus provide new catalytic routes to transform small molecules into valuable chemicals. However the redox chemistry of low valent f-elements is dominated by single-electron transfers while the reductions of CO_2 and N_2 require multi-electronic processes. Accordingly the first approach of this PhD work was the use of redox active ligands as electron reservoir to support f-element centres increasing the electron number available for reduction events. The coordination of uranium with tridentate Schiff base ligand was investigated and led to isolation of a dinuclear electron-rich species able to undertake up to eight-electron reduction combining the redox activity of the ligands and the uranium centres. In order to obtain electron-rich compounds potentially able to polarize the C=O bond of CO_2, the synthesis of hetero-bimetallic species supported by salophen Schiff base ligand was also studied. In a second approach we have used bulky ligands with strong donor-character to tune the reducing abilities of low valent f-elements. In this case a bimolecular electron-transfer process is often observed. The reactivity of the U(III) siloxid complex [U(OSi(OtBu)_3)_4K] was further investigated. Notably, reaction with Ph_3PS led to the formation of a terminal U(IV) sulfide complex with multiple U-S bond which was analysed by DFT studies to better understand the bonding nature. Preliminary studies on the role of the counter-cation (M) in the system [U(OSi(OtBu)_3)_4M] on the outcome of the reactivity with CS_2 and CO_2 have also been performed. The

  14. Molecular catalysis and high-volume organic synthesis

    Energy Technology Data Exchange (ETDEWEB)

    Khidekel, M L; Vasserberg, V E

    1977-01-01

    The field of catalysis is very wide. The properties of catalysts are briefly reviewed and compared with the properties of enzymes. Various uses of enxymes in industry (sugar from corn, cellulose breakdown, etc.) are pointed out. The types of homogeneous and heterogeneous catalysts for use in organic synthesis are discussed. 48 refs. (SJR)

  15. Molecular design, synthesis and evaluation of chemical biology tools

    NARCIS (Netherlands)

    Hoogenboom, Jorin

    2017-01-01

    Chapter 1 provides a perspective of synthetic organic chemistry as a discipline involved in the design, synthesis and evaluation of complex molecules. The reader is introduced with a brief history of synthetic organic chemistry, all the while dealing with different aspects of

  16. Synthesis of molecular imprinted beta cyclodextrins oligomers in water

    DEFF Research Database (Denmark)

    Yu, Donghong; Nielsen, Anne Louise; Bach, Lone

    2003-01-01

    compounds in aqueous solution and, therefore, molecular imprinting of cyclodextrins polymers in aqueous solution is of great interest. In this paper, molecular imprinting of beta cyclodextrins has been performed in water by use of diiodobenzene as template and epichlorohydrin as a crosslinker. Inclusion...

  17. Pharmacologic Evaluation of Antidepressant Activity and Synthesis of 2-Morpholino-5-phenyl-6H-1,3,4-thiadiazine Hydrobromide

    Directory of Open Access Journals (Sweden)

    Alexey P. Sarapultsev

    2016-05-01

    Full Text Available Substituted thiadiazines exert a reliable therapeutic effect in treating stress, and a schematic description of their ability to influence all aspects of a stress response has been depicted. This study was conducted to pharmacologically evaluate compound L-17, a substituted thiadiazine, (2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide for possible anti-psychotic/antidepressant activity. Compound L-17 was synthesized by cyclocondensation of α-bromoacetophenone with the original morpholine-4-carbothionic acid hydrazide. Pharmacologic evaluations were conducted using methods described by E.F. Lavretskaya (1985, and in accordance with published guidelines for studying drugs for neuroleptic activity. Compound L-17 was evaluated for various possible mechanisms of action, including its effects on cholinergic system agonists/antagonists, dopaminergic neurotransmission, the adrenergic system, and 5-HT3 serotonin receptors. One or more of these mechanisms may be responsible for the beneficial effects shown by thiadiazine compounds in experiments conducted to evaluate their activity in models of acute stress and acute myocardial infarction.

  18. Synthesis and molecular docking of pyrimidine incorporated novel ...

    Indian Academy of Sciences (India)

    APOORVA MISRA

    2018-03-09

    Mar 9, 2018 ... aDepartment of Chemistry, Banasthali Vidyapith, Banasthali, Rajasthan 304 022, India ... serotonin 5-HT6 receptor antagonist,22 hepatitis-A virus ..... Molecular docking structure and ligand protein binding sites of MTX- (a) ...

  19. Synthesis of homochiral tris-indanyl molecular rods

    DEFF Research Database (Denmark)

    Kjeldsen, Niels Due; Funder, Erik Daa; Gothelf, Kurt Vesterager

    2014-01-01

    Homochiral tris-indanyl molecular rods designed for supramolecular surface self-assembly were synthesized. The chiral indanol moiety was constructed via a Ti-mediated alkyne trimerization. Further manipulations resulted in a homochiral indanol monomer. This was employed as the precursor for succe...... for successive Sonogashira and Ohira-Bestman reactions towards the homochiral tris-indanyl molecular rods. The molecular rods will be applied for scanning tunnelling microscopy studies of their surface self-assembly and chirality.......Homochiral tris-indanyl molecular rods designed for supramolecular surface self-assembly were synthesized. The chiral indanol moiety was constructed via a Ti-mediated alkyne trimerization. Further manipulations resulted in a homochiral indanol monomer. This was employed as the precursor...

  20. Synthesis and pharmacological characterization of a novel nitric oxide-releasing diclofenac derivative containing a benzofuroxan moiety.

    Science.gov (United States)

    de Carvalho, Paulo Sérgio; Maróstica, Marta; Gambero, Alessandra; Pedrazzoli, José

    2010-06-01

    1-oxy-benzo[1,2,5]oxadiazol-5-ylmethyl [2-(2,6-dichloro-phenylamino)-phenyl]-acetate, a new diclofenac derivative bearing a benzofuroxan heterocyclic moiety in its structure, was prepared by the reaction of sodium diclofenac and 5-bromomethyl-benzo[1,2,5]oxadiazole 1-oxide. Pharmacological characterization of this modified diclofenac maintained the anti-inflammatory activity similar to its parent compound assayed in vitro and in vivo. The ulcerogenic properties of native diclofenac were not observed with this modified compound, despite the inhibition of prostaglandin E2 gastric content. The better gastric tolerability seems to be related to nitric oxide release ability. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

  1. Synthesis of Polyimides in Molecular-Scale Confinement for Low-Density Hybrid Nanocomposites.

    Science.gov (United States)

    Isaacson, Scott G; Fostvedt, Jade I; Koerner, Hilmar; Baur, Jeffery W; Lionti, Krystelle; Volksen, Willi; Dubois, Geraud; Dauskardt, Reinhold H

    2017-11-08

    In this work, we exploit a confinement-induced molecular synthesis and a resulting bridging mechanism to create confined polyimide thermoset nanocomposites that couple molecular confinement-enhanced toughening with an unprecedented combination of high-temperature properties at low density. We describe a synthesis strategy that involves the infiltration of individual polymer chains through a nanoscale porous network while simultaneous imidization reactions increase the molecular backbone stiffness. In the extreme limit where the confinement length scale is much smaller than the polymer's molecular size, confinement-induced molecular mechanisms give rise to exceptional mechanical properties. We find that polyimide oligomers can undergo cross-linking reactions even in such molecular-scale confinement, increasing the molecular weight of the organic phase and toughening the nanocomposite through a confinement-induced energy dissipation mechanism. This work demonstrates that the confinement-induced molecular bridging mechanism can be extended to thermoset polymers with multifunctional properties, such as excellent thermo-oxidative stability and high service temperatures (>350 °C).

  2. Molecular pathways involved in the early and late damage induced by testis ischemia: evidence for a rational pharmacological modulation.

    Science.gov (United States)

    Altavilla, D; Romeo, C; Squadrito, F; Marini, H; Morgia, G; Antonuccio, P; Minutoli, L

    2012-01-01

    Testicular torsion or torsion of the spermatic cord is a surgical emergency in which misdiagnosis and inappropriate treatment can lead to male infertility. Events occurring during testicular torsion and detorsion are representative of an ischemia-reperfusion injury observed in other organs. The two most important factors determining testicular damage are the degree of twisting and the early onset of a surgical treatment to counter-rotate both testis and spermatic cord for inducing reperfusion. The damage from reperfusion is more severe than that induced by ischemia and several mechanisms are implicated in the development of testicular damage following torsion and detorsion. However, these mechanisms have not yet been fully clarified and, as a consequence, there is still a strong need to identify specific pharmacological treatment to limit the damage triggered by the reperfusion procedures. Ischemia and reperfusion of testis result in elevated production of reactive oxygen species (ROS), activate mitogen activated protein kinases (MAPKs) and PPARβ/δ receptor, induce transcription factors and growth factors including NF-κB and VEGF, trigger apoptotic machinery and induce several inflammatory cytokines, including TNF-α and IL-1β . This pathological cascade is responsible for the testicular atrophy, decreased blood flow and impaired spermatogenesis. Several pharmacological approaches have been characterized as promising therapeutic agents for the management of testicular torsion and may be useful to ameliorate the sequel of this disease.

  3. Molecular Pharmacology of Rosmarinic and Salvianolic Acids: Potential Seeds for Alzheimer’s and Vascular Dementia Drugs

    Directory of Open Access Journals (Sweden)

    Solomon Habtemariam

    2018-02-01

    Full Text Available Both caffeic acid and 3,4-dihydroxyphenyllactic acid (danshensu are synthesized through two distinct routs of the shikimic acid biosynthesis pathway. In many plants, especially the rosemary and sage family of Lamiaceae, these two compounds are joined through an ester linkage to form rosmarinic acid (RA. A further structural diversity of RA derivatives in some plants such as Salvia miltiorrhiza Bunge is a form of RA dimer, salvianolic acid-B (SA-B, that further give rise to diverse salvianolic acid derivatives. This review provides a comprehensive perspective on the chemistry and pharmacology of these compounds related to their potential therapeutic applications to dementia. The two common causes of dementia, Alzheimer’s disease (AD and stroke, are employed to scrutinize the effects of these compounds in vitro and in animal models of dementia. Key pharmacological mechanisms beyond the common antioxidant and anti-inflammatory effects of polyphenols are highlighted with emphasis given to amyloid beta (Aβ pathologies among others and neuronal regeneration from stem cells.

  4. Boronate esters: Synthesis, characterization and molecular base receptor analysis

    Science.gov (United States)

    Gómez-Jaimes, Gelen; Barba, Victor

    2014-10-01

    The synthesis of three boronate esters obtained by reacting 4-fluorophenylboronic (1), 4-iodophenylboronic (2) and 3,4-chlorophenylboronic (3) acids with 2,4,5-trihidroxybenzaldehyde is reported. The structural characterization was determined by spectroscopic and spectrometric techniques. The boron atom was evaluated to acts as Lewis acid center in the reaction with pyridine (Py), triethylamine (TEA) and fluoride anion (F-). The titration method was followed by UV-Vis and 11B NMR spectroscopy; results indicate the good interaction with the fluoride ion but poor coordination towards pyridine in solution.

  5. Understanding the Synthesis and Properties of Molecular Silver Nanoparticles

    Science.gov (United States)

    Ashenfelter, Brian A.

    Molecular nanoparticles have emerged as an interesting class of materials whose atomically precise structures and discrete properties set them apart from their larger counterparts. Molecular silver nanoparticles are of particular interest because they provide a host of advantages as optical materials for possible use in sensing and imaging applications. However, relatively little is known about molecular silver nanoparticles including the details of their formation and their optical and mechanical properties. Size control remains a longstanding challenge in the production of glutathionate (SG) protected silver nanoparticles. Singular Ag:SG nanoparticle products have been difficult to obtain directly, but size focusing of larger distributions through attrition has been found to lead to useful isolation of particular species. Here, we present a methodology for controlling the size of Ag:SG molecular nanoparticles that leverages the stability of the most robust species. These results were then used to develop a facile approach for achieving two of the most stable species in the Ag:SG system. Molecular metal nanoparticles are known to be much more fluorescent than larger plasmonic nanoparticles, however the nature and origin of this fluorescence are not fully understood. Fluorescence can originate from either the quantum states within the metal core or mixed ligand states at the inorganic-organic interface. We have presented compelling evidence that fluorescence from molecular silver glutathionate nanoparticles has its origin in interfacial electronic states. Fluorescence spectra were found to be independent of size, with very similar wavelength and bandwidth, although the quantum yield was not. Excitation spectra indicated that the strongest fluorescence had its origin in that part of the spectrum that is dominated by ligand-related states. Further, excitations to strictly core states and to higher lying d-band states had little to no contribution to the fluorescence

  6. Synthesis and Pharmacological Evaluation of [11C]Granisetron and [18F]Fluoropalonosetron as PET Probes for 5-HT3 Receptor Imaging.

    Science.gov (United States)

    Mu, Linjing; Müller Herde, Adrienne; Rüefli, Pascal M; Sladojevich, Filippo; Milicevic Sephton, Selena; Krämer, Stefanie D; Thompson, Andrew J; Schibli, Roger; Ametamey, Simon M; Lochner, Martin

    2016-11-16

    Serotonin-gated ionotropic 5-HT 3 receptors are the major pharmacological targets for antiemetic compounds. Furthermore, they have become a focus for the treatment of irritable bowel syndrome (IBS) and there is some evidence that pharmacological modulation of 5-HT 3 receptors might alleviate symptoms of other neurological disorders. Highly selective, high-affinity antagonists, such as granisetron (Kytril) and palonosetron (Aloxi), belong to a family of drugs (the "setrons") that are well established for clinical use. To enable us to better understand the actions of these drugs in vivo, we report the synthesis of 8-fluoropalonosetron (15) that has a binding affinity (K i = 0.26 ± 0.05 nM) similar to the parent drug (K i = 0.21 ± 0.03 nM). We radiolabeled 15 by nucleophilic 18 F-fluorination of an unsymmetrical diaryliodonium palonosetron precursor and achieved the radiosynthesis of 1-(methyl- 11 C)-N-granisetron ([ 11 C]2) through N-alkylation with [ 11 C]CH 3 I, respectively. Both compounds [ 18 F]15 (chemical and radiochemical purity >95%, specific activity 41 GBq/μmol) and [ 11 C]2 (chemical and radiochemical purity ≥99%, specific activity 170 GBq/μmol) were evaluated for their utility as positron emission tomography (PET) probes. Using mouse and rat brain slices, in vitro autoradiography with both [ 18 F]15 and [ 11 C]2 revealed a heterogeneous and displaceable binding in cortical and hippocampal regions that are known to express 5-HT 3 receptors at significant levels. Subsequent PET experiments suggested that [ 18 F]15 and [ 11 C]2 are of limited utility for the PET imaging of brain 5-HT 3 receptors in vivo.

  7. Stereoselective synthesis and pharmacological evaluation of [4.3.3]propellan-8-amines as analogs of adamantanamines.

    Science.gov (United States)

    Torres-Gómez, Héctor; Lehmkuhl, Kirstin; Frehland, Bastian; Daniliuc, Constantin; Schepmann, Dirk; Ehrhardt, Christina; Wünsch, Bernhard

    2015-08-01

    Amantadine (1) exerts its anti-Parkinson effects by inhibition of the NMDA associated cation channel and its antiviral activity by inhibition of the M2 protein channel of influenza A viruses. Herein the synthesis, NMDA receptor affinity and anti-influenza activity of analogous propellanamines 3 are reported. The key steps in the synthesis of the diastereomeric propellanamines syn-3 and anti-3 are diastereoselective reduction of the ketone 7 with L-Selectride to give anti-11, Mitsunobu inversion of the alcohol anti-13 into syn-13, and SN2 substitution of diastereomeric mesylates syn-14 and anti-14 with NaN3. The affinity of the propellanamines syn-3 and anti-3 to the PCP binding site of the NMDA receptor is similar to that of amantadine (Ki=11 μM). However, both propellanamines syn-3 and anti-3 do not exhibit activity against influenza A viruses. Compared to amantadine (1), the structurally related propellanamines syn-3 and anti-3 retain the NMDA antagonistic activity but loose the antiviral activity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Synthesis and Pharmacological Screening of Several Aroyl and Heteroaroyl Selenylacetic Acid Derivatives as Cytotoxic and Antiproliferative Agents

    Directory of Open Access Journals (Sweden)

    Carmen Sanmartín

    2009-09-01

    Full Text Available The synthesis and cytotoxic activity of a series of twenty six aroyl and heteroaroyl selenylacetic acid derivatives of general formula Ar-CO-Se-CH2-COOH or Heterar-CO-Se-CH2-COOH are reported. The synthesis was carried out by reaction of acyl chlorides with sodium hydrogen selenide, prepared in situ, and this led to the formation of sodium aroylselenides that subsequently reacted with α-bromoacetic acid to produce the corresponding selenylacetic acid derivatives. All of the compounds were tested against a prostate cancer cell line (PC-3 and some of the more active compounds were assessed against a panel of four human cancer cell lines (CCRF-CEM, HTB-54, HT-29, MCF-7 and one mammary gland-derived non-malignant cell line (184B5. Some of the compounds exhibited remarkable cytotoxic and antiproliferative activities against MCF-7 and PC-3 that were higher than those of the reference compounds doxorubicin and etoposide, respectively. For example, in MCF-7 when Ar = phenyl, 3,5-dimethoxyphenyl or benzyl the TGI values were 3.69, 4.18 and 6.19 μM. On the other hand, in PC-3 these compounds showed values of 6.8, 4.0 and 2.9 μM. Furthermore, benzoylselenylacetic acid did not provoke apoptosis nor did it perturb the cell cycle in MCF-7.

  9. MCM-41 ordered mesoporous molecular sieves synthesis and characterization

    Directory of Open Access Journals (Sweden)

    Rogério A.A. Melo

    1999-07-01

    Full Text Available The aim of this work was to study the hydrothermal synthesis of Si and SiAlMCM-41 performed under both autogenic pressure and refluxing conditions. XRD data showed that the MCM-41 phase may be formed by both processes and that the synthesized material in the presence of Al and/or under reflux presents the hexagonally arrangement of less ordered mesopores. However, as verified by XRD and physisorption data, the order was improved with higher synthesis times. 29Si and 1H - 29Si C/P MAS NMR spectra showed that a great part of the Si atoms exists as silanol groups which originate resonance peaks at -110, -100 and -91 ppm. The presence of Al atoms may generate Si(3Si, Al and Si(2Si, 2Al environments which might be contributing to resonance peaks at -100 and -91 ppm. The 27Al MAS NMR spectrum of the as synthesized AlSiMCM-41 showed a resonance peak of tetrahedral framework aluminum close to 53 ppm and two others, one close to 14 ppm attributed to Al(H2O6+3 species and the other a weak signal close to 32 ppm attributed to pentacoordinated Al. 27Al MAS NMR spectra of the calcined sample showed a peak at 0 ppm corresponding to an hexacoordinated extra-framework aluminum formed during calcination.

  10. Synthesis, anti-microbial activity and molecular docking studies on ...

    Indian Academy of Sciences (India)

    Molecular structures of triazolylcoumarins 1–8. method and are ... organic layer was washed with water (100 mL) and sat- ... (0.5mmol) in a mixture of THF and water (1:1) solution. ..... for docking studies with the target DNA gyrase B (PDB.

  11. Synthesis, molecular and crystalline architectures, and properties of ...

    Indian Academy of Sciences (India)

    The construction1 of coordination compounds of cobalt(II) of different nuclearities is the centre of attrac- tion due to interesting structural and physico-chemical properties.1–5 ... Design SQUID MPMS-XL magnetometer working in the 2–300 K range. ..... Complex 1 adopts a molecular architecture cor- responding to the gross ...

  12. Microwave Assisted Synthesis of Some New Fused 1,2,4-Triazines Bearing Thiophene Moieties With Expected Pharmacological Activity

    Directory of Open Access Journals (Sweden)

    Mosselhi A. Mosselhi

    2011-06-01

    Full Text Available Rapid and efficient solvent-free synthesis of 4-amino-3-mercapto-6-[2-(2-thienylvinyl]-1,2,4-triazin-5(4H-one 1 under microwave irradiation is described. Some new fused heterobicyclic nitrogen systems such as 1,2,4-triazino[3,4-b][1,3,4]thiadiazinones, 1,3,4-thiadiazolo[2,3-c][1,2,4]triazinone and pyrazolo[5,1-c]-[1,2,4]triazine-7-carbonitrile, have been synthesized by treatment of 1 with bifunctional oxygen and halogen compounds, CS2/KOH and malononitrile via heterocyclization reactions, in addition to some uncondensed triazines. Structures of the products have been deduced from their elemental analysis and spectral data (IR, 1H-NMR, 13C-NMR. Select new synthesized compounds were screened as anticancer agents, with some showing activity as cytotoxic agents against different cancer cell lines.

  13. Developmental co-expression of small molecular weight apolipoprotein B synthesis and triacylglycerol secretion

    International Nuclear Information System (INIS)

    Coleman, R.A.; Haynes, E.B.; Sand, T.M.; Davis, R.A.

    1987-01-01

    The development of the liver's ability to coordinately express the synthesis and secretion of the two major components of very low density lipoproteins (VLDL): triacylglycerol (TG) and apolipoprotein B (apo B) was examined in cultured hepatocytes obtained from fetal, suckling and adult rats. Hepatocytes from fetal and suckling rats synthesized and secreted TG at rates lower than that displayed by adult cells. When TG synthesis was equalized by adding oleic acid to the culture medium, fetal cells still secreted only 39% as much TG as did adult cells. To determine the basis for the apparent defect in VLDL assembly/secretion displayed by fetal cells, the synthesis and secretion of [ 35 S]methionine-labeled apo B was quantified by immunoprecipitation. Although adult and fetal cells synthesized and secreted large molecular weight apo B at similar rates, the synthesis and secretion of small molecular weight apo B was 2-fold greater in adult cells. These data suggest that the ability to assemble/secrete VLDL triacylglycerol varies in parallel with the developmental expression of small molecular weight apo B. Furthermore, these studies show the usefulness of the cultured rat hepatocyte model for examining the ontogeny and regulation of VLDL assembly/secretion

  14. Poly[n]catenanes: Synthesis of molecular interlocked chains

    Science.gov (United States)

    Wu, Qiong; Rauscher, Phillip M.; Lang, Xiaolong; Wojtecki, Rudy J.; de Pablo, Juan J.; Hore, Michael J. A.; Rowan, Stuart J.

    2017-12-01

    As the macromolecular version of mechanically interlocked molecules, mechanically interlocked polymers are promising candidates for the creation of sophisticated molecular machines and smart soft materials. Poly[n]catenanes, where the molecular chains consist solely of interlocked macrocycles, contain one of the highest concentrations of topological bonds. We report, herein, a synthetic approach toward this distinctive polymer architecture in high yield (~75%) via efficient ring closing of rationally designed metallosupramolecular polymers. Light-scattering, mass spectrometric, and nuclear magnetic resonance characterization of fractionated samples support assignment of the high-molar mass product (number-average molar mass ~21.4 kilograms per mole) to a mixture of linear poly[7-26]catenanes, branched poly[13-130]catenanes, and cyclic poly[4-7]catenanes. Increased hydrodynamic radius (in solution) and glass transition temperature (in bulk materials) were observed upon metallation with Zn2+.

  15. Molecularly Imprinted Polymer Beads-Synthesis, Evaluation and Applications

    OpenAIRE

    Zhou, Tongchang

    2016-01-01

    Molecularly imprinted polymers (MIPs) are artificial receptors designed for the selective recognition of template molecules. These polymers have been applied in analytical separations, as chemical sensors and in drug delivery system due to their low cost and high stability. In recent years MIP beads, especially those with good selectivity in aqueous solution, have become attractive as they can be potentially used as selective adsorbents for the solid phase extraction (SPE) and chromatographic...

  16. Synthesis of a Molecularly Imprinted Polymer for Dioxin

    Directory of Open Access Journals (Sweden)

    Magda Brattoli

    2006-08-01

    Full Text Available A molecularly imprinted polymer for recognising selectively 2,3,7,8-tetrachlorodibenzodioxin (TCDD was made by a new non-covalent method employing a“dummy” template. The proposed way represents a simplification of a synthetic schemeproposed by Lübke et al.[1] for covalent imprinting. Comparison of extraction yields of thenovel polymer, a non imprinted polymer and an imprinting polymer, prepared by theoriginal procedure demonstrates the binding capacity of the proposed polymer, which is inprinciple applicable to solid phase extraction (SPE of dioxin.

  17. Metformin-like antidiabetic, cardio-protective and non-glycemic effects of naringenin: Molecular and pharmacological insights.

    Science.gov (United States)

    Nyane, Ntsoaki Annah; Tlaila, Thabiso Bethwel; Malefane, Tanki Gabriel; Ndwandwe, Dudu Edith; Owira, Peter Mark Oroma

    2017-05-15

    Metformin is a widely used drug for the treatment of type 2 diabetes (T2D). Its blood glucose-lowering effects are initially due to inhibition of hepatic glucose production and increased peripheral glucose utilization. Metformin has also been shown to have several beneficial effects on cardiovascular risk factors and it is the only oral antihyperglycaemic agent thus far associated with decreased macrovascular complications in patients with diabetes. Adenosine Monophosphate Activated-Protein Kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Recent evidence shows that pharmacological activation of AMPK improves blood glucose homeostasis, lipid profiles, blood pressure and insulin-resistance making it a novel therapeutic target in the treatment of T2D. Naringenin a flavonoid found in high concentrations as its glycone naringin in citrus fruits, has been reported to have antioxidant, antiatherogenic, anti- dyslipidemic and anti-diabetic effects. It has been shown that naringenin exerts its anti-diabetic effects by inhibition of gluconeogenesis through upregulations of AMPK hence metformin-like effects. Naringin has further been shown to have non-glycemic affects like metformin that mitigate inflammation and cell proliferation. This review evaluates the potential of naringenin as anti-diabetic, anti-dyslipidemic anti-inflammatory and antineoplastic agent similar to metformin and proposes its further development for therapeutic use in clinical practice. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. 3-pyrazolone analogues of the 3-isoxazolol metabotropic excitatory amino acid receptor agonist homo-AMPA. Synthesis and pharmacological testing

    DEFF Research Database (Denmark)

    Zimmermann, D.; Janin, Y.L.; Brehm, L.

    1999-01-01

    the terminal carboxyl group has been replaced by various bioisosteric groups, such as phosphonic acid or 3-isoxazolol groups, have been shown to interact selectively with different subtypes of mGlu receptors. In this paper we report the synthesis of the 3-pyrazolone bioisosteres of a-AA, compounds (RS)-2-amino......-4-(1,2-dihydro-5-methyl-3-oxo-3H-pyrazol-4-yl)butyric acid (1) and (RS)-2-amino-4-(1,2-dihydro-1,5-dimethyl-3-oxo-3H-pyrazol-4-yl)butyric acid (2). At a number of steps in the reaction sequences used, the reactions took unexpected courses and provided products which could not be transformed......We have previously shown that the higher homologue of (S)-glutamic acid [(S)-Glu], (S)-a-aminoadipic acid [(S)-a-AA] is selectively recognized by the mGlu and mGlu subtypes of the family of metabotropic glutamic acid (mGlu) receptors. Furthermore, a number of analogues of (S)-a-AA, in which...

  19. Synthesis of High-Molecular-Weight Multifunctional Glycerol Polyhydroxyurethanes PHUs

    Directory of Open Access Journals (Sweden)

    Bassam Nohra

    2016-09-01

    Full Text Available Glycerol carbonate acrylate is a 5-membered cyclic carbonate synthesized from glycerol that is used as a chemical coupling agent and has proven highly suitable for use in the synthesis of multifunctional polyhydroxyurethanes (PHUs. The multifunctionality of the structure of PHUs is determined by the density of the carbon-amine groups generated by the Aza-Michael reaction and that of the urethane groups and adjacent primary and secondary hydroxyl groups generated by aminolysis. Glycerol carbonate acrylate is polymerized with polyfunctional mono-, di-, tri, and tetra-amines, by type-AB polyaddition, either in bulk or in solution, through stepwise or one-pot reaction strategies in the absence of added catalysts. These approaches result in the generation of linear, interchain, and crosslinked structures, through the polyaddition of linear and branched amines to the ethylene and cyclic carbonate sites of glycerol carbonate acrylate. The resulting collection of organic molecules gives rise to polyethylene amino ester PHUs with a high molar mass, exceeding 20,000 g·mol−1, with uniform dispersity.

  20. Boron nitride ceramics from molecular precursors: synthesis, properties and applications.

    Science.gov (United States)

    Bernard, Samuel; Salameh, Chrystelle; Miele, Philippe

    2016-01-21

    Hexagonal boron nitride (h-BN) attracts considerable interest because its structure is similar to that of carbon graphite while it displays different properties which are of interest for environmental and green technologies. The polar nature of the B-N bond in sp(2)-bonded BN makes it a wide band gap insulator with different chemistry on its surface and particular physical and chemical properties such as a high thermal conductivity, a high temperature stability, a high resistance to corrosion and oxidation and a strong UV emission. It is chemically inert and nontoxic and has good environmental compatibility. h-BN also has enhanced physisorption properties due to the dipolar fields near its surface. Such properties are closely dependent on the processing method. Bottom-up approaches consist of transforming molecular precursors into non-oxide ceramics with retention of the structural units inherent to the precursor molecule. The purpose of the present review is to give an up-to-date overview on the most recent achievements in the preparation of h-BN from borazine-based molecular single-source precursors including borazine and 2,4,6-trichloroborazine through both vapor phase syntheses and methods in the liquid/solid state involving polymeric intermediates, called the Polymer-Derived Ceramics (PDCs) route. In particular, the effect of the chemistry, composition and architecture of the borazine-based precursors and derived polymers on the shaping ability as well as the properties of h-BN is particularly highlighted.

  1. Amide-linked Ethanolamine Conjugate of Gemfibrozil as a Profound HDL Enhancer: Design, Synthesis, Pharmacological Screening and Docking Study.

    Science.gov (United States)

    Rai, Himanshu; Dhaneshwar, Suneela S

    2015-01-01

    Elevated concentration of any or all types of lipids in the plasma including hypertriglyceridemia and hypercholesterolemia leads to atherosclerotic cardiovascular disease. Effective medication needs multiple drug therapy as recommended cholesterol and triglyceride levels are difficult to achieve by monotherapy and frequently require the use of more than one lipid-lowering medication. Gemfibrozil lowers plasma triglyceride-rich lipoproteins mainly VLDL and increases HDL. It is associated with short plasma half-life (1.5h) and GIT distress on long term use. In a study it was found that ethanolamine decreases serum cholesterol, especially VLDL cholesterol and LDL cholesterol in rats fed an HF/HC diet. In the present work, we thought of exploring the effect of co-drug of gemfibrozil with ethanolamine (GE-I) as a potential combination therapy for the management of mixed hyperlipidemia. Synthesis of GE-I was effected by CDI coupling. Structure was confirmed spectrally. Interestingly kinetic studies revealed that GE-I resisted chemical and enzymatic hydrolysis. In tritoninduced hyperlipidemia, significant lowering of serum lipid levels was observed. The hallmark of GEI was its profound effect on HDL level which was raised above the normal level by 15%. Docking study also supported modulatory effect of GE-I (docking score -7.012) on PPAR-α which was comparable to docking score of gemfibrozil (-9.432). These preliminary observations prompt us to consider GE-I as a novel, serendipitous, hybrid anti-hyperlipidemic new chemical entity which needs be studied extensively to prove it as an HDL enhancing anti-hyperlipidemic agent.

  2. Synthesis of Molecularly Imprinted Polymer for Sterol Separation

    Directory of Open Access Journals (Sweden)

    Yuangsawad Ratanaporn

    2016-01-01

    Full Text Available Molecular imprinted polymer (MIP was prepared by bulk polymerization in acetone using acrylamide as a functional monomer, ethylene glycol dimethacrylate as a crosslinker, stigmasterol as a template and benzoyl peroxide as an initiator. The obtained MIPs were characterized using a scanning electron microscope and a fourier transform infrared spectrophotometer. Performance in sterol adsorption of MIPs prepared under various conditions was investigated using a model solution of phytosterols in heptane, comparing with a nonimprinted polymer (NIP. Statistical analysis revealed that the amounts of crosslinker and template strongly affected the performance of MIP while the amount of solvent slightly affected the performance of MIP. MIP synthesized under the optimal condition had adsorption capacity of 1.28 mgsterols/gads which were 1.13 times of NIP.

  3. Network Pharmacology-Based Approach to Investigate the Analgesic Efficacy and Molecular Targets of Xuangui Dropping Pill for Treating Primary Dysmenorrhea

    Directory of Open Access Journals (Sweden)

    Jihan Huang

    2017-01-01

    Full Text Available This study aimed to evaluate the clinical analgesic efficacy and identify the molecular targets of XGDP for treating primary dysmenorrhea (PD by a network pharmacology approach. Analysis of pain disappearance rate of XGDP in PD treatment was conducted based on data from phase II and III randomized, double-blind, double-simulation, and positive parallel controlled clinical trials. The bioactive compounds were obtained by the absorption, distribution, metabolism, and excretion processes with oral bioavailability (OB and drug-likeness (DL evaluation. Subsequently, target prediction, pathway identification, and network construction were employed to clarify the mechanisms of the analgesic effect of XGDP on PD. The pain disappearance rates in phase II and III clinical trials of XGDP in PD treatment were 62.5% and 55.8%, respectively, yielding a significant difference (P<0.05 when compared with the control group using Tongjingbao granules (TJBG. Among 331 compounds, 53 compounds in XGDP were identified as the active compounds related to PD through OB, DL, and target prediction. The active compounds and molecular targets of XGDP were identified, and our study showed that XGDP may exert its therapeutic effects on PD through the regulation of the targets related to anti-inflammation analgesia and central analgesia and relieving smooth muscle contraction.

  4. Synthesis and Characterization of a Magnetically Active 19F Molecular Beacon.

    Science.gov (United States)

    Dempsey, Megan E; Marble, Hetal D; Shen, Tun-Li; Fawzi, Nicolas L; Darling, Eric M

    2018-02-21

    Gene expression is used extensively to describe cellular characteristics and behaviors; however, most methods of assessing gene expression are unsuitable for living samples, requiring destructive processes such as fixation or lysis. Recently, molecular beacons have become a viable tool for live-cell imaging of mRNA molecules in situ. Historically, beacon-mediated imaging has been limited to fluorescence-based approaches. We propose the design and synthesis of a novel molecular beacon for magnetic resonance detection of any desired target nucleotide sequence. The biologically compatible synthesis incorporates commonly used bioconjugation reactions in aqueous conditions and is accessible for laboratories without extensive synthesis capabilities. The resulting beacon uses fluorine ( 19 F) as a reporter, which is broadened, or turned "off", via paramagnetic relaxation enhancement from a stabilized nitroxide radical spin label when the beacon is not bound to its nucleic acid target. Therefore, the 19 F NMR signal of the beacon is quenched in its hairpin conformation when the spin label and the 19 F substituent are held in proximity, but the signal is recovered upon beacon hybridization to its specific complementary nucleotide sequence by physical separation of the radical from the 19 F reporter. This study establishes a path for magnetic resonance-based assessment of specific mRNA expression, providing new possibilities for applying molecular beacon technology in living systems.

  5. Pharmacological effects and molecular mechanisms of action of a herbal medicine based on Vitex agnus-castus

    Directory of Open Access Journals (Sweden)

    I. V. Vysotskaya

    2017-01-01

    Full Text Available Dyshormonal breast dysplasia is the most frequent pathology encountered by practitioners. The interest of clinicians to these processes is associated with several factors. On the one hand effective treatment, relieves symptoms, ensures the quality of life. On the other hand, mastitis is a risk factor for subsequent malignant tumor. Therefore, timely correction is a variant of primary prevention of breast cancer. The choice of the adequate tactics of conducting such patients from the existing diversity of dosage forms is the key to success. The paper discusses the main molecular mechanisms that are implemented with the use of the drug Mastodynon.

  6. A novel and lethal de novo LQT-3 mutation in a newborn with distinct molecular pharmacology and therapeutic response.

    Directory of Open Access Journals (Sweden)

    John R Bankston

    2007-12-01

    Full Text Available SCN5A encodes the alpha-subunit (Na(v1.5 of the principle Na(+ channel in the human heart. Genetic lesions in SCN5A can cause congenital long QT syndrome (LQTS variant 3 (LQT-3 in adults by disrupting inactivation of the Na(v1.5 channel. Pharmacological targeting of mutation-altered Na(+ channels has proven promising in developing a gene-specific therapeutic strategy to manage specifically this LQTS variant. SCN5A mutations that cause similar channel dysfunction may also contribute to sudden infant death syndrome (SIDS and other arrhythmias in newborns, but the prevalence, impact, and therapeutic management of SCN5A mutations may be distinct in infants compared with adults.Here, in a multidisciplinary approach, we report a de novo SCN5A mutation (F1473C discovered in a newborn presenting with extreme QT prolongation and differential responses to the Na(+ channel blockers flecainide and mexiletine. Our goal was to determine the Na(+ channel phenotype caused by this severe mutation and to determine whether distinct effects of different Na(+ channel blockers on mutant channel activity provide a mechanistic understanding of the distinct therapeutic responsiveness of the mutation carrier. Sequence analysis of the proband revealed the novel missense SCN5A mutation (F1473C and a common variant in KCNH2 (K897T. Patch clamp analysis of HEK 293 cells transiently transfected with wild-type or mutant Na(+ channels revealed significant changes in channel biophysics, all contributing to the proband's phenotype as predicted by in silico modeling. Furthermore, subtle differences in drug action were detected in correcting mutant channel activity that, together with both the known genetic background and age of the patient, contribute to the distinct therapeutic responses observed clinically.The results of our study provide further evidence of the grave vulnerability of newborns to Na(+ channel defects and suggest that both genetic background and age are

  7. [Molecular mechanism of Bupleuri Radix and Scutellariae Radix drug pair for depression based on integrative pharmacology platform of traditional Chinese medicine].

    Science.gov (United States)

    Wang, Jian-Ting; Wang, Shang; Liu, Song-Lin; Wang, Yan-Chun; Li, Jia-Geng; Chen, Yu

    2018-04-01

    Xiaochaihu decoction is a classic prescription of traditional Chinese medicine. Modern research has proved its anti-depression effect. However, its pharmacological mechanism for anti-depression effect is difficult to be unveiled because of the complexity of compound Chinese medicines. Bupleuri Radix and Scutellariae Radix is the core drug pair of Xiaochaihu decoction. In this research, Bupleuri Radix and Scutellariae Radix were analyzed by the integrative pharmacology platform to study its molecular mechanism for anti-depression. One hundred and sixteen active ingredients were predicted, 62 for Bupleuri Radix, mainly including saikosaponins, acids, alcohols, and 54 for Scutellariae Radix, mainly including flavonoids and glycosides. Its anti-depression effect was relevant to 118 core targets, including 22 known disease targets, such as serotonin receptor(HTR2C), activating transcription factor(ATF1, ATF2), δ opioid receptor(OPRD1), μ opioid receptor (OPRM1), κ opioid receptor(OPRK1), inositol monophosphatase(IMPA1), Toll-like receptor 4 (TLR4), histamine H1 receptor(HRH1), neurotrophic factor tyrosine kinase receptor1 (NTRK1), Glycogen synthetase kinase 3β(GSK3β), etc. The antidepressant effect involved positive regulation of transcription from RNA polymerase Ⅱ promoter, transcription factor binding, cytosol, transcriptional regulation of DNA template, enzyme binding, endocrine system, nervous system, neurotrophin signaling pathway, cell growth and death, signal transduction, thyroid hormone signaling pathway and other related biological processes and metabolic pathways. This study provides a scientific evidence for further study of the anti-depression mechanism of this drug pair. Copyright© by the Chinese Pharmaceutical Association.

  8. Molecular and pharmacological characterization of serotonin 5-HT2α and 5-HT7 receptors in the salivary glands of the blowfly Calliphora vicina.

    Science.gov (United States)

    Röser, Claudia; Jordan, Nadine; Balfanz, Sabine; Baumann, Arnd; Walz, Bernd; Baumann, Otto; Blenau, Wolfgang

    2012-01-01

    Secretion in blowfly (Calliphora vicina) salivary glands is stimulated by the biogenic amine serotonin (5-hydroxytryptamine, 5-HT), which activates both inositol 1,4,5-trisphosphate (InsP(3))/Ca(2+) and cyclic adenosine 3',5'-monophosphate (cAMP) signalling pathways in the secretory cells. In order to characterize the signal-inducing 5-HT receptors, we cloned two cDNAs (Cv5-ht2α, Cv5-ht7) that share high similarity with mammalian 5-HT(2) and 5-HT(7) receptor genes, respectively. RT-PCR demonstrated that both receptors are expressed in the salivary glands and brain. Stimulation of Cv5-ht2α-transfected mammalian cells with 5-HT elevates cytosolic [Ca(2+)] in a dose-dependent manner (EC(50) = 24 nM). In Cv5-ht7-transfected cells, 5-HT produces a dose-dependent increase in [cAMP](i) (EC(50) = 4 nM). We studied the pharmacological profile for both receptors. Substances that appear to act as specific ligands of either Cv5-HT(2α) or Cv5-HT(7) in the heterologous expression system were also tested in intact blowfly salivary gland preparations. We observed that 5-methoxytryptamine (100 nM) activates only the Cv5-HT(2α) receptor, 5-carboxamidotryptamine (300 nM) activates only the Cv5-HT(7) receptor, and clozapine (1 µM) antagonizes the effects of 5-HT via Cv5-HT(7) in blowfly salivary glands, providing means for the selective activation of each of the two 5-HT receptor subtypes. This study represents the first comprehensive molecular and pharmacological characterization of two 5-HT receptors in the blowfly and permits the analysis of the physiological role of these receptors, even when co-expressed in cells, and of the modes of interaction between the Ca(2+)- and cAMP-signalling cascades.

  9. Molecular and pharmacological characterization of serotonin 5-HT2α and 5-HT7 receptors in the salivary glands of the blowfly Calliphora vicina.

    Directory of Open Access Journals (Sweden)

    Claudia Röser

    Full Text Available Secretion in blowfly (Calliphora vicina salivary glands is stimulated by the biogenic amine serotonin (5-hydroxytryptamine, 5-HT, which activates both inositol 1,4,5-trisphosphate (InsP(3/Ca(2+ and cyclic adenosine 3',5'-monophosphate (cAMP signalling pathways in the secretory cells. In order to characterize the signal-inducing 5-HT receptors, we cloned two cDNAs (Cv5-ht2α, Cv5-ht7 that share high similarity with mammalian 5-HT(2 and 5-HT(7 receptor genes, respectively. RT-PCR demonstrated that both receptors are expressed in the salivary glands and brain. Stimulation of Cv5-ht2α-transfected mammalian cells with 5-HT elevates cytosolic [Ca(2+] in a dose-dependent manner (EC(50 = 24 nM. In Cv5-ht7-transfected cells, 5-HT produces a dose-dependent increase in [cAMP](i (EC(50 = 4 nM. We studied the pharmacological profile for both receptors. Substances that appear to act as specific ligands of either Cv5-HT(2α or Cv5-HT(7 in the heterologous expression system were also tested in intact blowfly salivary gland preparations. We observed that 5-methoxytryptamine (100 nM activates only the Cv5-HT(2α receptor, 5-carboxamidotryptamine (300 nM activates only the Cv5-HT(7 receptor, and clozapine (1 µM antagonizes the effects of 5-HT via Cv5-HT(7 in blowfly salivary glands, providing means for the selective activation of each of the two 5-HT receptor subtypes. This study represents the first comprehensive molecular and pharmacological characterization of two 5-HT receptors in the blowfly and permits the analysis of the physiological role of these receptors, even when co-expressed in cells, and of the modes of interaction between the Ca(2+- and cAMP-signalling cascades.

  10. Fulleropyrrolidine end-capped molecular wires for molecular electronics--synthesis, spectroscopic, electrochemical, and theoretical characterization

    DEFF Research Database (Denmark)

    Sørensen, Jakob Kryger; Fock, Jeppe; Pedersen, Anders Holmen

    2011-01-01

    In continuation of previous studies showing promising metal-molecule contact properties a variety of C(60) end-capped "molecular wires" for molecular electronics were prepared by variants of the Prato 1,3-dipolar cycloaddition reaction. Either benzene or fluorene was chosen as the central wire...... state. However, the fluorescence of C(60) was quenched by charge transfer from the wire to C(60). Quantum chemical calculations predict and explain the collapse of coherent electronic transmission through one of the fulleropyrrolidine-terminated molecular wires......., and synthetic protocols for derivatives terminated with one or two fullero[c]pyrrolidine "electrode anchoring" groups were developed. An aryl-substituted aziridine could in some cases be employed directly as the azomethine ylide precursor for the Prato reaction without the need of having an electron...

  11. Synthesis and reforming of high molecular-weigth compounds by the utilization of radiation

    International Nuclear Information System (INIS)

    Machi, Sueo

    1976-01-01

    Radiation effects on the synthesis are reforming of high molecular-weight compounds are reviewed. The report is divided into four main parts. The first part deals with the characteristics of the radiation processing. The reaction can be started in a wide range of temperature including very low temperature. Catalysts are unnecessary. The reaction velocity is fast, and the reaction in solid phase can be started uniformly. And the quality of products is well controllable. The second part deals with the synthesis of high molecular-weight compounds by radiation polymerization. Radical polymerization and ionizing polymerization, gas phase and liquid phase polymerization, the polymerization and copolymerization of fluorine-containing monomers, and solid phase polymerization and low temperature polymerization are included in this part. Attention is directed to the continuous production system for the radiation polymerization of ethylene developed by Japan Atomic Energy Research Institute. The third part deals with the reforming of high molecular-weight compounds by radiation graft polymerization. The combination of backbone polymers and monomers for reforming plastics and fibers, the membranes for reverse osmosis, porous membranes, and ion exchange membranes are included. The fourth part deals with the reforming of high molecular-weight compounds by the cross-linking. Polyethylene, PVC, ethyl acrylate copolymer and the like are included. (Iwakiri, K.)

  12. Pharmacological Profile of Quinoxalinone

    Directory of Open Access Journals (Sweden)

    Youssef Ramli

    2014-01-01

    Full Text Available Quinoxalinone and its derivatives are used in organic synthesis for building natural and designed synthetic compounds and they have been frequently utilized as suitable skeletons for the design of biologically active compound. This review covers updated information on the most active quinoxalinone derivatives that have been reported to show considerable pharmacological actions such as antimicrobial, anti-inflammatory, antidiabetic, antiviral, antitumor, and antitubercular activity. It can act as an important tool for chemists to develop newer quinoxalinone derivatives that may prove to be better agents in terms of efficacy and safety.

  13. Synthesis and Studies of Sulfur-Containing Heterocyclic Molecules for Molecular Electronics

    DEFF Research Database (Denmark)

    Mazzanti, Virginia

    This work describes the synthesis and studies of sulfur containing π conjugated heterocycles, which are considered interesting motifs in the field of molecular electronics. The first project, which is covered in Chapter 1, concerns the functionalization of tetracycle dibenzo[bc,fg][1,4]dithiapent......This work describes the synthesis and studies of sulfur containing π conjugated heterocycles, which are considered interesting motifs in the field of molecular electronics. The first project, which is covered in Chapter 1, concerns the functionalization of tetracycle dibenzo[bc,fg][1......,4]dithiapentalene (DDP). Attempts to prepare the S-O analog are also discussed. Chapter 2, focuses upon the studies performed on DDP and other sulfur containing π conjugated organic molecules. Organic Field Effect Transistor devices were fabricated and their performances were evaluated. Chapter 3 entails...... the synthesis of dimeric structures of redox active system tetrathiafulvalene (TTF). Molecules with different conjugation pathways bridging two TTFs were synthesized and studied using CV and DPV in order to probe the electronic interaction between these two redox units. The last aspect of this thesis, which...

  14. Molecular genetic and molecular evolutionary studies on the bacteriochlorophyll synthesis genes of Rhodobacter capsulatus

    Energy Technology Data Exchange (ETDEWEB)

    Burke-Agueero, D.H.

    1992-08-01

    Rhodobacter capsulatus, purple bacterium capable of either aerobic or photosynthetic growth, has proven to be very useful in genetic studies of photosynthesis. Forty-four genes clustered together within a 46 kilobase region are required to establish photosynthetic ability in R. capsulatus. Approximately twenty of these genes are involved in bacteriochlorophyll synthesis of which eight bch'' genes are the subject of this thesis. Six of these genes were found to code for the two ring reductases. The first converts protochlorophyllide (PChlide) into a chlorin, the immediate precursor to chlorophyll a, and then into a bacteriochlorin. Each reductase is shown to be made up of three subunits. PChlide reductase is coded by the genes bchN, bchB, and bchL. Proteins with amino acid sequences markedly similar to those of bchN and bchL have been shown in other organisms to be required for chlorophyll synthesis; hence, their designation as chlN and chlB. A third chloroplast-encoded gene of heretofore unknown function shares amino acid identities with bchB and is probably the third subunit of the plant PChlide reductase. The bchA locus, which encodes the chlorin reductase, is found to be made up of three separate, translationally coupled genes, referred to as bchX, bchY, and bchZ. Amino acid similarities between bchX, bchL, and the nitrogenase reductase protein nifH suggest that all three classes of proteins share certain three-dimensional structural features, including elements that are central to the enzymatic mechanism of nifH. PChlide reductase and chlorin reductase are clearly derived from a common ancestor. Several lines of analysis suggests the ancestor of both enzyme systems reduced PChlide twice to produce bacteriochlorophyll supporting the concept bacteriochlorophyll as the ancestral reaction center pigment.

  15. Molecular genetic and molecular evolutionary studies on the bacteriochlorophyll synthesis genes of Rhodobacter capsulatus

    Energy Technology Data Exchange (ETDEWEB)

    Burke-Agueero, Donald H. [Univ. of California, Berkeley, CA (United States)

    1992-08-01

    Rhodobacter capsulatus, purple bacterium capable of either aerobic or photosynthetic growth, has proven to be very useful in genetic studies of photosynthesis. Forty-four genes clustered together within a 46 kilobase region are required to establish photosynthetic ability in R. capsulatus. Approximately twenty of these genes are involved in bacteriochlorophyll synthesis of which eight ``bch`` genes are the subject of this thesis. Six of these genes were found to code for the two ring reductases. The first converts protochlorophyllide (PChlide) into a chlorin, the immediate precursor to chlorophyll a, and then into a bacteriochlorin. Each reductase is shown to be made up of three subunits. PChlide reductase is coded by the genes bchN, bchB, and bchL. Proteins with amino acid sequences markedly similar to those of bchN and bchL have been shown in other organisms to be required for chlorophyll synthesis; hence, their designation as chlN and chlB. A third chloroplast-encoded gene of heretofore unknown function shares amino acid identities with bchB and is probably the third subunit of the plant PChlide reductase. The bchA locus, which encodes the chlorin reductase, is found to be made up of three separate, translationally coupled genes, referred to as bchX, bchY, and bchZ. Amino acid similarities between bchX, bchL, and the nitrogenase reductase protein nifH suggest that all three classes of proteins share certain three-dimensional structural features, including elements that are central to the enzymatic mechanism of nifH. PChlide reductase and chlorin reductase are clearly derived from a common ancestor. Several lines of analysis suggests the ancestor of both enzyme systems reduced PChlide twice to produce bacteriochlorophyll supporting the concept bacteriochlorophyll as the ancestral reaction center pigment.

  16. New 1,2,4-triazine bearing compounds: molecular modeling, synthesis and biotesting

    Directory of Open Access Journals (Sweden)

    Negrutska V. V.

    2009-12-01

    Full Text Available Aim. To enlarge a spectrum of biologically active compounds in the series of the 1,2,4-triazino[5,6-b] [1,4]benzothiazine (1,2,4-TBT derivatives and reveal among them efficient inhibitors of RNA synthesis Methods. The methods of structure optimization of the 3-oxo-1,2,4-TBT by fragment-oriented substitution, the molecular doking of new structures in a virtual target, the rational chemical synthesis of the theoretically predicted compounds and their testing in the system of transcription in vitro. Results. The series of 1,2,4-TBT derivatives with substituents in the benzene and triazine cycles of a base molecule were synthesized. The testing of synthesized compounds in the in vitro transcription system directed by T7 RNA polymerase revealed the structure- and concentration-dependent inhibition of the RNA synthesis by some of these compounds. The experimental and virtual screening data for all investigated compounds have a good correlation. It was found that most effective derivative is the 3-oxo-8-butyl-1,2,4-TBT which completely inhibited transcription at the concentration of 6 mg/ml. Conclusions. The biotesting results allow us to assume that the inhibition of RNA synthesis is caused by binding of the 3-oxo- 8-butyl-1,2,4-TBT to both free RNA polymerase molecules and those including in a transcriptional complex with DNA

  17. The Experiences of and Attitudes toward Non-Pharmacological Interventions for Attention-Deficit/hyperactivity Disorder Used in School Settings: A Systematic Review and Synthesis of Qualitative Research

    Science.gov (United States)

    Moore, Darren A.; Gwernan-Jones, Ruth; Richardson, Michelle; Racey, Daniel; Rogers, Morwenna; Stein, Ken; Thompson-Coon, Jo; Ford, Tamsin J.; Garside, Ruth

    2016-01-01

    School-based non-pharmacological interventions are an important part of the treatment of attention-deficit/hyperactivity disorder (ADHD). We aimed to systematically review qualitative literature relating to the experience of and attitudes towards school-based non-pharmacological interventions for ADHD. Systematic searches of 20 electronic…

  18. Synthesis, pharmacology and molecular docking on multifunctional tacrine-ferulic acid hybrids as cholinesterase inhibitors against Alzheimer's disease.

    Science.gov (United States)

    Zhu, Jie; Yang, Hongyu; Chen, Yao; Lin, Hongzhi; Li, Qi; Mo, Jun; Bian, Yaoyao; Pei, Yuqiong; Sun, Haopeng

    2018-12-01

    The cholinergic hypothesis has long been a "polar star" in drug discovery for Alzheimer's disease (AD), resulting in many small molecules and biological drug candidates. Most of the drugs marketed for AD are cholinergic. Herein, we report our efforts in the discovery of cholinesterases inhibitors (ChEIs) as multi-target-directed ligands. A series of tacrine-ferulic acid hybrids have been designed and synthesised. All these compounds showed potent acetyl-(AChE) and butyryl cholinesterase(BuChE) inhibition. Among them, the optimal compound 10g, was the most potent inhibitor against AChE (electrophorus electricus (eeAChE) half maximal inhibitory concentration (IC 50 ) = 37.02 nM), it was also a strong inhibitor against BuChE (equine serum (eqBuChE) IC 50  = 101.40 nM). Besides, it inhibited amyloid β-protein self-aggregation by 65.49% at 25 μM. In subsequent in vivo scopolamine-induced AD models, compound 10g obviously ameliorated the cognition impairment and showed preliminary safety in hepatotoxicity evaluation. These data suggest compound 10g as a promising multifunctional agent in the drug discovery process against AD.

  19. Optimality principle for the coupled chemical reactions of ATP synthesis and its molecular interpretation

    Science.gov (United States)

    Nath, Sunil

    2018-05-01

    Metabolic energy obtained from the coupled chemical reactions of oxidative phosphorylation (OX PHOS) is harnessed in the form of ATP by cells. We experimentally measured thermodynamic forces and fluxes during ATP synthesis, and calculated the thermodynamic efficiency, η and the rate of free energy dissipation, Φ. We show that the OX PHOS system is tuned such that the coupled nonequilibrium processes operate at optimal η. This state does not coincide with the state of minimum Φ but is compatible with maximum Φ under the imposed constraints. Conditions that must hold for species concentration in order to satisfy the principle of optimal efficiency are derived analytically and a molecular explanation based on Nath's torsional mechanism of energy transduction and ATP synthesis is suggested. Differences of the proposed principle with Prigogine's principle are discussed.

  20. Molecular cloning and expression of Corynebacterium glutamicum genes for amino acid synthesis in Escherichia coli cells

    International Nuclear Information System (INIS)

    Beskrovnaya, O.Yu.; Fonshtein, M.Yu.; Kolibaba, L.G.; Yankovskii, N.K.; Debabov, V.G.

    1989-01-01

    Molecular cloning of Corynebacterium glutamicum genes for threonine and lysine synthesis has been done in Escherichia coli cells. The clonal library of EcoRI fragments of chromosomal DNA of C. glutamicum was constructed on the plasmid vector λpSL5. The genes for threonine and lysine synthesis were identified by complementation of E. coli mutations in thrB and lysA genes, respectively. Recombinant plasmids, isolated from independent ThrB + clone have a common 4.1-kb long EcoRI DNA fragment. Hybrid plasmids isolated from LysA + transductants of E. coli have common 2.2 and 3.3 kb long EcoRI fragments of C. glutamicum DNA. The hybrid plasmids consistently transduced the markers thrB + and lysA + . The Southern hybridization analysis showed that the cloned DNA fragments hybridized with the fragments of identical length in C. glutamicum chromosomes

  1. Optimisation of the synthesis of vancomycin-selective molecularly imprinted polymer nanoparticles using automatic photoreactor

    Science.gov (United States)

    Muzyka, Kateryna; Karim, Khalku; Guerreiro, Antonio; Poma, Alessandro; Piletsky, Sergey

    2014-03-01

    A novel optimized protocol for solid-state synthesis of molecularly imprinted polymer nanoparticles (nanoMIPs) with specificity for antibiotic vancomycin is described. The experimental objective was optimization of the synthesis parameters (factors) affecting the yield of obtained nanoparticles which have been synthesized using the first prototype of an automated solid-phase synthesizer. Applications of experimental design (or design of experiments) in optimization of nanoMIP yield were carried out using MODDE 9.0 software. The factors chosen in the model were the amount of functional monomers in the polymerization mixture, irradiation time, temperature during polymerization, and elution temperature. In general, it could be concluded that the irradiation time is the most important and the temperature was the least important factor which influences the yield of nanoparticles. Overall, the response surface methodology proved to be an effective tool in reducing time required for optimization of complex experimental conditions.

  2. Photocatalytic Properties of Nb/MCM-41 Molecular Sieves: Effect of the Synthesis Conditions

    Directory of Open Access Journals (Sweden)

    Caterine Daza Gomez

    2015-08-01

    Full Text Available The effect of synthesis conditions and niobium incorporation levels on the photocatalytic properties of Nb/MCM-41 molecular sieves was assessed. Niobium pentoxide supported on MCM-41 mesoporous silica was obtained using two methods: sol-gel and incipient impregnation, in each case also varying the percentage of niobium incorporation. The synthesized Nb-MCM-41 ceramic powders were characterized using the spectroscopic techniques of infrared spectroscopy (IR, Raman spectroscopy, X-ray diffraction (XRD, and transmission electron microscopy (TEM. The photodegradation capacity of the powders was studied using the organic molecule, methylene blue. The effect of both the method of synthesis and the percentage of niobium present in the sample on the photodegradation action of the solids was determined. The mesoporous Nb-MCM-41 that produced the greatest photodegradation response was obtained using the sol-gel method and 20% niobium incorporation.

  3. Tin-Assisted Synthesis of ɛ -Ga2O3 by Molecular Beam Epitaxy

    Science.gov (United States)

    Kracht, M.; Karg, A.; Schörmann, J.; Weinhold, M.; Zink, D.; Michel, F.; Rohnke, M.; Schowalter, M.; Gerken, B.; Rosenauer, A.; Klar, P. J.; Janek, J.; Eickhoff, M.

    2017-11-01

    The synthesis of ɛ -Ga2O3 and β -Ga2O3 by plasma-assisted molecular beam epitaxy on (001 )Al2O3 substrates is studied. The growth window of β -Ga2O3 in the Ga-rich regime, usually limited by the formation of volatile gallium suboxide, is expanded due to the presence of tin during the growth process, which stabilizes the formation of gallium oxides. X-ray diffraction, transmission electron microscopy, time-of-flight secondary-ion mass spectrometry, Raman spectroscopy, and atomic force microscopy are used to analyze the influence of tin on the layer formation. We demonstrate that it allows the synthesis of phase-pure ɛ -Ga2O3 . A growth model based on the oxidation of gallium suboxide by reduction of an intermediate sacrificial tin oxide is suggested.

  4. Ordered molecular arrays as templates: A new approach to synthesis of mesoporous materials

    Science.gov (United States)

    Behrens, P.; Stucky, G.

    There has been a growing interest in the extension of the microporous molecular sieve synthesis and applications to mesoscopic dimensions. Typical areas for the application of mesoscopic zeolite-type structures are in separation (e.g., protein separation and selective adsorption of large organic molecules from waste waters) and catalysis (e.g., processing of tar sand and of the high distillates of crude oils to valuable low-boiling products). Another is in the supramolecular assembly of molecular array and polymers for electronic and optical applications. In a new concept in the synthesis of porous material the templating agent is no longer a single, solvated, organic molecule or metal ion, but rather a self-assembled molecular array. This template leads to mesoporous materials with adjustable pore sizes between 16 and greater than 100 Angstrom, covering well the mesophorous range of greatest interest. The periodic arrangement of pores is very regular, and the pore size distribution measured by absorption is nearly as sharp as that of conventional zeolites.

  5. Control of molecular weight distribution in synthesis of poly(2-hydroxyethyl methacrylate) using ultrasonic irradiation.

    Science.gov (United States)

    Kubo, Masaki; Kondo, Takayuki; Matsui, Hideki; Shibasaki-Kitakawa, Naomi; Yonemoto, Toshikuni

    2018-01-01

    Poly(2-hydroxyethyl methacrylate) (PHEMA) was synthesized using ultrasonic irradiation without any chemical initiator. The effect of the ultrasonic power intensity on the time course of the conversion to polymer, the number average molecular weight, and the polydispersity were investigated in order to synthesize a polymer with a low molecular weight distribution (i.e., low polydispersity). The conversion to polymer increased with time. A higher ultrasonic power intensity resulted in a faster reaction rate. The number average molecular weight increased during the early stage of the reaction and then gradually decreased with time. A higher ultrasonic intensity resulted in a faster degradation rate of the polymer. The polydispersity decreased with time. This was because the degradation rate of a polymer with a higher molecular weight was faster than that of a polymer with a lower molecular weight. A polydispersity below 1.3 was obtained under ultrasonic irradiation. By changing the ultrasonic power intensity during the reaction, the number average molecular weight can be controlled while maintaining low polydispersity. When the ultrasonic irradiation was halted, the reactions stopped and the number average molecular weight and polydispersity did not change. On the basis of the experimental results, a kinetic model for synthesis of PHEMA under ultrasonic irradiation was constructed considering both polymerization and polymer degradation. The kinetic model was in good agreement with the experimental results for the time courses of the conversion to polymer, the number average molecular weight, and the polydispersity for various ultrasonic power intensities. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. [Pharmacological treatment].

    Science.gov (United States)

    Arriola Manchola, Enrique; Álaba Trueba, Javier

    2016-06-01

    Alzheimer's disease (AD) is a chronic degenerative and inflammatory process leading to synapticdysfunction and neuronal death. A review about the pharmacological treatment alternatives is made: acetylcholinesterase inhibitors (AChEI), a nutritional supplement (Souvenaid) and Ginkgo biloba. A special emphasis on Ginkgo biloba due to the controversy about its use and the approval by the European Medicines Agency is made. Copyright © 2016 Sociedad Española de Geriatría y Gerontología. Publicado por Elsevier España, S.L.U. All rights reserved.

  7. Synthesis of mesoporous SAPO-34 molecular sieves and their applications in dehydration of butanols and ethanol.

    Science.gov (United States)

    Jun, Jong Won; Jeon, Jaewoo; Kim, Chul-Ung; Jeong, Kwang-Eun; Jeong, Soon-Yong; Jhung, Sung Hwa

    2013-04-01

    Microporous SAPO-34 molecular sieves were hydrothermally synthesized with microwave irradiation in the presence of tetraethylammonium hydroxide (TEAOH) as a template. SAPO-34 molecular sieves with mesoporosity were also prepared in the presence of carbon black as a hard template. By increasing the content of the carbon black template in the synthesis, the mesopore volume increased. Dehydration of alcohols (butanols and ethanol) was carried out with the synthesized SAPO-34 molecular sieves, and the lifetime of the catalysts for the dehydration reaction increased as the mesoporosity increased. Moreover, the performance of the microporous catalyst synthesized with microwave was better than that of the catalyst obtained with conventional electric heating. The relative performance of the catalytic dehydration may be explained by the mesoporosity and the crystal size. Therefore, it may be concluded that small-sized SAPO-34 molecular sieves with high mesoporosity can be produced efficiently with microwave irradiation in the presence of carbon black template, and the molecular sieves are effective in the stable dehydration of alcohols.

  8. Biologic activities of molecular chaperones and pharmacologic chaperone imidazole-containing dipeptide-based compounds: natural skin care help and the ultimate challenge: implication for adaptive responses in the skin.

    Science.gov (United States)

    Babizhayev, Mark A; Nikolayev, Gennady M; Nikolayeva, Juliana G; Yegorov, Yegor E

    2012-03-01

    Accumulation of molecular damage and increased molecular heterogeneity are hallmarks of photoaged skin and pathogenesis of human cutaneous disease. Growing evidence demonstrates the ability of molecular chaperone proteins and of pharmacologic chaperones to decrease the environmental stress and ameliorate the oxidation stress-related and glycation disease phenotypes, suggesting that the field of chaperone therapy might hold novel treatments for skin diseases and aging. In this review, we examine the evidence suggesting a role for molecular chaperone proteins in the skin and their inducer and protecting agents: pharmacologic chaperone imidazole dipeptide-based agents (carcinine and related compounds) in cosmetics and dermatology. Furthermore, we discuss the use of chaperone therapy for the treatment of skin photoaging diseases and other skin pathologies that have a component of increased glycation and/or free radical-induced oxidation in their genesis. We examine biologic activities of molecular and pharmacologic chaperones, including strategies for identifying potential chaperone compounds and for experimentally demonstrating chaperone activity in in vitro and in vivo models of human skin disease. This allows the protein to function and traffic to the appropriate location in the skin, thereby increasing protein activity and cellular function and reducing stress on skin cells. The benefits of imidazole dipeptide antioxidants with transglycating activity (such as carcinine) in skin care are that they help protect and repair cell membrane damage and help retain youthful, younger-looking skin. All skin types will benefit from daily, topical application of pharmacologic chaperone antioxidants, anti-irritants, in combination with water-binding protein agents that work to mimic the structure and function of healthy skin. General strategies are presented addressing ground techniques to improve absorption of usually active chaperone proteins and dipeptide compounds, include

  9. Synthesis and Molecular Modeling of Thermally Stable DNA G-Quadruplexes with Anthraquinone Insertions

    DEFF Research Database (Denmark)

    Gouda, Alaa S.; Amine, Mahasen S.; Pedersen, Erik Bjerregaard

    2017-01-01

    Two new phosphoramidite building blocks for DNA synthesis were synthesized from 1,5- and 2,6-dihydroxyanthraquinones through alkylation with 3-bromo-1-propanol followed by DMT-protection. The novel synthesized 1,5- and 2,6-disubstituted anthraquinone monomers H15 and H26 are incorporated into a G...... anthraquinone-modified quadruplexes revealed no change of the antiparallel structure when compared with the wild type under potassium buffer conditions. The significantly increased thermostabilities were interpreted by molecular modeling of anthraquinone-modified G-quadruplexes....

  10. "Intelligent" design of molecular materials: Understanding the concepts of design in supramolecular synthesis of network solids

    Science.gov (United States)

    Moulton, Brian D.

    This work endeavors to delineate modern paradigms for crystal engineering, i.e. the design and supramolecular synthesis of functional molecular materials. Paradigms predicated on an understanding of the geometry of polygons and polyhedra are developed. The primary focus is on structural determination by single crystal X-ray crystallography, structural interpretation using a suite of graphical visualization and molecular modeling software, and on the importance of proper graphical representation in the presentation and explanation of crystal structures. A detailed analysis of a selected series of crystal structures is presented. The reduction of these molecular networks to schematic representations that illustrate their fundamental connectivity facilitates the understanding of otherwise complex supramolecular solids. Circuit symbols and Schlafli notation are used to describe the network topologies, which enables networks of different composition and metrics to be easily compared. This reveals that molecular orientations in the crystals and networks are commensurate with networks that can be derived from spherical close packed lattices. The development of a logical design strategy for a new class of materials based on our understanding of the chemical composition and topology of these networks is described. The synthesis and crystal structure of a series of new materials generated by exploitation of this design strategy is presented, in addition to a detailed analysis of the topology of these materials and their relationship to a 'parent' structure. In summary, this dissertation demonstrates that molecular polygons can self-assemble at their vertexes to produce molecular architectures and crystal structures that are consistent with long established geometric dogma. The design strategy represents a potentially broad ranging approach to the design of nanoporous structures from a wide range of chemical components that are based on molecular shape rather than chemical

  11. Novel multi-targeted agents for Alzheimer's disease: Synthesis, biological evaluation, and molecular modeling of novel 2-[4-(4-substitutedpiperazin-1-yl)phenyl]benzimidazoles.

    Science.gov (United States)

    Ozadali-Sari, Keriman; Tüylü Küçükkılınç, Tuba; Ayazgok, Beyza; Balkan, Ayla; Unsal-Tan, Oya

    2017-06-01

    The present study describes the synthesis, pharmacological evaluation (BChE/AChE inhibition, Aβ antiaggregation, and neuroprotective effects), and molecular modeling studies of novel 2-[4-(4-substitutedpiperazin-1-yl)phenyl]benzimidazole derivatives. The alkyl-substituted derivatives exhibited selective inhibition on BChE with varying efficiency. Compounds 3b and 3d were found to be the most potent inhibitors of BChE with IC 50 values of 5.18 and 5.22μM, respectively. The kinetic studies revealed that 3b is a partial non-competitive BChE inhibitor. Molecular modeling studies also showed that the alkyl-substituted derivatives were able to reach the catalytic anionic site of the BChE. The compounds with an inhibitory effect on BChE were subsequently screened for their Aβ antiaggregating and neuroprotective activities. Compounds 3a and 3b exerted a potential neuroprotective effect against H 2 O 2 and Aβ-induced cytotoxicity in SH-SY5Y cells. Collectively, 3b was found as the most promising compound for the development of multi-target directed ligands against Alzheimer's disease. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Eco-friendly synthesis, physicochemical studies, biological assay and molecular docking of steroidal oxime-ethers

    Science.gov (United States)

    Alam, Mahboob; Lee, Dong-Ung

    2015-01-01

    The aim of this study was to report the synthesis of biologically active compounds; 7-(2′-aminoethoxyimino)-cholest-5-ene (4), a steroidal oxime-ether and its derivatives (5, 6) via a facile microwave assisted solvent free reaction methodology. This new synthetic, eco-friendly, sustainable protocol resulted in a remarkable improvement in the synthetic efficiency (85-93 % yield) and high purity using basic alumina. The synthesized compounds were screened for their antibacterial against six bacterial strains by disc diffusion method and antioxidant potential by DPPH assay. The binding capabilities of a compound 6 exhibiting good antibacterial potential were assessed on the basis of molecular docking studies and four types of three-dimensional molecular field descriptors. Moreover the structure-antimicrobial activity relationships were studied using some physicochemical and quantum-chemical parameters with GAMESS interface as well as WebMO Job Manager by using the basic level of theory. Hence, this synthetic approach is believed to provide a better scope for the synthesis of steroidal oxime-ether analogues and will be a more practical alternative to the presently existing procedures. Moreover, detailed in silico docking studies suggested the plausible mechanism of steroidal oxime-ethers as effective antimicrobial agents. PMID:27330525

  13. Solid-Phase Synthesis of Molecularly Imprinted Polymer Nanoparticles with a Reusable Template - "Plastic Antibodies".

    Science.gov (United States)

    Poma, Alessandro; Guerreiro, Antonio; Whitcombe, Michael J; Piletska, Elena V; Turner, Anthony P F; Piletsky, Sergey A

    2013-06-13

    Molecularly Imprinted Polymers (MIPs) are generic alternatives to antibodies in sensors, diagnostics and separations. To displace biomolecules without radical changes in infrastructure in device manufacture, MIPs should share their characteristics (solubility, size, specificity and affinity, localized binding domain) whilst maintaining the advantages of MIPs (low-cost, short development time and high stability) hence the interest in MIP nanoparticles. Herein we report a reusable solid-phase template approach (fully compatible with automation) for the synthesis of MIP nanoparticles and their precise manufacture using a prototype automated UV photochemical reactor. Batches of nanoparticles (30-400 nm) with narrow size distributions imprinted with: melamine (d = 60 nm, K d = 6.3 × 10 -8 m), vancomycin (d = 250 nm, K d = 3.4 × 10 -9 m), a peptide (d = 350 nm, K d = 4.8 × 10 -8 m) and proteins have been produced. Our instrument uses a column packed with glass beads, bearing the template. Process parameters are under computer control, requiring minimal manual intervention. For the first time we demonstrate the reliable re-use of molecular templates in the synthesis of MIPs (≥ 30 batches of nanoMIPs without loss of performance). NanoMIPs are produced template-free and the solid-phase acts both as template and affinity separation medium.

  14. Synthesis and Guest Recognition of Switchable Pt-Salphen Based Molecular Tweezers

    Directory of Open Access Journals (Sweden)

    Lorien Benda

    2018-04-01

    Full Text Available Molecular tweezers are artificial receptors that have an open cavity generated by two recognition units pre-organized by a spacer. Switchable molecular tweezers, using a stimuli-responsive spacer, are particularly appealing as prototypes of the molecular machines that combine mechanical motion and allosteric recognition properties. In this present study, the synthesis of switchable molecular tweezers composed of a central terpyridine unit substituted in 4,4″ positions by two Pt(II-salphen complexes is reported. The terpyridine ligand can be reversibly converted upon Zn(II coordination from a free ‘U’-shaped closed form to a coordinated ‘W’ open form. This new substitution pattern enables a reverse control of the mechanical motion compared to the previously reported 6,6″ substituted terpyridine-based tweezers. Guest binding studies with aromatic guests showed an intercalation of coronene in the cavity created by the Pt-salphen moieties in the closed conformation. The formation of 1:1 host-guest complex was investigated by a combination of NMR studies and DFT calculations.

  15. Estrogen Regulates Protein Synthesis and Actin Polymerization in Hippocampal Neurons through Different Molecular Mechanisms

    Science.gov (United States)

    Briz, Victor; Baudry, Michel

    2014-01-01

    Estrogen rapidly modulates hippocampal synaptic plasticity by activating selective membrane-associated receptors. Reorganization of the actin cytoskeleton and stimulation of mammalian target of rapamycin (mTOR)-mediated protein synthesis are two major events required for the consolidation of hippocampal long-term potentiation and memory. Estradiol regulates synaptic plasticity by interacting with both processes, but the underlying molecular mechanisms are not yet fully understood. Here, we used acute rat hippocampal slices to analyze the mechanisms underlying rapid changes in mTOR activity and actin polymerization elicited by estradiol. Estradiol-induced mTOR phosphorylation was preceded by rapid and transient activation of both extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) and by phosphatase and tensin homolog (PTEN) degradation. These effects were prevented by calpain and ERK inhibitors. Estradiol-induced mTOR stimulation did not require activation of classical estrogen receptors (ER), as specific ERα and ERβ agonists (PPT and DPN, respectively) failed to mimic this effect, and ER antagonists could not block it. Estradiol rapidly activated both RhoA and p21-activated kinase (PAK). Furthermore, a specific inhibitor of RhoA kinase (ROCK), H1152, and a potent and specific PAK inhibitor, PF-3758309, blocked estradiol-induced cofilin phosphorylation and actin polymerization. ER antagonists also blocked these effects of estrogen. Consistently, both PPT and DPN stimulated PAK and cofilin phosphorylation as well as actin polymerization. Finally, the effects of estradiol on actin polymerization were insensitive to protein synthesis inhibitors, but its stimulation of mTOR activity was impaired by latrunculin A, a drug that disrupts actin filaments. Taken together, our results indicate that estradiol regulates local protein synthesis and cytoskeletal reorganization via different molecular mechanisms and signaling pathways. PMID:24611062

  16. Synthesis and pharmacological properties of new antihypertensive compounds, the [(benzodioxan - 1,4,)yl-5]-1 alkylamino-2 ethanols. Synthesis and properties of reversible ligands of central serotoninergic receptors: oxygenated isosteres of hydroxy-8 di-n-propylamino- 3 tetralin

    International Nuclear Information System (INIS)

    Perdicakis, Christine

    1988-01-01

    After some recalls on hypertension and on its various treatments, the first part of this thesis in pharmaceutical sciences addresses the synthesis of new molecules, the [(benzodioxan - 1,4,)yl-5]-1 alkylamino-2 ethanols. The author also explains the choice for this structure, and addresses the pharmacological activity of these molecules. The experimental study notably comprises the study of proton NMR spectra and of mass spectra, percentage analyses, fusion point measurements, and liquid-solid chromatography. Pharmacological tests have been performed on rats and on dogs, and did not completely gave the expected results. Therefore, the second part reports other researches related to the central nervous system with the study of the synthesis of radioactive ligands which allows a better knowledge on central serotoninergic receptors. The author reports the development of a new radio-ligand which selectively labels receptor sites of serotonin in the central nervous system [fr

  17. N-substituted-piperidines as Novel Anti-alzheimer Agents: Synthesis, antioxidant activity, and molecular docking study

    Directory of Open Access Journals (Sweden)

    Khairia M. Youssef

    2018-06-01

    Full Text Available Design, synthesis and evaluation of new acetylcholinesterase inhibitors by combining carbamoylpiperidine analogs containing nipecotic acid scaffold were described. Then, a series of hybrids have been developed by introducing Free radical scavengers. Molecular modeling was performed and structure activity relationships are discussed. Among the series, most potent compounds showed effective AchE inhibitions, high selectivity over butyrylcholinesterase and high radical scavenging activities. On the basis of this work, the ability of analogs containing nipecotic acid scaffold to serve in the design of N-benzyl-piperidine linked multipotent molecules for the treatment of Alzheimer Disease. Keywords: Synthesis, N-substituted-piperidines, Antioxidant activity, ATP chemiluminescence, Molecular modeling study

  18. Pharmacological effects of biotin.

    Science.gov (United States)

    Fernandez-Mejia, Cristina

    2005-07-01

    In the last few decades, more vitamin-mediated effects have been discovered at the level of gene expression. Increasing knowledge on the molecular mechanisms of these vitamins has opened new perspectives that form a connection between nutritional signals and the development of new therapeutic agents. Besides its role as a carboxylase prosthetic group, biotin regulates gene expression and has a wide repertoire of effects on systemic processes. The vitamin regulates genes that are critical in the regulation of intermediary metabolism: Biotin has stimulatory effects on genes whose action favors hypoglycemia (insulin, insulin receptor, pancreatic and hepatic glucokinase); on the contrary, biotin decreases the expression of hepatic phosphoenolpyruvate carboxykinase, a key gluconeogenic enzyme that stimulates glucose production by the liver. The findings that biotin regulates the expression of genes that are critical in the regulation of intermediary metabolism are in agreement with several observations that indicate that biotin supply is involved in glucose and lipid homeostasis. Biotin deficiency has been linked to impaired glucose tolerance and decreased utilization of glucose. On the other hand, the diabetic state appears to be ameliorated by pharmacological doses of biotin. Likewise, pharmacological doses of biotin appear to decrease plasma lipid concentrations and modify lipid metabolism. The effects of biotin on carbohydrate metabolism and the lack of toxic effects of the vitamin at pharmacological doses suggest that biotin could be used in the development of new therapeutics in the treatment of hyperglycemia and hyperlipidemia, an area that we are actively investigating.

  19. Demonstration of extensive GABA synthesis in the small population of GAD positive neurons in cerebellar cultures by the use of pharmacological tools

    DEFF Research Database (Denmark)

    Sonnewald, Ursula; Kortner, Trond M; Qu, Hong

    2006-01-01

    by labeling from [U-(13)C]glutamine added on day 7. Altogether the findings show continuous GABA synthesis and degradation throughout the culture period in the cerebellar neurons. At 10 microM AOAA, GABA synthesis from [U-(13)C]glutamine was not affected, indicating that transaminases are not involved in GABA...... that GABA synthesis is taking place via GAD in a subpopulation of the cerebellar neurons, throughout the culture period....

  20. Conception and synthesis of new molecular cages for xenon MRI applications

    International Nuclear Information System (INIS)

    Delacour, L.

    2011-01-01

    Non-invasive proton magnetic resonance imaging ( 1 H MRI) is a powerful clinical tool for the detection of numerous diseases. Although MRI contrast agents are often used to improve diagnostic specificity, this technique has limited applications in molecular imaging because of its inherently low sensitivity when compared to nuclear medicine or fluorescence imaging. Laser-polarized 129 Xe NMR spectroscopy is a promising tool to circumvent sensitivity limitations. Indeed, optical pumping increases the nuclear spin polarization of xenon by several orders of magnitude (10 4 to 10 5 ), thus small amounts of gas dissolved in biological tissues (blood, lungs...) can be rapidly detected with an excellent signal-to-noise ratio. In addition, the high polarizability of the xenon electron cloud, which induces a very high sensitivity to its environment, makes this nucleus very attractive for molecular imaging. Detection of biomolecules can be achieved by biosensors, which encapsulate xenon atoms in molecular cages that have been functionalized to bind the desired biological target. Cage molecules such as cryptophanes have high affinity for xenon and thus appear as ideal candidates for its encapsulation. During this PhD thesis we worked on the synthesis and the functionalization of new cryptophanes. (author) [fr

  1. New Diethyl Ammonium Salt of Thiobarbituric Acid Derivative: Synthesis, Molecular Structure Investigations and Docking Studies

    Directory of Open Access Journals (Sweden)

    Assem Barakat

    2015-11-01

    Full Text Available The synthesis of the new diethyl ammonium salt of diethylammonium(E-5-(1,5-bis(4-fluorophenyl-3-oxopent-4-en-1-yl-1,3-diethyl-4,6-dioxo-2-thioxohexaydropyrimidin-5-ide 3 via a regioselective Michael addition of N,N-diethylthiobarbituric acid 1 to dienone 2 is described. In 3, the carboanion of the thiobarbituric moiety is stabilized by the strong intramolecular electron delocalization with the adjacent carbonyl groups and so the reaction proceeds without any cyclization. The molecular structure investigations of 3 were determined by single-crystal X-ray diffraction as well as DFT computations. The theoretically calculated (DFT/B3LYP geometry agrees well with the crystallographic data. The effect of fluorine replacement by chlorine atoms on the molecular structure aspects were investigated using DFT methods. Calculated electronic spectra showed a bathochromic shift of the π-π* transition when fluorine is replaced by chlorine. Charge decomposition analyses were performed to study possible interaction between the different fragments in the studied systems. Molecular docking simulations examining the inhibitory nature of the compound show an anti-diabetic activity with Pa (probability of activity value of 0.229.

  2. Synthesis and Antitubercular Activity of Some Novel Thiazolidinone ...

    African Journals Online (AJOL)

    In order to further assess the pharmacological profile of this class of compounds, it was thought worthwhile to synthesize some new congeners of heterocycles by incorporating thiadiazole and thiazolidinone moieties in a single molecular framework. The present work deals with the synthesis of these compounds as well as.

  3. Molecular Expression and Pharmacological Evidence for a Functional Role of Kv7 Channel Subtypes in Guinea Pig Urinary Bladder Smooth Muscle

    Science.gov (United States)

    Afeli, Serge A. Y.; Malysz, John; Petkov, Georgi V.

    2013-01-01

    Voltage-gated Kv7 (KCNQ) channels are emerging as essential regulators of smooth muscle excitability and contractility. However, their physiological role in detrusor smooth muscle (DSM) remains to be elucidated. Here, we explored the molecular expression and function of Kv7 channel subtypes in guinea pig DSM by RT-PCR, qRT-PCR, immunohistochemistry, electrophysiology, and isometric tension recordings. In whole DSM tissue, mRNAs for all Kv7 channel subtypes were detected in a rank order: Kv7.1~Kv7.2Kv7.3~Kv7.5Kv7.4. In contrast, freshly-isolated DSM cells showed mRNA expression of: Kv7.1~Kv7.2Kv7.5Kv7.3~Kv7.4. Immunohistochemical confocal microscopy analyses of DSM, conducted by using co-labeling of Kv7 channel subtype-specific antibodies and α-smooth muscle actin, detected protein expression for all Kv7 channel subtypes, except for the Kv7.4, in DSM cells. L-364373 (R-L3), a Kv7.1 channel activator, and retigabine, a Kv7.2-7.5 channel activator, inhibited spontaneous phasic contractions and the 10-Hz electrical field stimulation (EFS)-induced contractions of DSM isolated strips. Linopiridine and XE991, two pan-Kv7 (effective at Kv7.1-Kv7.5 subtypes) channel inhibitors, had opposite effects increasing DSM spontaneous phasic and 10 Hz EFS-induced contractions. EFS-induced DSM contractions generated by a wide range of stimulation frequencies were decreased by L-364373 (10 µM) or retigabine (10 µM), and increased by XE991 (10 µM). Retigabine (10 µM) induced hyperpolarization and inhibited spontaneous action potentials in freshly-isolated DSM cells. In summary, Kv7 channel subtypes are expressed at mRNA and protein levels in guinea pig DSM cells. Their pharmacological modulation can control DSM contractility and excitability; therefore, Kv7 channel subtypes provide potential novel therapeutic targets for urinary bladder dysfunction. PMID:24073284

  4. Synthesis and molecular characterization of chitosan based polyurethane elastomers using aromatic diisocyanate.

    Science.gov (United States)

    Zia, Khalid Mahmood; Anjum, Sohail; Zuber, Mohammad; Mujahid, Muhammad; Jamil, Tahir

    2014-05-01

    The present research work was performed to synthesize a new series of chitosan based polyurethane elastomers (PUEs) using poly(ɛ-caprolactone) (PCL). The chitosan based PUEs were prepared by step-growth polymerization technique using poly(ɛ-caprolactone) (PCL) and 2,4-toluene diisocyanate (TDI). In the second step the PU prepolymer was extended with different mole ratios of chitosan and 1,4-butane diol (BDO). Molecular engineering was carried out during the synthesis. The conventional spectroscopic characterization of the synthesized samples using FT-IR confirms the existence of the proposed chitosan based PUEs structure. Internal morphology of the prepared PUEs was studied using SEM analysis. The SEM images confirmed the incorporation of chitosan molecules into the PU backbone. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Synthesis, characterization, and catalytic properties of stable mesoporous molecular sieve MCM-41 prepared from zeolite mordenite

    International Nuclear Information System (INIS)

    Wang Shan; Dou Tao; Li Yuping; Zhang Ying; Li Xiaofeng; Yan Zichun

    2004-01-01

    Mesoporous molecular sieves (denoted as M-MCM-41) with ordered hexagonal structure have been successfully synthesized from the assembly of precursors from preformed zeolite Mordenite with CTAB surfactant micelle in alkaline media. The samples were characterized by XRD, N 2 adsorption, IR and DTG. The materials exhibit highly hydrothermal stability, as compared with conventional MCM-41. Characterization results indicate that the mesoporous walls of M-MCM-41 contain the secondary building units similar to those in microporous crystal of zeolite Mordenite. In catalytic dealkylation of C10 + aromatic hydrocarbon, M-MCM-41 shows higher activities in comparison with Mordenite and MCM-41, which would be ascribed to the combination of advantages of both MCM-41 (large pores) and Mordenite (strong acidity). Furthermore, this synthesis strategy could be used as a new general method for the preparation of hydrothermally stable mesoporous aluminosilicate materials under alkaline conditions

  6. Synthesis and analytical applications of molecularly imprinted polymers on the surface of carbon nanotubes: a review

    International Nuclear Information System (INIS)

    Dai, Hao; Xiao, Deli; Li, Hui; Yuan, Danhua; Zhang, Chan; He, Hua

    2015-01-01

    This review (with 142 references) summarize the state of the art in molecularly imprinting technology as applied to the surface of carbon nanotubes (CNTs) which result in so-called CNTs-MIPs. These nanomaterials offer a remedy to the flaws of traditional MIPs, such as poor site accessibility for templates, slow mass transfer and template leakage. They also are flexible in that different materials can be integrated with CNTs. Given the advantages of using CNT-MIPs, this technology has experienced rapid expansion, not the least because CNT-MIPs can be produced at low cost and by a variety of synthetic approaches. We summarize methods of, and recent advances in the synthesis of CNT-MIPs, and then highlight some representative applications. We also comment on their potential future developments and research directions. (author)

  7. Molecular hijacking of siroheme for the synthesis of heme and d1 heme.

    Science.gov (United States)

    Bali, Shilpa; Lawrence, Andrew D; Lobo, Susana A; Saraiva, Lígia M; Golding, Bernard T; Palmer, David J; Howard, Mark J; Ferguson, Stuart J; Warren, Martin J

    2011-11-08

    Modified tetrapyrroles such as chlorophyll, heme, siroheme, vitamin B(12), coenzyme F(430), and heme d(1) underpin a wide range of essential biological functions in all domains of life, and it is therefore surprising that the syntheses of many of these life pigments remain poorly understood. It is known that the construction of the central molecular framework of modified tetrapyrroles is mediated via a common, core pathway. Herein a further branch of the modified tetrapyrrole biosynthesis pathway is described in denitrifying and sulfate-reducing bacteria as well as the Archaea. This process entails the hijacking of siroheme, the prosthetic group of sulfite and nitrite reductase, and its processing into heme and d(1) heme. The initial step in these transformations involves the decarboxylation of siroheme to give didecarboxysiroheme. For d(1) heme synthesis this intermediate has to undergo the replacement of two propionate side chains with oxygen functionalities and the introduction of a double bond into a further peripheral side chain. For heme synthesis didecarboxysiroheme is converted into Fe-coproporphyrin by oxidative loss of two acetic acid side chains. Fe-coproporphyrin is then transformed into heme by the oxidative decarboxylation of two propionate side chains. The mechanisms of these reactions are discussed and the evolutionary significance of another role for siroheme is examined.

  8. Molecular Design of Bioinspired Nanostructures for Biomedical Applications: Synthesis, Self-Assembly and Functional Properties

    Science.gov (United States)

    Xu, Hesheng Victor; Zheng, Xin Ting; Mok, Beverly Yin Leng; Ibrahim, Salwa Ali; Yu, Yong; Tan, Yen Nee

    2016-08-01

    Biomolecules are the nanoscale building blocks of cells, which play multifaceted roles in the critical biological processes such as biomineralization in a living organism. In these processes, the biological molecules such as protein and nucleic acids use their exclusive biorecognition properties enabled from their unique chemical composition, shape and function to initiate a cascade of cellular events. The exceptional features of these biomolecules, coupled with the recent advancement in nanotechnology, have led to the emergence of a new research field that focuses on the molecular design of bioinspired nanostructures that inherit the extraordinary function of natural biomaterials. These “bioinspired” nanostructures could be formulated by biomimetic approaches through either self-assembling of biomolecules or acting as a biomolecular template/precursor to direct the synthesis of nanocomposite. In either situation, the resulting nanomaterials exhibit phenomenal biocompatibility, superb aqueous solubility and excellent colloidal stability, branding them exceptionally desirable for both in vitro and in vivo biomedical applications. In this review, we will present the recent developments in the preparation of “bioinspired” nanostructures through biomimetic self-assembly and biotemplating synthesis, as well as highlight their functional properties and potential applications in biomedical diagnostics and therapeutic delivery. Lastly, we will conclude this topic with some personal perspective on the challenges and future outlooks of the “bioinspired” nanostructures for nanomedicine.

  9. Molecular dynamics investigations of BioH protein substrate specificity for biotin synthesis.

    Science.gov (United States)

    Xue, Qiao; Cui, Ying-Lu; Zheng, Qing-Chuan; Zhang, Hong-Xing

    2016-05-01

    BioH, an enzyme of biotin synthesis, plays an important role in fatty acid synthesis which assembles the pimelate moiety. Pimeloyl-acyl carrier protein (ACP) methyl ester, which is long known to be a biotin precursor, is the physiological substrate of BioH. Azelayl methyl ester, which has a longer chain than pimeloyl methyl ester, conjugated to ACP is also indeed accepted by BioH with very low rate of hydrolysis. To date, the substrate specificity for BioH and the molecular origin for the experimentally observed rate changes of hydrolysis by the chain elongation have remained elusive. To this end, we have investigated chain elongation effects on the structures by using the fully atomistic molecular dynamics simulations combined with binding free energy calculations. The results indicate that the substrate specificity is determined by BioH together with ACP. The added two methylenes would increase the structural flexibility by protein motions at the interface of ACP and BioH, instead of making steric clashes with the side chains of the BioH hydrophobic cavity. On the other hand, the slower hydrolysis of azelayl substrate is suggested to be associated with the loose of contacts between BioH and ACP, and with the lost electrostatic interactions of two ionic/hydrogen bonding networks at the interface of the two proteins. The present study provides important insights into the structure-function relationships of the complex of BioH with pimeloyl-ACP methyl ester, which could contribute to further understanding about the mechanism of the biotin synthetic pathway, including the catalytic role of BioH.

  10. Molecular structure design and soft template synthesis of aza-, oxaaza- and thiaazamacrocyclic metal chelates in the gelatin matrix

    Directory of Open Access Journals (Sweden)

    Oleg V. Mikhailov

    2017-01-01

    Full Text Available The data about of soft template synthesis proceeding in gelatin matrices in [3d-element M(II ion – (N,S- or (N,O,S-ambidentate ligson – mono- or dicarbonyl ligson] systems, have been considered and discussed. The chemical nature of the final products of template synthesis formed under these specific conditions, has been compared with the chemical nature of the final products formed by template synthesis in solutions. It has been noted that in many cases, the nature and chemical composition of these products differ substantially. Specific features of the DFT calculated molecular structures of the macrocyclic compounds that can be formed due to the template synthesis in the systems indicated above, have been discussed, too. The review covers the period 1990–2015.

  11. Synthesis, characterization, molecular docking and in vitro antimalarial properties of new carboxamides bearing sulphonamide.

    Science.gov (United States)

    Ugwu, D I; Okoro, U C; Ukoha, P O; Okafor, S; Ibezim, A; Kumar, N M

    2017-07-28

    Sulphonamides and carboxamides have shown large number of pharmacological properties against different types of diseases among which is malaria. Twenty four new carboxamide derivatives bearing benzenesulphonamoyl alkanamides were synthesized and investigated for their in silico and in vitro antimalarial and antioxidant properties. The substituted benzenesulphonyl chlorides (1a-c) were treated with various amino acids (2a-h) to obtain the benzenesulphonamoyl alkanamides (3a-x) which were subsequently treated with benzoyl chloride to obtain the N-benzoylated derivatives (5a-f, i-n and q-v). Further reactions of the N-benzoylated derivatives or proline derivatives with 4-aminoacetophenone (6) using boric acid as a catalyst gave the sulphonamide carboxamide derivatives (7a-x) in excellent yields. The in vitro antimalarial studies showed that all synthesized compounds had antimalarial property. Compound 7k, 7c, 7l, 7s, and 7j had mean MIC value of 0.02, 0.03, 0.05, 0.06 and 0.08 μM respectively comparable with chloroquine 0.06 μM. Compound 7c was the most potent antioxidant agent with IC 50 value of 0.045 mM comparable with 0.34 mM for ascorbic acid. In addition to the successful synthesis of the target molecules using boric acid catalysis, the compounds were found to have antimalarial and antioxidant activities comparable with known antimalarial and antioxidant drugs. The class of compounds reported herein have the potential of reducing oxidative stress arising from malaria parasite and chemotherapeutic agent used in the treatment of malaria. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  12. Synthesis, Bioevaluation and Molecular Dynamic Simulation Studies of Dexibuprofen–Antioxidant Mutual Prodrugs

    Directory of Open Access Journals (Sweden)

    Zaman Ashraf

    2016-12-01

    Full Text Available Dexibuprofen–antioxidant conjugates were synthesized with the aim to reduce its gastrointestinal effects. The esters analogs of dexibuprofen 5a–c were obtained by reacting its –COOH group with chloroacetyl derivatives 3a–c. The in vitro hydrolysis data confirmed that synthesized prodrugs 5a–c were stable in stomach while undergo significant hydrolysis in 80% human plasma and thus release free dexibuprofen. The minimum reversion was observed at pH 1.2 suggesting that prodrugs are less irritating to stomach than dexibuprofen. The anti-inflammatory activity of 5c (p < 0.001 is more significant than the parent dexibuprofen. The prodrug 5c produced maximum inhibition (42.06% of paw-edema against egg-albumin induced inflammation in mice. Anti-pyretic effects in mice indicated that prodrugs 5a and 5b showed significant inhibition of pyrexia (p < 0.001. The analgesic activity of 5a is more pronounced compared to other synthesized prodrugs. The mean percent inhibition indicated that the prodrug 5a was more active in decreasing the number of writhes induced by acetic acid than standard dexibuprofen. The ulcerogenic activity results assured that synthesized prodrugs produce less gastrointestinal adverse effects than dexibuprofen. The ex vivo antiplatelet aggregation activity results also confirmed that synthesized prodrugs are less irritant to gastrointestinal mucosa than the parent dexibuprofen. Molecular docking analysis showed that the prodrugs 5a–c interacts with the residues present in active binding sites of target protein. The stability of drug–target complexes is verified by molecular dynamic simulation study. It exhibited that synthesized prodrugs formed stable complexes with the COX-2 protein thus support our wet lab results. It is therefore concluded that the synthesized prodrugs have promising pharmacological activities with reduced gastrointestinal adverse effects than the parent drug.

  13. Molecular design, synthesis and physical properties of novel Cytisine-derivatives - Experimental and theoretical study

    Science.gov (United States)

    Ivanova, Bojidarka; Spiteller, Michael

    2013-02-01

    The paper presented a comprehensive theoretical and experimental study on the molecular drugs-design, synthesis, isolation, physical spectroscopic and mass spectrometric elucidation of novel functionalization derivatives of Cytisine (Cyt), using nucleosidic residues. Since these alkaloids have established biochemical profile, related the binding affinity of the nicotinic acetylcholine receptors (nAChRs), particularly α7 sub-type, the presented correlation between the molecular structure and properties allowed to evaluated the highlights of the biochemical hypothesises related the Schizophrenia. The anticancer activity of α7 subtype agonists and the crucial role of the nucleoside-based medications in the cancer therapy provided opportunity for further study on the biochemical relationship between Schizophrenia and few kinds of cancers, which has been hypothesized recently. The physical electronic absorptions (EAs), circular dichroic (CD) and Raman spectroscopic (RS) properties as well as mass spectrometric (MS) data, obtained using electrospray ionization (ESI) and atmospheric-pressure chemical ionization (APCI) methods under the positive single (MS) and tandem (MS/MS) modes of operation are discussed. Taking into account reports on a fatal intoxication of Cyt, the presented data would be of interest in the field of forensic chemistry, through development of highly selective and sensitive analytical protocols. Quantum chemical method is used to predict the physical properties of the isolated alkaloids, their affinity to the receptor loop and gas-phase stabilized species, observed mass spectrometrically.

  14. Cyclopenta[b]naphthalene cyanoacrylate dyes: synthesis and evaluation as fluorescent molecular rotors.

    Science.gov (United States)

    Kocsis, Laura S; Elbel, Kristyna M; Hardigree, Billie A; Brummond, Kay M; Haidekker, Mark A; Theodorakis, Emmanuel A

    2015-03-14

    We describe the design, synthesis and fluorescent profile of a family of environment-sensitive dyes in which a dimethylamino (donor) group is conjugated to a cyanoacrylate (acceptor) unit via a cyclopenta[b]naphthalene ring system. This assembly satisfies the typical D-π-A motif of a fluorescent molecular rotor and exhibits solvatochromic and viscosity-sensitive fluorescence emission. The central naphthalene ring system of these dyes was synthesized via a novel intramolecular dehydrogenative dehydro-Diels-Alder (IDDDA) reaction that permits incorporation of the donor and acceptor groups in variable positions around the aromatic core. A bathochromic shift of excitation and emission peaks was observed with increasing solvent polarity but the dyes exhibited a complex emission pattern with a second red emission band when dissolved in nonpolar solvents. Consistent with other known molecular rotors, the emission intensity increased with increasing viscosity. Interestingly, closer spatial proximity between the donor and the acceptor groups led to decreased viscosity sensitivity combined with an increased quantum yield. This observation indicates that structural hindrance of intramolecular rotation dominates when the donor and acceptor groups are in close proximity. The examined compounds give insight into how excited state intramolecular rotation can be influenced by both the solvent and the chemical structure.

  15. Design, synthesis, α-glucosidase inhibitory activity, molecular docking and QSAR studies of benzimidazole derivatives

    Science.gov (United States)

    Dinparast, Leila; Valizadeh, Hassan; Bahadori, Mir Babak; Soltani, Somaieh; Asghari, Behvar; Rashidi, Mohammad-Reza

    2016-06-01

    In this study the green, one-pot, solvent-free and selective synthesis of benzimidazole derivatives is reported. The reactions were catalyzed by ZnO/MgO containing ZnO nanoparticles as a highly effective, non-toxic and environmentally friendly catalyst. The structure of synthesized benzimidazoles was characterized using spectroscopic technics (FT-IR, 1HNMR, 13CNMR). Synthesized compounds were evaluated for their α-glucosidase inhibitory potential. Compounds 3c, 3e, 3l and 4n were potent inhibitors with IC50 values ranging from 60.7 to 168.4 μM. In silico studies were performed to explore the binding modes and interactions between enzyme and synthesized benzimidazoles. Developed linear QSAR model based on density and molecular weight could predict bioactivity of newly synthesized compounds well. Molecular docking studies revealed the availability of some hydrophobic interactions. In addition, the bioactivity of most potent compounds had good correlation with estimated free energy of binding (ΔGbinding) which was calculated according to docked best conformations.

  16. Synthesis and Surface-Specific Analysis of Molecular Constituents Relevant to Biogenic Secondary Organic Aerosol Material

    Science.gov (United States)

    Be, A. G.; Upshur, M. A.; Chase, H. M.; Geiger, F.; Thomson, R. J.

    2017-12-01

    Secondary organic aerosol (SOA) particles formed from the oxidation of biogenic volatile organic compounds (BVOCs) remain a principal, yet elusive, class of airborne particulate matter that impacts the Earth's radiation budget. Given the characteristic molecular complexity comprising biogenic SOA particles, chemical information selective to the gas-aerosol interface may be valuable in the investigation of such systems, as surface considerations likely dictate the phenomena driving particle evolution mechanisms and climate effects. In particular, cloud activation processes may be parameterized using the surface tension depression that coincides with partitioning of surface-active organic species to the gas-droplet interface. However, the extent to which surface chemical processes, such as cloud droplet condensation, are influenced by the chemical structure and reactivity of individual surface-active molecules in SOA particles is largely unknown. We seek to study terpene-derived organic species relevant to the surfaces of biogenic SOA particles via synthesis of putative oxidation products followed by analysis using surface-selective physicochemical measurements. Using dynamic surface tension measurements, considerable differences are observed in the surface tension depression of aqueous pendant droplets that contain synthetically prepared ozonolysis products derived from abundant terpene precursors. Furthermore, sum frequency generation spectroscopy is utilized for comparison of the surface vibrational spectral responses of synthesized reference compounds with those observed for laboratory aerosol toward probing the surface composition of SOA material. Such ongoing findings highlight the underlying importance of molecular structure and reactivity when considering the surface chemistry of biogenic terpene-derived atmospheric aerosols.

  17. Molecular Consortia—Various Structural and Synthetic Concepts for More Effective Therapeutics Synthesis

    Directory of Open Access Journals (Sweden)

    Anna Pawełczyk

    2018-04-01

    Full Text Available The design and discovery of novel drug candidates are the initial and most probably the crucial steps in the drug development process. One of the tasks of medicinal chemistry is to produce new molecules that have a desired biological effect. However, even today the search for new pharmaceuticals is a very complicated process that is hard to rationalize. Literature provides many scientific reports on future prospects of design of potentially useful drugs. Many trends have been proposed for the design of new drugs containing different structures (dimers, heterodimers, heteromers, adducts, associates, complexes, biooligomers, dendrimers, dual-, bivalent-, multifunction drugs and codrugs, identical or non-identical twin drugs, mixed or combo drugs, supramolecular particles and various nanoindividuals. Recently much attention has been paid to different strategies of molecular hybridization. In this paper, various molecular combinations were described e.g., drug–drug or drug-non-drug combinations which are expressed in a schematic multi-factor form called a molecular matrix, consisting of four factors: association mode, connection method, and the number of elements and linkers. One of the most popular trends is to create small–small molecule combinations such as different hybrids, codrugs, drug–drug conjugates (DDCs and small-large molecule combinations such as antibody-drug conjugates (ADCs, polymer-drug conjugates (PDCs or different prodrugs and macromolecular therapeutics. A review of the structural possibilities of active framework combinations indicates that a wide range of potentially effective novel-type compounds can be formed. What is particularly important is that new therapeutics can be obtained in fast, efficient, and selective methods using current trends in chemical synthesis and the design of drugs such as the “Lego” concept or rational green approach.

  18. NONLINEAR OPTICAL MOLECULAR CRYSTAL BASED ON 2,6-DIAMINOPYRIDINE: SYNTHESIS AND CHARACTERIZATION

    Directory of Open Access Journals (Sweden)

    I. M. Pavlovetc

    2014-05-01

    Full Text Available The paper deals with investigation of a new nonlinear optical material based on nonlinear optical chromophore (4-Nitrophenol and aminopyridine (2,6-Diaminopyridine. Calculation results are presented for molecular packing in the crystalline compound, based on the given components. According to these results the finite material must have a noncentrosymmetric lattice, which determines the presence of the second order nonlinear optical response. Investigations carried out in this work confirm these calculations. Results of experiments are given describing the co-crystallization of these components and the following re-crystallization of the obtained material. In order to get a monocrystal form, the optimal conditions for the synthesis of molecular crystals based on these components are determined. Sufficiently large homogeneous crystals are obtained, that gave the possibility to record their spectra in the visible and near infrared parts of the spectrum, to determine their nonlinear optical properties and the level of homogeneity. Their optical (optical transmission and optical laser damage threshold and nonlinear optical properties are presented. For observation and measurement of the nonlinear optical properties an installation was built which implements the comparative method for measurements of nonlinear optical properties. A potassium titanyl oxide phosphate crystal was used as a sample for comparison. Results are given for the conversion efficiency of the primary laser radiation in the second optical harmonic relative to the signal obtained on the potassium titanyl oxide phosphate crystal. Obtained results show that the molecular co-crystal based on 2,6-Diaminopyridine is a promising nonlinear optical material for generating the second optical harmonic on the Nd: YAG laser (532 nm.

  19. Enzymatic synthesis of RNAs capped with nucleotide analogues reveals the molecular basis for substrate selectivity of RNA capping enzyme: impacts on RNA metabolism.

    Directory of Open Access Journals (Sweden)

    Moheshwarnath Issur

    Full Text Available RNA cap binding proteins have evolved to specifically bind to the N7-methyl guanosine cap structure found at the 5' ends of eukaryotic mRNAs. The specificity of RNA capping enzymes towards GTP for the synthesis of this structure is therefore crucial for mRNA metabolism. The fact that ribavirin triphosphate was described as a substrate of a viral RNA capping enzyme, raised the possibility that RNAs capped with nucleotide analogues could be generated in cellulo. Owing to the fact that this prospect potentially has wide pharmacological implications, we decided to investigate whether the active site of the model Paramecium bursaria Chlorella virus-1 RNA capping enzyme was flexible enough to accommodate various purine analogues. Using this approach, we identified several key structural determinants at each step of the RNA capping reaction and generated RNAs harboring various different cap analogues. Moreover, we monitored the binding affinity of these novel capped RNAs to the eIF4E protein and evaluated their translational properties in cellulo. Overall, this study establishes a molecular rationale for the specific selection of GTP over other NTPs by RNA capping enzyme It also demonstrates that RNAs can be enzymatically capped with certain purine nucleotide analogs, and it also describes the impacts of modified RNA caps on specific steps involved in mRNA metabolism. For instance, our results indicate that the N7-methyl group of the classical N7-methyl guanosine cap is not always indispensable for binding to eIF4E and subsequently for translation when compensatory modifications are present on the capped residue. Overall, these findings have important implications for our understanding of the molecular determinants involved in both RNA capping and RNA metabolism.

  20. Design, synthesis, and preliminary pharmacological evaluation of 1, 4-diazabicyclo[4.3.0]nonan-9-ones as a new class of highly potent nootropic agents.

    Science.gov (United States)

    Manetti, D; Ghelardini, C; Bartolini, A; Bellucci, C; Dei, S; Galeotti, N; Gualtieri, F; Romanelli, M N; Scapecchi, S; Teodori, E

    2000-05-18

    Several 4-substituted 1,4-diazabicyclo[4.3.0]nonan-9-ones have been synthesized and tested in vivo on mouse passive avoidance test, to evaluate their nootropic activity. The results show that they represent a new class of nootropic drugs with a pharmacological profile very similar to that of piracetam, showing much higher potency with respect to the reference. Among the compounds studied, 7 (DM 232) shows outstanding potency, being active at the dose of 0. 001 mg kg(-1) sc.

  1. Review of the chemistry and pharmacology of 7-Methyljugulone.

    Science.gov (United States)

    Mbaveng, Armelle T; Kuete, Victor

    2014-03-01

    Naphthoquinone is a class of phenolic compounds derived from naphthalene. 7-Methyljuglone (7-MJ) is a naphthoquinone also known as ramentaceone or 6-Methyl-8-hydroxy-1,4-naphthoquinone or 5-Hydroxy-7-methyl-1,4-naphthoquinone or 7-Methyl-5-hydroxy-1,4-naphthoquinone or 5-Hydroxy-7-methyl-,1,4-naphtoquinone or 7-Methyl-5-hydroxynaphthalene-1,4-dione. This compound is a biologically active naphtoquinone, with a molecular weight of 188 g/mol mostly isolated in the genus Diospyros and Euclea. This review was aimed at providing available chemically and pharmacological data on 7-MJ. The chemical and pharmacological data were retrieved from the well-known scientific websites such as Pubmed, Google Scholar, Reaxys, Scirus, Scopus, Sciencedirect, Web-of-knowledge and Scifinder. 7-MJ was reported to have a variety of pharmacological activities such as antibacterial, antifungal, anticancer, antitubercular, anti-inflammatory and antiviral activities. The hemi-synthesis of the compound have been described. The present review pooled out together the knowledge on 7-MJ, and can serve as the start point for future research and valorization accomplishments.

  2. Synthesis of molecular imprinting polymers for extraction of gallic acid from urine.

    Science.gov (United States)

    Bhawani, Showkat Ahmad; Sen, Tham Soon; Ibrahim, Mohammad Nasir Mohammad

    2018-02-21

    The molecularly imprinted polymers for gallic acid were synthesized by precipitation polymerization. During the process of synthesis a non-covalent approach was used for the interaction of template and monomer. In the polymerization process, gallic acid was used as a template, acrylic acid as a functional monomer, ethylene glycol dimethacrylate as a cross-linker and 2,2'-azobisisobutyronitrile as an initiator and acetonitrile as a solvent. The synthesized imprinted and non-imprinted polymer particles were characterized by using Fourier-transform infrared spectroscopy and scanning electron microscopy. The rebinding efficiency of synthesized polymer particles was evaluated by batch binding assay. The highly selective imprinted polymer for gallic acid was MIPI1 with a composition (molar ratio) of 1:4:20, template: monomer: cross-linker, respectively. The MIPI1 showed highest binding efficiency (79.50%) as compared to other imprinted and non-imprinted polymers. The highly selective imprinted polymers have successfully extracted about 80% of gallic acid from spiked urine sample.

  3. Synthesis, cytotoxicity and molecular modelling studies of new phenylcinnamide derivatives as potent inhibitors of cholinesterases.

    Science.gov (United States)

    Saeed, Aamer; Mahesar, Parvez Ali; Zaib, Sumera; Khan, Muhammad Siraj; Matin, Abdul; Shahid, Mohammad; Iqbal, Jamshed

    2014-05-06

    The present study reports the synthesis of cinnamide derivatives and their biological activity as inhibitors of both cholinesterases and anticancer agents. Controlled inhibition of brain acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) may slow neurodegeneration in Alzheimer's diseases (AD). The anticholinesterase activity of phenylcinnamide derivatives was determined against Electric Eel acetylcholinesterase (EeAChE) and horse serum butyrylcholinesterase (hBChE) and some of the compounds appeared as moderately potent inhibitors of EeAChE and hBChE. The compound 3-(2-(Benzyloxy)phenyl)-N-(3,4,5-trimethoxyphenyl)acrylamide (3i) showed maximum activity against EeAChE with an IC50 0.29 ± 0.21 μM whereas 3-(2-chloro-6-nitrophenyl)-N-(3,4,5-trimethoxyphenyl)acrylamide (3k) was proved to be the most potent inhibitor of hBChE having IC50 1.18 ± 1.31 μM. To better understand the enzyme-inhibitor interaction of the most active compounds toward cholinesterases, molecular modelling studies were carried out on high-resolution crystallographic structures. The anticancer effects of synthesized compounds were also evaluated against cancer cell line (lung carcinoma). The compounds may be useful leads for the design of a new class of anticancer drugs for the treatment of cancer and cholinesterase inhibitors for Alzheimer's disease (AD). Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  4. Synthesis, Biological Evaluation, and Molecular Modeling Studies of New Oxadiazole-Stilbene Hybrids against Phytopathogenic Fungi

    Science.gov (United States)

    Jian, Weilin; He, Daohang; Song, Shaoyun

    2016-08-01

    Natural stilbenes (especially resveratrol) play important roles in plant protection by acting as both constitutive and inducible defenses. However, their exogenous applications on crops as fungicidal agents are challenged by their oxidative degradation and limited availability. In this study, a new class of resveratrol-inspired oxadiazole-stilbene hybrids was synthesized via Wittig-Horner reaction. Bioassay results indicated that some of the compounds exhibited potent fungicidal activity against Botrytis cinerea in vitro. Among these stilbene hybrids, compounds 11 showed promising inhibitory activity with the EC50 value of 144.6 μg/mL, which was superior to that of resveratrol (315.6 μg/mL). Remarkably, the considerably abnormal mycelial morphology was observed in the presence of compound 11. The inhibitory profile was further proposed by homology modeling and molecular docking studies, which showed the possible interaction of resveratrol and oxadiazole-stilbene hybrids with the cytochrome P450-dependent sterol 14α-demethylase from B. cinerea (BcCYP51) for the first time. Taken together, these results would provide new insights into the fungicidal mechanism of stilbenes, as well as an important clue for biology-oriented synthesis of stilbene hybrids with improved bioactivity against plant pathogenic fungi in crop protection.

  5. Synthesis, molecular modeling and biological evaluation of PSB as targeted antibiotics.

    Science.gov (United States)

    Cheng, Kui; Zheng, Qing-Zhong; Hou, Jin; Zhou, Yang; Liu, Chang-Hong; Zhao, Jing; Zhu, Hai-Liang

    2010-04-01

    We described here the design, synthesis, molecular modeling, and biological evaluation of a series of peptide and Schiff bases (PSB) small molecules, inhibitors of Escherichia coli beta-Ketoacyl-acyl carrier protein synthase III (ecKAS III). The initial lead compound was reported by us previously, we continued to carry out structure-activity relationship studies and optimize the lead structure to potent inhibitors in this research. The results demonstrated that both N-(2-(3,5-dichloro-2-hydroxybenzylideneamino)propyl)-2-hydroxybenzamide (1f) and 2-hydroxy-N-(2-(2-hydroxy-5-iodobenzylideneamino)propyl)-4-methylbenzamide (3e) posses good ecKAS III inhibitory activity and well binding affinities by bonding Gly152/Gly209 of ecKAS III and fit into the mouth of the substrate tunnel, and can be as potential antibiotics agent, displaying minimal inhibitory concentration values in the range 0.20-3.13microg/mL and 0.39-3.13microg/mL against various bacteria. Copyright 2010 Elsevier Ltd. All rights reserved.

  6. Synthesis and Characterization of Nanocrystalline Aluminophosphate AlPO4-5 Molecular Sieve

    Directory of Open Access Journals (Sweden)

    Asir Alnaama

    2018-03-01

    Full Text Available Nanocrystalline aluminophosphate AlPO4-5 molecular sieves were synthesized by hydrothermal method (HTS. Synthesis parameters like time and temperature of crystallization were investigated. Type of template (R and ratio of R/P2O5 were studied also. Characterization of the synthesized AlPO4-5 were done by powder X-ray diffraction (XRD, scanning electron microscopy (SEM/EDX, Fourier transform infrared (FTIR, differential scanning calorimetry-thermogravimetry analysis (DSC-TGA, and N2 adsorption-desorption BET analysis. XRD patterns results showed excellent crystallinity for two types of templates, di-n-propylamine (DPA and tetrapropyl ammonium hydroxide (TPAOH for alumminophosphate five (AFI structure. Nano-level for particle size of 66 nm was revealed by AFM test. Good thermal stability was obtained in DSC-TGA results. Best time and temperature of crystallization of 24h and 190 O C were got. Optimum R/P2O5 for two kind of template was established.

  7. Influence of ionizing radiation on synthesis and molecular heterogeneity of catalase in tissue culture of Rauwolfia serpentina

    International Nuclear Information System (INIS)

    Komov, V.P.; Bespalova, E.V.; Strelkova, M.A.

    1998-01-01

    Changes in activity and molecular heterogeneity of catalase in tissue culture of Rauwolfia serpentina following irradiation in early growth period at the doses of 8 and 50 Gy has been studied. Ionizing radiation accelerate the synthesis and degradation rates of catalase and total protein. A comparative study of changes in enzyme and protein turnover during growth on irradiated and non-irradiated medium has been made [ru

  8. Potent New Small-Molecule Inhibitor of Botulinum Neurotoxin Serotype A Endopeptidase Developed by Synthesis-Based Computer-Aided Molecular Design

    Science.gov (United States)

    2009-11-01

    simulations; (4) synthesis and evaluation of the molecules from Step 2 or 3 (e.g., synthesizing and testing AHP). From synthetic chemistry point of view...2000) Synthesis of 6H-indolo [2,3-b][1,6]naphthyridines and related compounds as the 5-Aza analogues of ellipticine alkaloids . J Org Chem 65: 7977–7983...Potent New Small-Molecule Inhibitor of Botulinum Neurotoxin Serotype A Endopeptidase Developed by Synthesis -Based Computer-Aided Molecular Design

  9. A Network of AOPs for reduced thyroid hormone synthesis derived from inhibition of Thyroperoxidase - A common Molecular Initiating Event Leading to Species-Specific Indices of Adversity.

    Science.gov (United States)

    This collection of 3 AOPs describe varying outcomes of adversity dependent upon species in response to inhibition of thyroperoxidase (TPO) during development. Chemical inhibition of TPO, the molecular-initiating event (MIE), results in decreased thyroid hormone (TH) synthesis, a...

  10. Molecular dynamics approaches to the design and synthesis of PCB targeting molecularly imprinted polymers: interference to monomer-template interactions in imprinting of 1,2,3-trichlorobenzene.

    Science.gov (United States)

    Cleland, Dougal; Olsson, Gustaf D; Karlsson, Björn C G; Nicholls, Ian A; McCluskey, Adam

    2014-02-07

    The interactions between each component of the pre-polymerisation mixtures used in the synthesis of molecularly imprinted polymers (MIP) specific for 1,2,3,4,5-pentachlorobenzene (1) and 1,2,3-trichlorobenzene (2) were examined in four molecular dynamics simulations. These simulations revealed that the relative frequency of functional monomer-template (FM-T) interactions was consistent with results obtained by the synthesis and evaluation of the actual MIPs. The higher frequency of 1 interaction with trimethylstyrene (TMS; 54.7%) than 1 interaction with pentafluorostyrene (PFS; 44.7%) correlated with a higher imprinting factor (IF) of 2.1 vs. 1.7 for each functional monomer respectively. The higher frequency of PFS interactions with 2 (29.6%) than TMS interactions with 2 (1.9%) also correlated well with the observed differences in IF (3.7) of 2 MIPs imprinted using PFS as the FM than the IF (2.8) of 2 MIPs imprinted using TMS as the FM. The TMS-1 interaction dominated the molecular simulation due to high interaction energies, but the weaker TMS-2 resulted in low interaction maintenance, and thus lower IF values. Examination of the other pre-polymerisation mixture components revealed that the low levels of TMS-2 interaction was, in part, due to interference caused by the cross linker (CL) ethyleneglycol dimethylacrylate (EGDMA) interactions with TMS. The main reason was, however, attributed to MeOH interactions with TMS in both a hydrogen bond and perpendicular configuration. This positioned a MeOH directly above the π-orbital of all TMS for an average of 63.8% of MD2 creating significant interference to π-π stacking interactions between 2 and TMS. These findings are consistent with the deviation from the 'normal' molecularly imprinted polymer synthesis ratio of 1 : 4 : 20 (T : FM : CL) of 20 : 1 : 29 and 15 : 6 : 29 observed with 2 and TMS and PFS respectively. Our molecular dynamics simulations correctly predicted the high level

  11. Synthesis and characterization of sugar based low molecular weight gelators and the preparation of chiral sulfinamides

    Science.gov (United States)

    Mangunuru, Hari Prasad Reddy

    Low molecular weight gelators (LMWGs) have received considerable attention in the field of chemistry from last few decades. These compounds form self-assembled fibrous networks like micelles, cylindrical, sheets, fibers, layers and so on. The fibrous network entraps the solvent and forms gel, because of the self-assembly phenomenon and their demonstrated potential uses in a variety of areas, ranging from environmental to medicinal applications. Sugars are good starting materials to synthesize the new class of LMWG's, because these are different from some expensive materials, these are natural products. We have synthesized and characterized the LMGS's based on D-glucose and D-glucosamine. D-glucosamine is the versatile starting material to make different peptoids and triazoles. Several series of compounds were synthesized using compounds 1-3 as starting material and studied the gelation behavior all the compounds. We have studied the self-assembling properties of a new class of tripeptoids, synthesized by one-pot Ugi reaction from simple starting materials. Among the focused library of tripeptoids synthesized, we found that several efficient low molecular weight organogelators were obtained for aqueous DMSO and ethanol mixtures. We have also synthesized and characterized a series of monosaccharide triazole derivatives. These compounds were synthesized from N-acetyl glucosamine and D-glucose via a Cu(I) catalyzed azide/alkyne cycloaddition reaction (CuAAc). The compounds have been screened for their gelation properties and several efficient low molecular weight organo/hydro gelators were obtained, among these compounds, five per-acetyl glucosamine derivatives and one peracetyl glucose derivative were able to form gels in water. These new molecules are expected to be useful in drug delivery and tissue engineering.*. Asymmetric synthesis of chiral amines is a challenging in synthetic organic chemistry. The development of new catalysts for asymmetric organic

  12. Synthesis and Supramolecular Chemistry of Novel Liquid Crystalline Crown Ether-Substituted Phthalocyanines : Toward Molecular Wires and Molecular Ionoelectronics

    NARCIS (Netherlands)

    Nostrum, Cornelus F. van; Picken, Stephen J.; Schouten, Arend-Jan; Nolte, Roeland J.M.

    1995-01-01

    The synthesis of the metal-free and the dihydroxysilicon derivatives of tetrakis[4’,5’-bis(decoxy)benzo-18-crown-6]phthalocyanine is described. The metal-free phthalocyanine is liquid crystalline and exhibits a crystalline phase to mesophase transition at 148 °C. The structures of the crystalline

  13. Design and synthesis of single-source molecular precursors to homogeneous multi-component oxide materials

    Science.gov (United States)

    Fujdala, Kyle Lee

    This dissertation describes the syntheses of single-source molecular precursors to multi-component oxide materials. These molecules possess a core metal or element with various combinations of -OSi(O tBu)3, -O2P(OtBu) 2, and -OB[OSi(OtBu)3] 2 ligands. Such molecules decompose under mild thermolytic conditions (models for oxide-supported metal species and multi-component oxides. Significantly, the first complexes to contain three or more heteroelements suitable for use in the TMP method have been synthesized. Compounds for use as single-source molecular precursors have been synthesized containing Al, B, Cr, Hf, Mo, V, W, and Zr, and their thermal transformations have been examined. Heterogeneous catalytic reactions have been examined for selected materials. Also, cothermolyses of molecular precursors and additional molecules (i.e., metal alkoxides) have been utilized to provide materials with several components for potential use as catalysts or catalyst supports. Reactions of one and two equivs of HOSi(OtBu) 3 with Cr(OtBu)4 afforded the first Cr(IV) alkoxysiloxy complexes (tBuO) 3CrOSi(OtBu)3 and ( tBuO)2Cr[OSi(OtBu) 3]2, respectively. The high-yielding, convenient synthesis of (tBuO)3CrOSi(O tBu)3 make this complex a useful single-source molecular precursor, via the TMP method, to Cr/Si/O materials. The thermal transformations of (tBuO)3CrOSi(O tBu)3 and (tBuO) 2Cr[OSi(OtBu)3]2 to chromia-silica materials occurr at low temperatures (≤180°C), to give isobutene as the major carbon-containing product. The material generated from the solid-state conversion of (tBuO) 3CrOSi(OtBu)3 (CrOS ss) has an unexpectedly high surface area of 315 m2 g-1 that is slightly reduced to 275 m2 g-1 after calcination at 500°C in O2. The xerogel obtained by the thermolysis of an n-octane solution of (tBuO)3CrOSi(O tBu)3 (CrOSixg) has a surface area of 315 m2 g-1 that is reduced to 205 m2 g-1 upon calcination at 500°C. Powder X-ray diffraction (PXRD) analysis revealed that Cr2O 3 is

  14. Solvent effect on the synthesis of clarithromycin: A molecular dynamics study

    Science.gov (United States)

    Duran, Dilek; Aviyente, Viktorya; Baysal, Canan

    2004-02-01

    Clarithromycin (6- O-methylerythromycin A) is a 14-membered macrolide antibiotic which is active in vitro against clinically important gram-positive and gram-negative bacteria. The selectivity of the methylation of the C-6 OH group is studied on erythromycin A derivatives. To understand the effect of the solvent on the methylation process, detailed molecular dynamics (MD) simulations are performed in pure DMSO, pure THF and DMSO:THF (1:1) mixture by using the anions at the C-6, C-11 and C-12 positions of 2',4''-[ O-bis(TMS)]erythromycin A 9-[ O-(dimethylthexylsilyl)oxime] under the assumption that the anions are stable on the sub-nanosecond time scale. The conformations of the anions are not affected by the presence of the solvent mixture. The radial distribution functions are computed for the distribution of different solvent molecules around the `O-' of the anions. At distances shorter than 5 Å, DMSO molecules are found to cluster around the C-11 anion, whereas the anion at the C-12 position is surrounded by the THF molecules. The anion at the C-6 position is not blocked by the solvent molecules. The results are consistent with the experimental finding that the methylation yield at the latter position is increased in the presence of a DMSO:THF (1:1) solvent mixture. Thus, the effect of the solvent in enhancing the yield during the synthesis is not by changing the conformational properties of the anions, but rather by creating a suitable environment for methylation at the C-6 position.

  15. Synthesis and Evaluation of CO2 Thickeners Designed with Molecular Modeling

    Energy Technology Data Exchange (ETDEWEB)

    Robert Enick; Erick Beckman; J. Karl Johnson

    2009-08-31

    The objective of this research was to use molecular modeling techniques, coupled with our prior experimental results, to design, synthesize and evaluate inexpensive, non-fluorous carbon dioxide thickening agents. The first type of thickener that was considered was associating polymers. Typically, these thickeners are copolymers that contain a highly CO{sub 2}-philic monomer, and a small concentration of a CO{sub 2}-phobic associating monomer. Yale University was solely responsible for the synthesis of a second type of thickener; small, hydrogen bonding compounds. These molecules have a core that contains one or more hydrogen-bonding groups, such as urea or amide groups. Non-fluorous, CO{sub 2}-philic functional groups were attached to the hydrogen bonding core of the compound to impart CO{sub 2} stability and macromolecular stability to the linear 'stack' of these compounds. The third type of compound initially considered for this investigation was CO{sub 2}-soluble surfactants. These surfactants contain conventional ionic head groups and composed of CO{sub 2}-philic oligomers (short polymers) or small compounds (sugar acetates) previously identified by our research team. Mobility reduction could occur as these surfactant solutions contacted reservoir brine and formed mobility control foams in-situ. The vast majority of the work conducted in this study was devoted to the copolymeric thickeners and the small hydrogen-bonding thickeners; these thickeners were intended to dissolve completely in CO{sub 2} and increase the fluid viscosity. A small but important amount of work was done establishing the groundwork for CO{sub 2}-soluble surfactants that reduced mobility by generating foams in-situ as the CO{sub 2}+surfactant solution mixed with in-situ brine.

  16. Synthesis of Sub-10 nm Two-Dimensional Covalent Organic Thin Film with Sharp Molecular Sieving Nanofiltration

    KAUST Repository

    Gadwal, Ikhlas

    2018-04-06

    We demonstrated here a novel and facile synthesis of two-dimensional (2D) covalent organic thin film with pore size around 1.5 nm using a planar, amphiphilic and substituted heptacyclic truxene based triamine and a simple dialdehyde as building blocks by dynamic imine bond formation at the air/water interface using Langmuir–Blodgett (LB) method. Optical microscopy (OM), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and atomic force microscopy (AFM), all unanimously showed the formation of large, molecularly thin and free-standing membrane that can be easily transferred on different substrate surfaces. The 2D membrane supported on a porous polysulfone showed a rejection rate of 64 and 71% for NaCl and MgSO4, respectively, and a clear molecular sieving at molecular size around 1.3 nm, which demonstrated a great potential in the application of pretreatment of seawater desalination and separation of organic molecules.

  17. Imides: forgotten players in the Ugi reaction. One-pot multicomponent synthesis of quinazolinones.

    Science.gov (United States)

    Mossetti, Riccardo; Pirali, Tracey; Saggiorato, Dèsirèe; Tron, Gian Cesare

    2011-06-28

    Up to now, the synthesis of quinazolinones has required lengthy synthetic procedures. Here, we describe an innovative one-pot multicomponent reaction leading to highly substituted quinazolinones. We believe that this novel transformation may open the door for the generation of new and pharmacologically active quinazolinones, but, most important of all, the resurrection of the imide-Ugi scaffold paves the way for the synthesis of novel molecular architectures. This journal is © The Royal Society of Chemistry 2011

  18. Design, Synthesis, and Pharmacological Evaluation of Novel Multisubstituted Pyridin-3-amine Derivatives as Multitargeted Protein Kinase Inhibitors for the Treatment of Non-Small Cell Lung Cancer.

    Science.gov (United States)

    Zhu, Wei; Chen, Hui; Wang, Yulan; Wang, Jiang; Peng, Xia; Chen, Xianjie; Gao, Yinglei; Li, Chunpu; He, Yulong; Ai, Jing; Geng, Meiyu; Zheng, Mingyue; Liu, Hong

    2017-07-27

    A novel series of pyridin-3-amine derivatives were designed, synthesized, and evaluated as multitargeted protein kinase inhibitors for the treatment of non-small cell lung cancer (NSCLC). Hit 1 was first disclosed by in silico screening against fibroblast growth factor receptors (FGFR), which was subsequently validated by in vitro experiments. The structure-activity relationship (SAR) of its analogues was then explored to afford novel FGFR inhibitors 2a-2p and 3a-3q. Among them, 3m showed potent inhibition against FGFR1, 2, and 3. Interestingly, compound 3m not only inhibited various phosphorylation and downstream signaling across different oncogenic forms in FGFR-overactivated cancer cells but also showed nanomolar level inhibition against several other NSCLC-related oncogene kinases, including RET, EGFR, EGFR/T790M/L858R, DDR2, and ALK. Finally, in vivo pharmacology evaluations of 3m showed significant antitumor activity (TGI = 66.1%) in NCI-H1581 NSCLC xenografts with a good pharmacokinetic profile.

  19. Gamma-aminobutyric acid esters. 1. Synthesis, brain uptake, and pharmacological studies of aliphatic and steroid esters of gamma-aminobutyric acid

    International Nuclear Information System (INIS)

    Shashoua, V.E.; Jacob, J.N.; Ridge, R.; Campbell, A.; Baldessarini, R.J.

    1984-01-01

    Labeled and unlabeled aliphatic and steroid esters of gamma-amino[U- 14 C]butyric acid (GABA) were synthesized and tested for their capacity to penetrate the blood-brain barrier and for evidence of central neuropharmacological activity in rodents. The uptake of the labeled 9,12,15-octadecatrienyl (linolenyl), 3-cholesteryl, 1-butyl, and the 9-fluoro-11 beta,17-dihydroxy-16 alpha-methyl-3,20-dioxopregna -1,4-dien-21-yl (dexamethasone) esters of GABA into mouse brain increased 2-, 25-, 74-, and 81-fold over GABA, respectively. The cholesteryl ester of GABA depressed the general motor activity of mice and rats in a dose-dependent manner, whereas the 1-butyl, linolenyl, and dexamethasone esters were inactive by this test. Studies of the rates of hydrolysis, GABA receptor binding capacity, and octanol/water partition coefficients indicated that pharmacological activity of the esters after entry into the central nervous system (CNS) was dependent on their capacity to release GABA by enzymatic hydrolysis and their lipid solubility

  20. 1-cyclohexyl-x-methoxybenzene derivatives, novel psychoactive substances seized on the internet market. Synthesis and in vivo pharmacological studies in mice.

    Science.gov (United States)

    Fantinati, Anna; Ossato, Andrea; Bianco, Sara; Canazza, Isabella; De Giorgio, Fabio; Trapella, Claudio; Marti, Matteo

    2017-05-01

    Among novel psychoactive substances notified to EMCDDA and Europol were 1-cyclohexyl-x-methoxybenzene stereoisomers (ortho, meta, and para). These substances share some structural characteristics with phencyclidine and tramadol. Nowadays, no information on the pharmacological and toxicological effects evoked by 1-cyclohexyl-x-methoxybenzene are reported. The aim of this study was to investigate the effect evoked by each one stereoisomer on visual stimulation, body temperature, acute thermal pain, and motor activity in mice. Mice were evaluated in behavioral tests carried out in a consecutive manner according to the following time scheme: observation of visual placing response, measures of core body temperature, determination of acute thermal pain, and stimulated motor activity. All three stereoisomers dose-dependent inhibit visual placing response (rank order: meta > ortho > para), induce hyperthermia at lower and hypothermia at higher doses (meta > ortho > para) and cause analgesia to thermal stimuli (para > meta = ortho), while they do not alter motor activity. For the first time, this study demonstrates that systemic administration of 1-cyclohexyl-x-methoxybenzene compounds markedly inhibit visual response, promote analgesia, and induce core temperature alterations in mice. This data, although obtained in animal model, suggest their possible hazard for human health (i.e., hyperthermia and sensorimotor alterations). In particular, these novel psychoactive substances may have a negative impact in many daily activities, greatly increasing the risk factors for workplace accidents and traffic injuries. Copyright © 2017 John Wiley & Sons, Ltd.

  1. Microwave radiation hydrothermal synthesis and characterization of micro- and mesoporous composite molecular sieve Y/SBA-15

    Directory of Open Access Journals (Sweden)

    Wenyuan Wu

    2017-05-01

    Full Text Available A microwave radiation hydrothermal method to control synthesis of micro- and mesoporous Y/SBA-15 composite molecular sieves was reported. The synthesized SBA-15 and Y/SBA-15 were characterized by scanning electron microscopy (SEM and N2 adsorption–desorption. The three kinds of different concentrations of hydrochloric acid (0.75 M, 2 M and 3.25 M were used to investigate the effect on Y/SBA-15. The analysis results of the composite products indicated that the optimization synthesis condition employed zeolite type Y and TEOS as silicon sources under 0.75 M hydrochloric acid by the microwave radiation hydrothermal synthesis method. The N2 adsorption–desorption test results of micro–mesoporous composite molecular sieve type Y/SBA-15 in mesoporous extent indicated that SBET is 355.529 m2/g, D‾BET is 4.050 nm, and mesoporous aperture focuses on the distribution region of 5.3 nm. It was found that the received composite product has an appropriate proportion of smaller size, larger size pore structure and the thicker pore wall. In addition, its internal channels have a high degree of order and smooth flow in long-range channels.

  2. A systems biology-based approach to uncovering the molecular mechanisms underlying the effects of dragon's blood tablet in colitis, involving the integration of chemical analysis, ADME prediction, and network pharmacology.

    Directory of Open Access Journals (Sweden)

    Haiyu Xu

    Full Text Available Traditional Chinese medicine (TCM is one of the oldest East Asian medical systems. The present study adopted a systems biology-based approach to provide new insights relating to the active constituents and molecular mechanisms underlying the effects of dragon's blood (DB tablets for the treatment of colitis. This study integrated chemical analysis, prediction of absorption, distribution, metabolism, and excretion (ADME, and network pharmacology. Firstly, a rapid, reliable, and accurate ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry method was employed to identify 48 components of DB tablets. In silico prediction of the passive absorption of these compounds, based on Caco-2 cell permeability, and their P450 metabolism enabled the identification of 22 potentially absorbed components and 8 metabolites. Finally, networks were constructed to analyze interactions between these DB components/metabolites absorbed and their putative targets, and between the putative DB targets and known therapeutic targets for colitis. This study provided a great opportunity to deepen the understanding of the complex pharmacological mechanisms underlying the effects of DB in colitis treatment.

  3. Automated synthesis with HPLC purification of 18F-FMISO as specific molecular imaging probe of tumor hypoxia

    International Nuclear Information System (INIS)

    Wang Mingwei; Zhang Yingjian; Zhang Yongping

    2012-01-01

    An improved automated synthesis of 1-H-1-(3-[ 18 F] fluoro-2-hydroxypropyl)-2-nitro-imidazole ( 18 F-FMISO), a specific molecular imaging probe of tumor hypoxia, was developed using an upgraded Explora GN module integrated with Explora LC for HPLC purification in this study. The radiochemical synthesis of 18 F-FMISO was started with precursor 1-( 2'-nitro-1'-imidazolyl)-2-O-tetrahydropyranyl-3-O-tosyl-propanediol (NITTP) and included nucleophilic [ 18 F] radio-fluorination at 120℃ for 5 min and hydrolysis at 130℃ for 8 min. The automated synthesis of 18 F-FMISO, presenting fast, reliable and multi-run features, could be completed with the total synthesis time of less than 65 min and radiochemical yield of 25%∼35% (without decay correction). The quality control of 18 F-FMISO was identical with the radiopharmaceutical requirements, especially the radiochemical purity of greater than 99% and high chemical purity and specific activity own to HPLC purification. (authors)

  4. Mechanochemical synthesis of bumetanide-4-aminobenzoic acid molecular cocrystals: a facile and green approach to drug optimization.

    Science.gov (United States)

    Bruni, Giovanna; Maietta, Mariarosa; Berbenni, Vittorio; Mustarelli, Piercarlo; Ferrara, Chiara; Freccero, Mauro; Grande, Vincenzo; Maggi, Lauretta; Milanese, Chiara; Girella, Alessandro; Marini, Amedeo

    2014-08-07

    Molecular cocrystals are of growing interest in pharmaceutics for their improved physicochemical properties. Their mechanochemical synthesis is very promising, being easy, cheap, and "green". Here, for the first time, we report on cocrystallization of bumetanide, a diuretic and natriuretic active principle, and 4-aminobenzoic acid. The synthesis is performed both by wet and dry grinding. The cocrystal formation was investigated with a wide range of techniques, including solid-state NMR, IR, XRD, microscopy, and thermal analysis. Wet and dry grinding procedures led to different cocrystal polymorphs. In particular, the dry method gave a cocrystal by powder amorphization and subsequent crystallization. DFT calculations at the B3LYP/6-31+G(d,p) level of theory shed light on the H-bond scheme at the basis of cocrystal formation. The cocrystals showed improved solubility and dissolution rate with respect to the drug alone. This could guarantee a faster absorption and a better bioavailability of the active principle.

  5. Synthesis, spectral characterization, and pharmacological screening of some 4-[{1-(arylmethylidene}-amino]-3-(4-pyridyl-5-mercapto-4H-1,2,4-triazole derivatives

    Directory of Open Access Journals (Sweden)

    Anees A Siddiqui

    2010-01-01

    Full Text Available Background : Pain is an unpleasant and subjective sensation that results from a harmful sensorial stimulation, which alerts the body about current or potential damage to its tissues and organs. Fever is a complex physiological response triggered by infections or aseptic stimuli. Elevation in body temperature occurs when the concentration of prostaglandin E 2 (PGE 2 increases within parts of the brain. Triazole derivatives have been found to possess various pharmacological and biological activities, such as, anti-inflammatory, analgesics, antipyretic, and antifungal. Materials and Methods : Various 4-[{1-(arylmethylidene}-amino]-3-(4-pyridyl-5-mercapto-4H-1,2,4-triazole derivatives were synthesized by a sequence of reactions starting from isonicotinic acid hydrazide. The synthesized compounds were screened for in-vivo analgesic by the tail-flick method and anti-pyretic activities at a dose of 25 and 100 mg/kg body weight respectively. The antipyretic activity was evaluated using Brewer′s yeast induced pyrexia in rats. Fever was induced by subcutaneously injecting 20 ml/kg of 20% aqueous suspension of Brewer′s yeast in normal saline. Results and Discussion : The analgesic screening results revealed that the compounds 3b, 3c, and 3d exhibited excellent analgesic activity at 60 and 90 minutes compared to the standard drug (Analgin. Results revealed that the compounds 3a, 3e, and 3f significantly decreased the temperature of pyretic (P<0.001 rats at one, three and six hours after compound administration as compared to Aspirin (standard drug. Conclusion : Compounds 3b, 3c, and 3d exhibited significant analgesic activity comparable with the standard drug analgin, using the tail flick model. Compounds 3a, 3e, and 3f showed significant anti-pyretic activities comparable with the standard drug aspirin using the yeast-induced pyrexia model.

  6. Quantification of low molecular weight selenium metabolites in human plasma after treatment with selenite in pharmacological doses by LC-ICP-MS

    DEFF Research Database (Denmark)

    Flouda, Konstantina; Dersch, Julie Maria; Gabel-Jensen, Charlotte

    2016-01-01

    The paper presents an analytical method for quantification of low molecular weight (LMW) selenium compounds in human plasma based on liquid chromatography inductively coupled plasma mass spectrometry (LC-ICP-MS) and post column isotope dilution-based quantification. Prior to analysis, samples were...

  7. The state of the art in non-pharmacological interventions for developmental stuttering. Part 2: qualitative evidence synthesis of views and experiences.

    Science.gov (United States)

    Johnson, Maxine; Baxter, Susan; Blank, Lindsay; Cantrell, Anna; Brumfitt, Shelagh; Enderby, Pam; Goyder, Elizabeth

    2016-01-01

    A range of interventions have been developed to treat stuttering in recent years. The effectiveness of these interventions has largely been assessed in studies focusing on the impact of specific types of therapy on patient outcomes. Relatively little is known about the factors that influence how the delivery and impact of different types of intervention may be experienced from the perspective of both people who deliver as well as those who receive interventions. To synthesize the available evidence in relation to factors that might enhance or mitigate against successful outcomes following interventions for stuttering by identifying and synthesizing relevant qualitative research that explored the experiences of people delivering and receiving interventions that aim to improve fluency. We carried out a systematic review including research that had used in-depth interviews and focus groups and conducted a substantive qualitative analysis of the data collected. Included study populations were either adults or children affected by a diagnosed stutter and/or providers of therapy for stuttering. An iterative approach was used to search for published qualitative evidence in relevant databases from 1990 to 2014. Retrieved citations were sifted for relevance and the data from articles that met the inclusion criteria were extracted. Each included paper was assessed for quality and a thematic analysis and synthesis of findings was carried out. Synthesized qualitative evidence highlights the changing experiences for people who stutter both historically and, for individuals, over the life course. Barriers and facilitators to the implementation of interventions for stuttering are encountered at the individual, intervention, interpersonal and social levels. Interventions may be particularly pertinent at certain transition points in the life course. Attention to emotional as well as practical aspects of stuttering is valued by people receiving therapy. The client

  8. Synthesis of a novel iron oxide contrast agent as a platform for multimodal molecular imaging

    International Nuclear Information System (INIS)

    Borny, R.

    2014-01-01

    The purpose of this thesis was to create and characterize a functionalizable multimodal iron oxide nanoparticle, compare it with previously available designs and to create red blood cell carriers to increase the circulation time in vivo. The optimization of biological and physicochemical properties of the particles required the introduction of a new synthesis protocol: to reduce the reticuloendothelial uptake as well as to avoid extensive renal clearance, the overall hydrodynamic size was adjusted to 40 nm. The improvement of the chemical stability necessitated cross-linking of the dextran cage. Amine groups were created on the surface to enable particle functionalization. The synthesized nanoparticles (xION aerosole ) were precipitated from Fe 2+ and Fe 3+ (ratio 2:1) in the presence of monodispersed 10 kD dextran. The surface was cross-linked with epichlorohydrin and nucleophilized with ammonia. Ultrafiltration and dialysis was used for purification. The synthesized xION aerosole particles were compared with available products (Endorem®, Guerbet; Resovist®, Schering; Rienso®, Takeda). The hydrodynamic diameter and the core size were determined by transmission electron microscopy, electron tomography, laser light scattering and electron tomography. The amine groups were accessed by incubation with fluorescin isothiocyanate and the Fe 2+ /Fe 3+ ratio by Mössbauer spectroscopy. The relaxivity was measured at 1.5 T and 20°C. The physicochemical stability was assessed by Zeta potential, UV light irradiation till 9 Joule as well as laser light scattering during thermal cycling between 20 and 80°C. Three human cell lines (HAEC, HASMC, HELA) were used to evaluate the cellular uptake. The synthesized particles are stable at a broad pH range, biocompatible and have a potentially longer plasma half-life. Moreover, the relaxivity is comparable with commercial products and the particles are detectable at nanomolar concentrations. The theoretically postulated

  9. [{sup 11}C]SMe-ADAM, an imaging agent for the brain serotonin transporter: synthesis, pharmacological characterization and microPET studies in rats

    Energy Technology Data Exchange (ETDEWEB)

    Zessin, Joerg [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany)]. E-mail: j.zessin@fz-rossendorf.de; Deuther-Conrad, Winnie [Institut fuer Interdisziplinaere Isotopenforschung, 04318 Leipzig (Germany); Kretzschmar, Marion [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany); Wuest, Frank [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany); Pawelke, Beate [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany); Brust, Peter [Institut fuer Interdisziplinaere Isotopenforschung, 04318 Leipzig (Germany); Steinbach, Joerg [Institut fuer Interdisziplinaere Isotopenforschung, 04318 Leipzig (Germany); Bergmann, Ralf [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany)

    2006-01-15

    N,N-Dimethyl-2-(2-amino-4-methylthiophenylthio)benzylamine (S Me-Adam, 1) is a highly potent and selective inhibitor of the serotonin transporter (SPERT). This compound was labeled with carbon-11 by methylation of the S-desmethyl precursor 10 with [{sup 11}C]methyl iodide to obtain the potential positron emission tomography (PET) radioligand [{sup 11}C]S Me-Adam. The radiochemical yield was 27{+-}5%, and the specific radioactivity was 26-40 GBq/{mu}mol at the end of synthesis. Ex vivo and in vivo biodistribution experiments in rats demonstrated a rapid accumulation of the radiotracer in brain regions known to be rich in SPERT, such as the thalamus/hypothalamus region (3.59{+-}0.41%ID/g at 5 min after injection). The specific uptake reached a thalamus to cerebellum ratio of 6.74{+-}0.95 at 60 min postinjection. The [{sup 11}C]SMe-ADAM uptake in the thalamus was significantly decreased by pretreatment with fluoxetine to 38{+-}11% of the control value. Furthermore, no metabolites of [{sup 11}C]SMe-ADAM could be detected in the SERT-rich regions of the rat brain. It is concluded that [{sup 11}C]SMe-ADAM may be a suitable PET ligand for SERT imaging in the living brain.

  10. [11C]SMe-ADAM, an imaging agent for the brain serotonin transporter: synthesis, pharmacological characterization and microPET studies in rats

    International Nuclear Information System (INIS)

    Zessin, Joerg; Deuther-Conrad, Winnie; Kretzschmar, Marion; Wuest, Frank; Pawelke, Beate; Brust, Peter; Steinbach, Joerg; Bergmann, Ralf

    2006-01-01

    N,N-Dimethyl-2-(2-amino-4-methylthiophenylthio)benzylamine (S Me-Adam, 1) is a highly potent and selective inhibitor of the serotonin transporter (SPERT). This compound was labeled with carbon-11 by methylation of the S-desmethyl precursor 10 with [ 11 C]methyl iodide to obtain the potential positron emission tomography (PET) radioligand [ 11 C]S Me-Adam. The radiochemical yield was 27±5%, and the specific radioactivity was 26-40 GBq/μmol at the end of synthesis. Ex vivo and in vivo biodistribution experiments in rats demonstrated a rapid accumulation of the radiotracer in brain regions known to be rich in SPERT, such as the thalamus/hypothalamus region (3.59±0.41%ID/g at 5 min after injection). The specific uptake reached a thalamus to cerebellum ratio of 6.74±0.95 at 60 min postinjection. The [ 11 C]SMe-ADAM uptake in the thalamus was significantly decreased by pretreatment with fluoxetine to 38±11% of the control value. Furthermore, no metabolites of [ 11 C]SMe-ADAM could be detected in the SERT-rich regions of the rat brain. It is concluded that [ 11 C]SMe-ADAM may be a suitable PET ligand for SERT imaging in the living brain

  11. [11C]SMe-ADAM, an imaging agent for the brain serotonin transporter: synthesis, pharmacological characterization and microPET studies in rats.

    Science.gov (United States)

    Zessin, Jörg; Deuther-Conrad, Winnie; Kretzschmar, Marion; Wüst, Frank; Pawelke, Beate; Brust, Peter; Steinbach, Jörg; Bergmann, Ralf

    2006-01-01

    N,N-Dimethyl-2-(2-amino-4-methylthiophenylthio)benzylamine (SMe-ADAM, 1) is a highly potent and selective inhibitor of the serotonin transporter (SERT). This compound was labeled with carbon-11 by methylation of the S-desmethyl precursor 10 with [(11)C]methyl iodide to obtain the potential positron emission tomography (PET) radioligand [(11)C]SMe-ADAM. The radiochemical yield was 27 +/- 5%, and the specific radioactivity was 26-40 GBq/micromol at the end of synthesis. Ex vivo and in vivo biodistribution experiments in rats demonstrated a rapid accumulation of the radiotracer in brain regions known to be rich in SERT, such as the thalamus/hypothalamus region (3.59 +/- 0.41%ID/g at 5 min after injection). The specific uptake reached a thalamus to cerebellum ratio of 6.74 +/- 0.95 at 60 min postinjection. The [(11)C]SMe-ADAM uptake in the thalamus was significantly decreased by pretreatment with fluoxetine to 38 +/- 11% of the control value. Furthermore, no metabolites of [(11)C]SMe-ADAM could be detected in the SERT-rich regions of the rat brain. It is concluded that [(11)C]SMe-ADAM may be a suitable PET ligand for SERT imaging in the living brain.

  12. Synthesis and pharmacological evaluation of N-substituted 2-(2-oxo-2H-chromen-4-yloxy)propanamide as cyclooxygenase inhibitors.

    Science.gov (United States)

    Rambabu, D; Mulakayala, Naveen; Ismail; Kumar, K Ravi; Kumar, G Pavan; Mulakayala, Chaitanya; Kumar, Chitta Suresh; Kalle, Arunasree M; Rao, M V Basaveswara; Oruganti, Srinivas; Pal, Manojit

    2012-11-01

    A series of novel N-substituted 2-(2-oxo-2H-chromen-4-yloxy)propanamide derivatives were synthesized via converting the readily available 4-hydroxy coumarin to the corresponding ethyl 2-(2-oxo-2H-chromen-4-yloxy)propanoate followed by hydrolysis and then reacting with different substituted amines. The molecular structures of two representative compounds, that is, 3 and 5l were confirmed by single crystal X-ray diffraction study. All the compounds synthesized were evaluated for their cyclooxygenase (COX) inhibiting properties in vitro. The compound 5i showed balanced selectivity towards COX-2 over COX-1 inhibition and good docking scores when docked into the COX-2 protein. Copyright © 2012 Elsevier Ltd. All rights reserved.

  13. Solid-Phase Synthesis of Molecularly Imprinted Polymer Nanoparticles with a Reusable Template – “Plastic Antibodies”

    Science.gov (United States)

    Poma, Alessandro; Guerreiro, Antonio; Whitcombe, Michael J.; Piletska, Elena V.; Turner, Anthony P.F.; Piletsky, Sergey A.

    2016-01-01

    Molecularly Imprinted Polymers (MIPs) are generic alternatives to antibodies in sensors, diagnostics and separations. To displace biomolecules without radical changes in infrastructure in device manufacture, MIPs should share their characteristics (solubility, size, specificity and affinity, localized binding domain) whilst maintaining the advantages of MIPs (low-cost, short development time and high stability) hence the interest in MIP nanoparticles. Herein we report a reusable solid-phase template approach (fully compatible with automation) for the synthesis of MIP nanoparticles and their precise manufacture using a prototype automated UV photochemical reactor. Batches of nanoparticles (30-400 nm) with narrow size distributions imprinted with: melamine (d = 60 nm, Kd = 6.3 × 10−8 m), vancomycin (d = 250 nm, Kd = 3.4 × 10−9 m), a peptide (d = 350 nm, Kd = 4.8 × 10−8 m) and proteins have been produced. Our instrument uses a column packed with glass beads, bearing the template. Process parameters are under computer control, requiring minimal manual intervention. For the first time we demonstrate the reliable re-use of molecular templates in the synthesis of MIPs (≥ 30 batches of nanoMIPs without loss of performance). NanoMIPs are produced template-free and the solid-phase acts both as template and affinity separation medium. PMID:26869870

  14. Improved synthesis with high yield and increased molecular weight of poly(alpha,beta-malic acid) by direct polycondensation.

    Science.gov (United States)

    Kajiyama, Tetsuto; Kobayashi, Hisatoshi; Taguchi, Tetsushi; Kataoka, Kazunori; Tanaka, Junzo

    2004-01-01

    The development of synthetic biodegradable polymers, such as poly(alpha-hydroxy acid), is particularly important for constructing medical devices, including scaffolds and sutures, and has attracted growing interest in the biomedical field. Here, we report a novel approach to preparing high molecular weight poly(malic acid) (HMW--PMA) as a biodegradable and bioabsorbable water-soluble polymer. We investigated in detail the reaction conditions for the simple direct polycondensation of l-malic acid, including the reaction times, temperatures, and catalysts. The molecular weight of synthesized alpha,beta-PMA is dependent on both the reaction temperature and time. The optimum reaction condition to obtain alpha,beta-PMA by direct polycondensation using tin(II) chloride as a catalyst was thus determined to be 110 degrees C for 45 h with a molecular weight of 5300. The method for alpha,beta-PMA synthesis established here will facilitate production of alpha,beta-PMA of various molecular weights, which may have a potential utility as biomaterials.

  15. Synthesis of sp3-rich scaffolds for molecular libraries through complexity-generating cascade reactions

    DEFF Research Database (Denmark)

    Flagstad, Thomas; Min, Geanna; Bonnet, K.

    2016-01-01

    An efficient strategy for the synthesis of complex small molecules from simple building blocks is presented. Key steps of the strategy include tandem Petasis and Diels–Alder reactions, and divergent complexity-generating cyclization cascades from a key dialdehyde intermediate. The methodology...

  16. Automatic reactor for solid-phase synthesis of molecularly imprinted polymeric nanoparticles (MIP NPs) in water.

    Science.gov (United States)

    Poma, Alessandro; Guerreiro, Antonio; Caygill, Sarah; Moczko, Ewa; Piletsky, Sergey

    We report the development of an automated chemical reactor for solid-phase synthesis of MIP NPs in water. Operational parameters are under computer control, requiring minimal operator intervention. In this study, "ready for use" MIP NPs with sub-nanomolar affinity are prepared against pepsin A, trypsin and α-amylase in only 4 hours.

  17. Automatic reactor for solid-phase synthesis of molecularly imprinted polymeric nanoparticles (MIP NPs) in water

    OpenAIRE

    Poma, Alessandro; Guerreiro, Antonio; Caygill, Sarah; Moczko, Ewa; Piletsky, Sergey

    2014-01-01

    We report the development of an automated chemical reactor for solid-phase synthesis of MIP NPs in water. Operational parameters are under computer control, requiring minimal operator intervention. In this study, “ready for use” MIP NPs with sub-nanomolar affinity are prepared against pepsin A, trypsin and α-amylase in only 4 hours.

  18. Synthesis and properties of ionic polyurethane dispersions: influence of polyol molecular weight

    International Nuclear Information System (INIS)

    Valipour Ebrahimi, M.; Barikani, M.; Mohammad Seyed Mohaghegh, S.

    2006-01-01

    A series of water dispersible polyurethanes containing carboxylate anion as the hydrophilic pendant group were prepared from toluene diisocyanate (TDI), 1,4- butanediol (1,4-BDO), dimethylol propionic acid and different molecular weight of polytetramethylene glycol . IR Spectroscopy was used to check the end of polymerization reaction and characterization of polymer. The effect of polytetramethylene glycol molecular weight was studied on the particle size distribution, contact angle, and mechanical and thermal properties of the emulsion-cast films. Average particle size of prepared polyurethane emulsions decreases with increasing the polytetramethylene glycol molecular weight. Tensile strength and hardness decrease and elongation-at-break and contact angle increase with increase of the polytetramethylene glycol molecular weight. Thermal property and thermal stability are also effected by variation of polytetramethylene glycol molecular weight. The thermal stability increases with increasing polytetramethylene glycol molecular weight. Glass transition temperature (T g ) moved toward the lower temperatures by increasing molecular weight of the polyol. Decrease in T g and tensile properties are interpreted in terms of the decrease in hard segments and the increase in chain flexibility and phase separation in high molecular weight polytetramethylene glycol based polyurethane

  19. Towards a molecular interpretation of astringency: synthesis, 3D structure, colloidal state, and human saliva protein recognition of procyanidins.

    Science.gov (United States)

    Cala, Olivier; Fabre, Sandy; Pinaud, Noël; Dufourc, Erick J; Fouquet, Eric; Laguerre, Michel; Pianet, Isabelle

    2011-07-01

    Astringency is a sensation in the mouth used in judging the quality of red wine. The rough, dry, and puckering sensation called astringency is the result of an interaction between tannins and saliva proteins, mainly proline-rich proteins (PRP), which leads to the formation and precipitation of a complex. A dry and rough sensation is then perceived in the mouth. To get an insight into astringency at the molecular level we investigated: (i) An efficient and iterative method for 4-8 procyanidin synthesis, which gives rise to all possible 4-8 procyanidins up to the tetramer with total control of degree of oligomerization and stereochemistry. (ii) The 3D-structural preferences, which take into account their internal movements, using 2D NMR and molecular modeling. (iii) The self-association process in water or hydroalcoholic solutions using diffusion NMR spectroscopy that gives the active proportion of tannins able to fix proteins. (iv) A comprehensive description of the PRP-procyanidin complex formation to get information about stoichiometry, binding site localization, and affinity constants for different procyanidins. The data collected suggest that the interactions are controlled by both procyanidin conformational and colloidal state preferences. All these results provide new insights into the molecular interpretation of tannin astringency. © Georg Thieme Verlag KG Stuttgart · New York.

  20. In situ synthesis of molecularly imprinted nanoparticles in porous support membranes using high-viscosity polymerization solvents.

    Science.gov (United States)

    Renkecz, Tibor; László, Krisztina; Horváth, Viola

    2012-06-01

    There is a growing need in membrane separations for novel membrane materials providing selective retention. Molecularly imprinted polymers (MIPs) are promising candidates for membrane functionalization. In this work, a novel approach is described to prepare composite membrane adsorbers incorporating molecularly imprinted microparticles or nanoparticles into commercially available macroporous filtration membranes. The polymerization is carried out in highly viscous polymerization solvents, and the particles are formed in situ in the pores of the support membrane. MIP particle composite membranes selective for terbutylazine were prepared and characterized by scanning electron microscopy and N₂ porosimetry. By varying the polymerization solvent microparticles or nanoparticles with diameters ranging from several hundred nanometers to 1 µm could be embedded into the support. The permeability of the membranes was in the range of 1000 to 20,000 Lm⁻²  hr⁻¹  bar⁻¹. The imprinted composite membranes showed high MIP/NIP (nonimprinted polymer) selectivity for the template in organic media both in equilibrium-rebinding measurements and in filtration experiments. The solid phase extraction of a mixture of the template, its analogs, and a nonrelated compound demonstrated MIP/NIP selectivity and substance selectivity of the new molecularly imprinted membrane. The synthesis technique offers a potential for the cost-effective production of selective membrane adsorbers with high capacity and high throughput. Copyright © 2012 John Wiley & Sons, Ltd.

  1. Synthesis and In Vitro and In Vivo Evaluation of Iodine-131-Labeled Folates: Potential Molecular Diagnostic and Therapeutic Radiopharmaceuticals

    International Nuclear Information System (INIS)

    Al Jammaz, I.

    2009-01-01

    Molecular targeting imaging has a great potential to be able to image molecular changes that are currently defined as predisease states which facilitate earlier detection of cancer and consequently, the greatest chance of cure. Advancement of scintigraphic imaging and radiotherapy is highly determined by development of more specific radiotracers. The Membrane-associated-folic acid receptor is a glycosylphospstidylinositol protein that overexpressed in approximately 100% of serious ovarian adenocarcinomas and various epithelial cancers including cervical, colorectal and renal cancers. Meanwhile, this receptor is highly restricted in most normal tissues which make these tumors as an excellent candidates for molecular targeting imaging and therapy through the folate receptor system. As part of our on-going research effort to develop prosthetic precursors for radiohalogenation of bioactive molecules, we have previously reported the synthesis and biological characterization of [ 18 F]- fluorobenzene and pyridine carbohydrazide-folate conjugates ([ 18 F]-SFB and [ 18 F]-SFP-folates). We here report the synthesis and biological characterization of [ 131 I]-iodobenzenecarbohydrazide-folate conjugate ([ 131 I]-SIB-folate) as a potential therapeutic radiopharmaceutical. The synthetic approaches for preparation of [ 131 I]iodobenzene carbohydrazide-folates ([ 131 I]-SIB-folate) entailed sequence of reactions. Hydrazide-folate was reacted with N-succinimidyl-m-[131I]-iodobenzoate-carboxylate ([ 131 I]-SIB) to give [ 131 I]-SIB-folate conjugate. Radiochemical yield was greater than 80% and synthesis times were ranging between 40-45 min. Radiochemical purity was also greater than 97% without HPLC purification. These synthetic approaches hold considerable promise as rapid and simple method for the radiohalogenation of folate in high radiochemical yield in short time. In vitro tests on KB cell line has shown that significant amount of the radioconjugate associated with cell

  2. Organic synthesis

    International Nuclear Information System (INIS)

    Lallemand, J.Y.; Fetizon, M.

    1988-01-01

    The 1988 progress report of the Organic Synthesis Chemistry laboratory (Polytechnic School, France), is presented. The laboratory activities are centered on the chemistry of natural products, which have a biological activity and on the development of new reactions, useful in the organic synthesis. The research works involve the following domains: the natural products chemistry which are applied in pharmacology, the plants and insects chemistry, the organic synthesis, the radical chemistry new reactions and the bio-organic physicochemistry. The published papers, the congress communications and the thesis are listed [fr

  3. Biological and Pharmacological properties

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. Biological and Pharmacological properties. NOEA inhibits Ceramidase. Anandamide inhibits gap junction conductance and reduces sperm fertilizing capacity. Endogenous ligands for Cannabinoid receptors (anandamide and NPEA). Antibacterial and antiviral ...

  4. Synthesis and application of magnetic molecularly imprinted polymers in sample preparation.

    Science.gov (United States)

    Huang, Shuyao; Xu, Jianqiao; Zheng, Jiating; Zhu, Fang; Xie, Lijun; Ouyang, Gangfeng

    2018-04-12

    Magnetic molecularly imprinted polymers (MMIPs) have superior advantages in sample pretreatment because of their high selectivity for target analytes and the fast and easy isolation from samples. To meet the demand of both good magnetic property and good extraction performance, MMIPs with various structures, from traditional core-shell structures to novel composite structures with a larger specific surface area and more accessible binding sites, are fabricated by different preparation technologies. Moreover, as the molecularly imprinted polymer (MIP) layers determine the affinity, selectivity, and saturated adsorption amount of MMIPs, the development and innovation of the MIP layer are attracting attention and are reviewed here. Many studies that used MMIPs as sorbents in dispersive solid-phase extraction of complex samples, including environmental, food, and biofluid samples, are summarized. Graphical abstract The application of magnetic molecularly imprinted polymers (MIPs) in the sample preparation procedure improves the analytical performances for complex samples. MITs molecular imprinting technologies.

  5. Pharmacological screening technologies for venom peptide discovery.

    Science.gov (United States)

    Prashanth, Jutty Rajan; Hasaballah, Nojod; Vetter, Irina

    2017-12-01

    Venomous animals occupy one of the most successful evolutionary niches and occur on nearly every continent. They deliver venoms via biting and stinging apparatuses with the aim to rapidly incapacitate prey and deter predators. This has led to the evolution of venom components that act at a number of biological targets - including ion channels, G-protein coupled receptors, transporters and enzymes - with exquisite selectivity and potency, making venom-derived components attractive pharmacological tool compounds and drug leads. In recent years, plate-based pharmacological screening approaches have been introduced to accelerate venom-derived drug discovery. A range of assays are amenable to this purpose, including high-throughput electrophysiology, fluorescence-based functional and binding assays. However, despite these technological advances, the traditional activity-guided fractionation approach is time-consuming and resource-intensive. The combination of screening techniques suitable for miniaturization with sequence-based discovery approaches - supported by advanced proteomics, mass spectrometry, chromatography as well as synthesis and expression techniques - promises to further improve venom peptide discovery. Here, we discuss practical aspects of establishing a pipeline for venom peptide drug discovery with a particular emphasis on pharmacology and pharmacological screening approaches. This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.' Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Synthesis of single crystal manganese oxide octahedral molecular sieve (OMS) nanostructures with tunable tunnels and shapes.

    Science.gov (United States)

    Li, Wei-Na; Yuan, Jikang; Gomez-Mower, Sinue; Sithambaram, Shantakumar; Suib, Steven L

    2006-02-23

    A new and facile route is reported to manipulate the self-assembly synthesis of hierarchically ordered Rb-OMS-2 and pyrolusite with an interesting flowerlike morphology by a direct and mild reaction between rubidium chromateand manganese sulfate without any organic templates. The crystal forms, morphologies, and tunnel sizes of the obtained OMS materials can be controlled. A mechanism for the growth of manganese dioxides with flowerlike architectures was proposed. The obtained products exhibit potential for use in catalysis and other applications.

  7. Aging changes of molecular synthesis in the respiratory organs as revealed by microscopic radioautography

    International Nuclear Information System (INIS)

    Nagata, T.

    2001-01-01

    For the purpose of elucidating the aging changes of macromolecular synthesis such as DNA, RNA, proteins, glycoproteins, glycides and lipids in various organ systems of experimental animals and men, we have studied respiratory organs of aging mice as a series of systematic studies using light and electron microscopic radioautography in various organ systems after incorporations with macromolecular precursors. The experimental animals mainly used were dd Y strain mice at various aging groups from embryo to postnatal day 1 and 3, weeks 1 and 2, months 1, 2, 6, 12 up to 2 year senescent stages. The animals were injected with such macromolecular precursors as 3 H - thymidine for DNA, 3 H-uridine for RNA, 3 H-leucine for proteins, 35 SO 4 for glycoproteins. The results demonstrated that these precursors were incorporated into various cell types in the lungs and tracheas at various ages from perinatal to juvenile, mature and senescent stages showing specific patterns of macromolecular synthesis. It is concluded that these specific pattern of macromolecular synthesis in respective cell types demonstrated the organ specificity of aging. (author)

  8. Potential New H1N1 Neuraminidase Inhibitors from Ferulic Acid and Vanillin: Molecular Modelling, Synthesis and in Vitro Assay

    Science.gov (United States)

    Hariono, Maywan; Abdullah, Nurshariza; Damodaran, K. V.; Kamarulzaman, Ezatul E.; Mohamed, Nornisah; Hassan, Sharifah Syed; Shamsuddin, Shaharum; Wahab, Habibah A.

    2016-12-01

    We report the computational and experimental efforts in the design and synthesis of novel neuraminidase (NA) inhibitors from ferulic acid and vanillin. Two proposed ferulic acid analogues, MY7 and MY8 were predicted to inhibit H1N1 NA using molecular docking. From these two analogues, we designed, synthesised and evaluated the biological activities of a series of ferulic acid and vanillin derivatives. The enzymatic H1N1 NA inhibition assay showed MY21 (a vanillin derivative) has the lowest IC50 of 50 μM. In contrast, the virus inhibition assay showed MY15, a ferulic acid derivative has the best activity with the EC50 of ~0.95 μM. Modelling studies further suggest that these predicted activities might be due to the interactions with conserved and essential residues of NA with ΔGbind values comparable to those of oseltamivir and zanamivir, the two commercial NA inhibitors.

  9. Synthesis and characterization of a helicene-based imidazolium salt and its application in organic molecular electronics.

    Science.gov (United States)

    Storch, Jan; Zadny, Jaroslav; Strasak, Tomas; Kubala, Martin; Sykora, Jan; Dusek, Michal; Cirkva, Vladimir; Matejka, Pavel; Krbal, Milos; Vacek, Jan

    2015-02-02

    Herein we demonstrate the synthesis of a helicene-based imidazolium salt. The salt was prepared by starting from racemic 2-methyl[6]helicene, which undergoes radical bromination to yield 2-(bromomethyl)[6]helicene. Subsequent treatment with 1-butylimidazole leads to the corresponding salt 1-butyl-3-(2-methyl[6]helicenyl)-imidazolium bromide. The prepared salt was subsequently characterized by using NMR spectroscopy and X-ray analysis, various optical spectrometric techniques, and computational chemistry tools. Finally, the imidazolium salt was immobilized onto a SiO2 substrate as a crystalline or amorphous deposit. The deposited layers were used for the development of organic molecular semiconductor devices and the construction of a fully reversible humidity sensor. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Efficient and Scalable Synthesis of 4-Carboxy-Pennsylvania Green Methyl Ester: A Hydrophobic Building Block for Fluorescent Molecular Probes.

    Science.gov (United States)

    Woydziak, Zachary R; Fu, Liqiang; Peterson, Blake R

    2014-01-01

    Fluorinated fluorophores are valuable tools for studies of biological systems. However, amine-reactive single-isomer derivatives of these compounds are often very expensive. To provide an inexpensive alternative, we report a practical synthesis of 4-carboxy-Pennsylvania Green methyl ester. Derivatives of this hydrophobic fluorinated fluorophore, a hybrid of the dyes Oregon Green and Tokyo Green, are often cell permeable, enabling labeling of intracellular targets and components. Moreover, the low pKa of Pennsylvania Green (4.8) confers bright fluorescence in acidic cellular compartments such as endosomes, enhancing its utility for chemical biology investigations. To improve access to the key intermediate 2,7-difluoro-3,6-dihydroxyxanthen-9-one, we subjected bis-(2,4,5-trifluorophenyl)methanone to iterative nucleophilic aromatic substitution by hydroxide on scales of > 40 g. This intermediate was used to prepare over 15 grams of pure 4-carboxy-Pennsylvania Green methyl ester in 28% overall yield without requiring chromatography. This compound can be converted into the amine reactive N -hydroxysuccinimidyl ester in essentially quantitative yield for the synthesis of a wide variety of fluorescent molecular probes.

  11. A versatile single molecular precursor for the synthesis of layered oxide cathode materials for Li-ion batteries.

    Science.gov (United States)

    Li, Maofan; Liu, Jiajie; Liu, Tongchao; Zhang, Mingjian; Pan, Feng

    2018-02-01

    A carbonyl-bridged single molecular precursor LiTM(acac) 3 [transition metal (TM) = cobalt/manganese/nickel (Co/Mn/Ni), acac = acetylacetone], featuring a one-dimensional chain structure, was designed and applied to achieve the layered oxide cathode materials: LiTMO 2 (TM = Ni/Mn/Co, NMC). As examples, layered oxides, primary LiCoO 2 , binary LiNi 0.8 Co 0.2 O 2 and ternary LiNi 0.5 Mn 0.3 Co 0.2 O 2 were successfully prepared to be used as cathode materials. When they are applied to lithium-ion batteries (LIBs), all exhibit good electrochemical performance because of their unique morphology and great uniformity of element distribution. This versatile precursor is predicted to accommodate many other metal cations, such as aluminum (Al 3+ ), iron (Fe 2+ ), and sodium (Na + ), because of the flexibility of organic ligand, which not only facilitates the doping-modification of the NMC system, but also enables synthesis of Na-ion layered oxides. This opens a new direction of research for the synthesis of high-performance layered oxide cathode materials for LIBs.

  12. Approaches for introducing high molecular diversity in scaffolds: fast parallel synthesis of highly substituted 1H-quinolin-4-one libraries.

    Science.gov (United States)

    Kuznetsov, Vladimir; Gorohovsky, Sofia; Levy, Amalia; Meir, Simcha; Shkoulev, Vladimir; Menashe, Naim; Greenwald, Moshe; Aizikovich, Alexander; Ofer, Dror; Byk, Gerardo; Gellerman, Garry

    2004-01-01

    We have developed a two steps strategy for the parallel synthesis of highly diversified quinolin-ones. In the first step we have combined and improved different synthetic methods for generating quinolin-4-ones bearing four different substitutions at specific positions using round bottomed flasks. The synthesis was assessed for a large number of substituted quinolin-4-ones. In the second step, the improved method was adapted to a parallel array synthesis using a 12 positions carrousel as demonstrated for the synthesis of 42-variable quinolin-4-ones. The first combinatorial library set 14(a-x) was obtained with a chemical purity of more than 95% without purification, the second library set 15(a-r), which included two synthetic steps, needed combinatorial purification using an innovative parallel purifier. The proposed approach contributes to a more extensive diversification of molecular scaffolds in general and provides access to highly substituted quinolinones in particular.

  13. Synthesis and properties of aqueous polyurethane dispersions: Influence of molecular weight of polyethylene glycol

    Energy Technology Data Exchange (ETDEWEB)

    Mumtaz, Fatima; Zuber, Mohammad; Zia, Khalid Mahmood [Government College University, Faisalabad (Pakistan); Jamil, Tahir [University of the Punjab, Lahore (Pakistan); Hussain, Rizwan [National Engineering and Scientific Commission (NESCOM), Islamabad (Pakistan)

    2013-12-15

    Aqueous polyurethane dispersions (PUDs) have recently emerged as important alternatives to their solvent-based counterparts for various applications due to increasing health and environmental awareness. A series of aqueous polyurethane dispersions containing carboxylate anion as hydrophilic pendant groups were synthesized through step growth polymerization reaction using hexamethylene diisocyanate (HDI), 1,4-butanediol (1,4-BDO), dimethylol propionic acid (DMPA) and polyethylene glycol (PEG) of different molecular weight. Effect of PEG molecular weight was investigated on molecular structure, contact angle measurement, and physical and adhesive properties of PU emulsions. Fourier transform infrared spectroscopy (FT-IR) was used to check the completion of polymerization reaction. Contact angle measurement indicated that the hydrophilicity of polymer increases by increasing molecular weight of PEG with a corresponding decrease in contact angle. Results of T-peel test showed a decrease in peel strength by increasing molecular weight of PEG. Moreover, solid contents%, drying time and storage stability suggested fast drying properties and greater stability of aqueous PU dispersions.

  14. Pharmacological chaperoning: a primer on mechanism and pharmacology.

    Science.gov (United States)

    Leidenheimer, Nancy J; Ryder, Katelyn G

    2014-05-01

    Approximately forty percent of diseases are attributable to protein misfolding, including those for which genetic mutation produces misfolding mutants. Intriguingly, many of these mutants are not terminally misfolded since native-like folding, and subsequent trafficking to functional locations, can be induced by target-specific, small molecules variably termed pharmacological chaperones, pharmacoperones, or pharmacochaperones (PCs). PC targets include enzymes, receptors, transporters, and ion channels, revealing the breadth of proteins that can be engaged by ligand-assisted folding. The purpose of this review is to provide an integrated primer of the diverse mechanisms and pharmacology of PCs. In this regard, we examine the structural mechanisms that underlie PC rescue of misfolding mutants, including the ability of PCs to act as surrogates for defective intramolecular interactions and, at the intermolecular level, overcome oligomerization deficiencies and dominant negative effects, as well as influence the subunit stoichiometry of heteropentameric receptors. Not surprisingly, PC-mediated structural correction of misfolding mutants normalizes interactions with molecular chaperones that participate in protein quality control and forward-trafficking. A variety of small molecules have proven to be efficacious PCs and the advantages and disadvantages of employing orthostatic antagonists, active-site inhibitors, orthostatic agonists, and allosteric modulator PCs are considered. Also examined is the possibility that several therapeutic agents may have unrecognized activity as PCs, and this chaperoning activity may mediate/contribute to therapeutic action and/or account for adverse effects. Lastly, we explore evidence that pharmacological chaperoning exploits intrinsic ligand-assisted folding mechanisms. Given the widespread applicability of PC rescue of mutants associated with protein folding disorders, both in vitro and in vivo, the therapeutic potential of PCs is vast

  15. Synthesis of cerium oxide catalysts supported on MCM-41 molecular sieve

    International Nuclear Information System (INIS)

    Souza, E.L.S.; Barros, T.R.B.; Sousa, B.V. de

    2016-01-01

    Porous materials have been widely studied as catalysts and catalyst support. The MCM-41 structure is the one that has been most studied because of its application possibilities in chemical processes. This work aimed to obtain and characterize cerium oxide catalysts supported on MCM-41 molecular sieve. The molecular sieve was synthesized by the conventional method with the following molar composition: 1 SiO2: 0.30 CTABr: NH3 11: 144 H2O. Then, 25% w/w cerium was incorporated into the MCM-41 using the wet impregnation process and the material obtained was activated by calcination. From the XRD patterns was confirmed the structure of the molecular sieve, and were identified the cerium oxide phases in its structure. The textural catalysts characteristics were investigated by isotherms of N2 adsorption/desorption (BET method). (author)

  16. Synthesis, characterization and pharmacological evaluation of ...

    African Journals Online (AJOL)

    microscope (SEM), mass spectrometry (EI-MS), ultraviolet-visible (UV-Vis) spectrophotometry, ... The new compounds were also investigated for their alkaline phosphatase (ALPs) inhibition, .... The antimicrobial properties of OMZ, HQL and.

  17. Synthesis, Spectroscopic and Pharmacological Studies of Bivalent ...

    African Journals Online (AJOL)

    NICO

    A series of metal complexes of Cu(II), Zn(II) and Hg(II) having the general composition [M(L)2X2] [where L .... determined by carrageenan induced paw oedema model. The .... C–N deformation.21 In each complex, two thiourea ligands coor-.

  18. Synthesis, characterization and pharmacological evaluation of ...

    African Journals Online (AJOL)

    electrolytes. Ni(II) complex exhibited antioxidant activity (30.48 ± 0.32 μM) higher than those of BHT (standard) and other complexes. Stronger inhibition of ALPs by Ni (II) mixed ligand complex compared to the other complexes was evident.

  19. Synthesis of a pH-Sensitive Hetero[4]Rotaxane Molecular Machine that Combines [c2]Daisy and [2]Rotaxane Arrangements.

    Science.gov (United States)

    Waelès, Philip; Riss-Yaw, Benjamin; Coutrot, Frédéric

    2016-05-10

    The synthesis of a novel pH-sensitive hetero[4]rotaxane molecular machine through a self-sorting strategy is reported. The original tetra-interlocked molecular architecture combines a [c2]daisy chain scaffold linked to two [2]rotaxane units. Actuation of the system through pH variation is possible thanks to the specific interactions of the dibenzo-24-crown-8 (DB24C8) macrocycles for ammonium, anilinium, and triazolium molecular stations. Selective deprotonation of the anilinium moieties triggers shuttling of the unsubstituted DB24C8 along the [2]rotaxane units. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Some new methyl-8-methoxypsoralens: synthesis, photobinding to DNA, photobiological properties and molecular modelling.

    Science.gov (United States)

    Gia, O; Anselmo, A; Pozzan, A; Antonello, C; Magno, S M; Uriarte, E

    1997-01-01

    The tricyclic structure of known natural photochemotherapeutic drugs such as 8-methoxypsoralen and 5-methoxypsoralen is often taken as a model in the search of new photosensitizer agents with less phototoxic and mutagenic effects. This paper describes the synthesis, characterization, photobinding to DNA, photobiological properties and computational chemistry of some 8-methoxypsoralen derivatives bearing two or three methyl groups at the key positions of the two photoactive double bonds. Results showed that photoreactivity and photobiological behaviour depend on the pattern of methyl substitutions. Antiproliferative activity in cell lines shows good correlation with DNA interaction data.

  1. Catalytic Synthesis of n-Butyl Oleate by Cerium Complex Doped Y/SBA-15 Composite Molecular Sieve

    Science.gov (United States)

    Shi, Chunwei; Bian, Xue; Wu, Yongfu; Cong, Yufeng; Pei, Mingyuan

    2018-01-01

    Cerium ion was successfully incorporated into Y/SBA-15 micro-mesoporous molecular sieves via the hydrothermal synthesis method to give a series of composite materials. The prepared materials were thoroughly characterized using Fourier transform infrared spectroscopy (FT-IR), X-ray fluorescence spectroscopy (XRF), scanning electron microscopy-energy dispersive spectroscopy (SEM-EDS) and differential thermo gravimetric analysis (TG-DTG). The results showed that the prepared composite materials retained the highly ordered mesoporous two-dimensional hexagonal structure of SBA-15 and the octagonal structure of Y. The catalyst Ce-Y/SBA-15 was prepared and characterized, then the esterification of n-butanol and oleic acid was studied with bismuth phosphotungstate as a catalyst. Using this model reaction, the effects of Ce-HY/SBA-15, molar ratio of alcohol to oleic acid, amount of catalysts, reaction time and reaction temperature were investigated. The experimental results show that the optimal reaction conditions were: 1.8:1 molar ratio of alcohol to acid, 5 % catalyst amount (based on weight of oleic acid), 4 h reaction time and reflux conditions. Under these conditions, the yield of esterification was 90.6 %. The results suggest that the addition of Ce can effectively improve the catalytic properties of composite molecular sieves.

  2. Asymmetric Synthesis of Second-Generation Light-Driven Molecular Motors

    NARCIS (Netherlands)

    van Leeuwen, Thomas; Danowski, Wojciech; Otten, Edwin; Wezenberg, Sander J; Feringa, Ben L

    2017-01-01

    The enantiomeric homogeneity of light-driven molecular motors based on overcrowded alkenes is crucial in their application as either unidirectional rotors or as chiral multistate switches. It was challenging to obtain these compounds as single enantiomers via the established synthetic procedures due

  3. Branched polyacrylamides : Synthesis and effect of molecular architecture on solution rheology

    NARCIS (Netherlands)

    Wever, D. A. Z.; Picchioni, F.; Broekhuis, A. A.

    2013-01-01

    Linear, star and comb-like polyacrylamides (PAM) have been prepared by atomic transfer radical polymerization (ATRP) in aqueous media at room temperature. The influence of the molecular architecture of PAM on the rheological properties in aqueous solution has been investigated. The well-known theory

  4. Synthesis and chemistry of chromium in CrAPO-5 molecular sieves

    NARCIS (Netherlands)

    Weckhuysen, B.M.; Schoonheydt, R.A.

    1994-01-01

    CrAPO-5 molecular sieves were synthesized hydrothermally starting with different Cr precursors and Cr and template contents. The behavior of Cr was investigated spectroscopically by diffuse reflectance spectroscopy (d.r.s.) and electron spin resonance (e.s.r.). In the gels, Cr 3+ and Cr 8+ are

  5. Tri-partite complex for axonal transport drug delivery achieves pharmacological effect

    Directory of Open Access Journals (Sweden)

    Frederickson Martyn

    2010-01-01

    Full Text Available Abstract Background Targeted delivery of pharmaceutical agents into selected populations of CNS (Central Nervous System neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior. Results We developed chemical synthesis methodologies for assembling these tripartite complexes using a variety of axonal transport facilitators including nerve growth factor, wheat germ agglutinin, and synthetic facilitators derived from phage display work. Loading of up to 100 drug molecules per complex was achieved. Conjugation methods were used that allowed the drugs to be released in active form inside the cell body after transport. Intramuscular and intradermal injection proved effective for introducing pharmacologically effective doses into selected populations of CNS neurons. Pharmacological efficacy with gabapentin in a paw withdrawal latency model revealed a ten fold increase in half life and a 300 fold decrease in necessary dose relative to systemic administration for gabapentin when the drug was delivered by axonal transport using the tripartite vehicle. Conclusion Specific targeting of selected subpopulations of CNS neurons for drug delivery by axonal

  6. Pharmacological features of osthole

    Directory of Open Access Journals (Sweden)

    Agata Jarząb

    2017-05-01

    Full Text Available Coumarins are a group of naturally occurring compounds common in the plant world. These substances and their derivatives exhibit a broad range of biological activities.One of the naturally occurring coumarins is osthole, which can most frequently be found in plants of the Apiaceae family. Cnidium monnieri (L. Cusson ex Juss. Angelica pubescens Maxim. and Peucedanum ostruthium (L.. It has anti-proliferative, anti-inflammatory, anti-convulsant, and antiallergic properties; apart from that, inhibition of platelet aggregation has also been proved. The impact of osthole on bone metabolism has been demonstrated; also its hepatoprotective and neuroprotective properties have been confirmed. The inhibitory effect of this metokcompound on the development of neurodegenerative diseases has been proved in experimental models. Anticancer features of osthole have been also demonstrated both in vitro on different cell lines, and in vivo using animals xenografts. Osthole inhibited proliferation, motility and invasiveness of tumor cells, which may be associated with the induction of apoptosis and cell cycle slowdown. The exact molecular mechanism of osthole anti-cancer mode of action has not been fully elucidated. A synergistic effect of osthole with other anti-tumor substances has been also reported. Modification of its chemical structure led to the synthesis of many derivatives with significant anticancer effects.To sum up, osthole is an interesting therapeutic option, due to both its direct effect on tumor cells, as well as its neuroprotective or anti-inflammatory properties. Thus, there is a chance to use osthole or its synthetic derivatives in the treatment of cancer.

  7. A Straightforward Route to Tetrachloroauric Acid from Gold Metal and Molecular Chlorine for Nanoparticle Synthesis

    Directory of Open Access Journals (Sweden)

    Shirin R. King

    2015-08-01

    Full Text Available Aqueous solutions of tetrachloroauric acid of high purity and stability were synthesised using the known reaction of gold metal with chlorine gas. The straightforward procedure developed here allows the resulting solution to be used directly for gold nanoparticle synthesis. The procedure involves bubbling chlorine gas through pure water containing a pellet of gold. The reaction is quantitative and progressed at a satisfactory rate at 50 °C. The gold(III chloride solutions produced by this method show no evidence of returning to metallic gold over at least twelve months. This procedure also provides a straightforward method to determine the concentration of the resulting solution using the initial mass of gold and volume of water.

  8. Poly[ n ]catenanes: Synthesis of molecular interlocked chains

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Qiong; Rauscher, Phillip M.; Lang, Xiaolong; Wojtecki, Rudy J.; de Pablo, Juan J.; Hore, Michael J. A.; Rowan, Stuart J.

    2017-11-30

    As the macromolecular version of mechanically interlocked molecules, mechanically interlocked polymers are promising candidates for the creation of sophisticated molecular machines and smart soft materials. Poly[n]catenanes, where the molecular chains consist solely of interlocked macrocycles, contain one of the highest concentrations of topological bonds. We report, herein, a synthetic approach toward this distinctive polymer architecture in high yield (similar to 75%) via efficient ring closing of rationally designed metallosupramolecular polymers. Light-scattering, mass spectrometric, and nuclear magnetic resonance characterization of fractionated samples support assignment of the high-molar mass product (number-average molar mass similar to 21.4 kilograms per mole) to a mixture of linear poly[7-26]catenanes, branched poly[13-130]catenanes, and cyclic poly[4-7]catenanes. Increased hydrodynamic radius (in solution) and glass transition temperature (in bulk materials) were observed upon metallation with Zn2+.

  9. Synthesis and Characterization of Magnetic-Graphene Molecularly Imprinted Polymers for Selective Recognition of Ltryptophan

    Directory of Open Access Journals (Sweden)

    Zhang Yi

    2017-01-01

    Full Text Available In this paper, a novel molecular imprinted polymer using L-tryptophan(L-Trp as the template, dopamine(DA as both functional monomer and cross linking agent, magnetic graphene as the supporting matrix was synthesized. The prepared magnetic-graphene molecularly imprinted polymers(Fe3O4@GO-MIPs were characterized by Fourier transform infrared spectrometer(FT-IR, transmission electron microscopy (TEM, vibrating sample magnetometer (VSM, respectively. The results showed that when the molar ratio of L- tryptophan and dopamine was 1:4 and the reaction temperature was 60 °C, Fe3O4@GO-MIPs had the best adsorption quantity of 31.9 mg/g. The rebinding experiments indicated that Fe3O4@GO-MIPs not only have outstanding affinity and selectivity towards L-Trp over structurally related compounds but also easily reach the magnetic separation under an external magnetic field.

  10. Experimental mixture design as a tool for the synthesis of antimicrobial selective molecularly imprinted monodisperse microbeads.

    Science.gov (United States)

    Benito-Peña, Elena; Navarro-Villoslada, Fernando; Carrasco, Sergio; Jockusch, Steffen; Ottaviani, M Francesca; Moreno-Bondi, Maria C

    2015-05-27

    The effect of the cross-linker on the shape and size of molecular imprinted polymer (MIP) beads prepared by precipitation polymerization has been evaluated using a chemometric approach. Molecularly imprinted microspheres for the selective recognition of fluoroquinolone antimicrobials were prepared in a one-step precipitation polymerization procedure using enrofloxacin (ENR) as the template molecule, methacrylic acid as functional monomer, 2-hydroxyethyl methacrylate as hydrophilic comonomer, and acetonitrile as the porogen. The type and amount of cross-linker, namely ethylene glycol dimethacrylate, divinylbenzene or trimethylolpropane trimethacrylate, to obtain monodispersed MIP spherical beads in the micrometer range was optimized using a simplex lattice design. Particle size and morphology were assessed by scanning electron microscopy, dynamic light scattering, and nitrogen adsorption measurements. Electron paramagnetic resonance spectroscopy in conjunction with a nitroxide as spin probe revealed information about the microviscosity and polarity of the binding sites in imprinted and nonimprinted polymer beads.

  11. Synthesis, QSAR, and Molecular Dynamics Simulation of Amidino-substituted Benzimidazoles as Dipeptidyl Peptidase III Inhibitors.

    Science.gov (United States)

    Rastija, Vesna; Agić, Dejan; Tomiš, Sanja; Nikolič, Sonja; Hranjec, Marijana; Grace, Karminski-Zamola; Abramić, Marija

    2015-01-01

    A molecular modeling study is performed on series of benzimidazol-based inhibitors of human dipeptidyl peptidase III (DPP III). An eight novel compounds were synthesized in excellent yields using green chemistry approach. This study is aimed to elucidate the structural features of benzimidazole derivatives required for antagonism of human DPP III activity using Quantitative Structure-Activity Relationship (QSAR) analysis, and to understand the mechanism of one of the most potent inhibitor binding into the active site of this enzyme, by molecular dynamics (MD) simulations. The best model obtained includes S3K and RDF045m descriptors which have explained 89.4 % of inhibitory activity. Depicted moiety for strong inhibition activity matches to the structure of most potent compound. MD simulation has revealed importance of imidazolinyl and phenyl groups in the mechanism of binding into the active site of human DPP III.

  12. Synthesis of a nanoporous molecularly imprinted polymers for dibutyl Phthalate extracted from Trichoderma Harzianum

    Directory of Open Access Journals (Sweden)

    Maede Shahiri Tabarestani

    2016-07-01

    Full Text Available In this study, molecularly imprinted polymers were synthesized for dibutyl phthalate as a bioactive chemical compound with antifungal activity which produced by Trichoderma Harzianum (JX1738521. The molecularly imprinted polymers were synthesized via precipitation polymerization method from methacrylic acid, dibutyl phthalate and trimetylolpropantrimethacrylate as a functional monomer, template and cross-linker, respectively. After removal of the template by the eluent from the MIPs, the leached nanoparticles of the MIPs had a good binding capacity as equal 830 mg/g. The polymer particles have been evaluated by field emission scan electron microscopy and Brunauer–Emmett–Teller  techniques. The excellent specific surface area in the molecularly imprinted polymers as equal to 690.301 m2/g comparatively to non-imprinted polymers (ca. 89.894 m2/g, confirms that the nanoporous MIPs were synthesized, successfully. The results indicated that the nanoporous MIPs can be used in solid phase extraction. This is a novel method for separation of the bioactive compounds from fungi secondary metabolites in biological control.

  13. Synthesis and Theoretical Study of Molecularly Imprinted Nanospheres for Recognition of Tocopherols

    Directory of Open Access Journals (Sweden)

    Chartchalerm Isarankura-Na-Ayudhya

    2009-08-01

    Full Text Available Molecular imprinting is a technology that facilitates the production of artificial receptors toward compounds of interest. The molecularly imprinted polymers act as artificial antibodies, artificial receptors, or artificial enzymes with the added benefit over their biological counterparts of being highly durable. In this study, we prepared molecularly imprinted polymers for the purpose of binding specifically to tocopherol (vitamin E and its derivative, tocopherol acetate. Binding of the imprinted polymers to the template was found to be two times greater than that of the control, non-imprinted polymers, when using only 10 mg of polymers. Optimization of the rebinding solvent indicated that ethanol-water at a molar ratio of 6:4 (v/v was the best solvent system as it enhanced the rebinding performance of the imprinted polymers toward both tocopherol and tocopherol acetate with a binding capacity of approximately 2 mg/g of polymer. Furthermore, imprinted nanospheres against tocopherol was successfully prepared by precipitation polymerization with ethanol-water at a molar ratio of 8:2 (v/v as the optimal rebinding solvent. Computer simulation was also performed to provide mechanistic insights on the binding mode of template-monomer complexes. Such polymers show high potential for industrial and medical applications, particularly for selective separation of tocopherol and derivatives.

  14. Synthesis and characterization of montmorillonite clay intercalated with molecular magnetic compounds

    Energy Technology Data Exchange (ETDEWEB)

    Martins, Marcel G.; Martins, Daniel O.T.A.; Carvalho, Beatriz L.C. de [Instituto de Química, Universidade Federal Fluminense, Niterói, RJ 24.020–150 (Brazil); Mercante, Luiza A. [Laboratório Nacional de Nanotecnologia para o Agronegócio (LNNA), Embrapa Instrumentação, São Carlos, SP 13560 970 (Brazil); Soriano, Stéphane [Instituto de Física, Universidade Federal Fluminense, Niterói, RJ 24.210 346 (Brazil); Andruh, Marius [Inorganic Chemistry Laboratory, Faculty of Chemistry, University of Bucharest, Str. Dumbrava Rosie nr. 23, Bucharest (Romania); Vieira, Méri D., E-mail: gqimeri@vm.uff.br [Instituto de Química, Universidade Federal Fluminense, Niterói, RJ 24.020–150 (Brazil); Vaz, Maria G.F., E-mail: mariavaz@vm.uff.br [Instituto de Química, Universidade Federal Fluminense, Niterói, RJ 24.020–150 (Brazil)

    2015-08-15

    In this work montmorillonite (MMT) clay, whose matrix was modified with an ammonium salt (hexadecyltrimethylammonium bromide – CTAB), was employed as an inorganic host for the intercalation of three different molecular magnetic compounds through ion exchange: a nitronyl nitroxide derivative 2-[4-(N-ethyl)-pyridinium]-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (p-EtRad{sup +}) and two binuclear coordination compounds, [Ni(valpn)Ln]{sup 3+}, where H{sub 2}valpn stands for 1,3-propanediyl-bis(2-iminomethylene-6-methoxy-phenol), and Ln=Gd{sup III}; Dy{sup III}. The pristine MMT and the intercalated materials were characterized by X-ray powder diffraction (XRD), infrared spectroscopy (IR), scanning electron microscopy (SEM), thermogravimetric analysis (TGA) and magnetic measurements. The X-ray diffraction data analysis showed an increase of the interlamellar space of the intercalated MMT, indicating the intercalation of the magnetic compounds. Furthermore, the magnetic properties of the hybrid compounds were investigated, showing similar behavior as the pure magnetic guest species. - Graphical abstract: Montmorillonite clay was employed as inorganic host for the intercalation of three different molecular magnetic compounds through ion exchange - Highlights: • Montmorillonite was employed as a host material. • Three molecular magnetic compounds were intercalated through ion exchange. • The compounds were successful intercalated maintaining the layered structure. • The hybrid materials exhibited similar magnetic behavior as the pure magnetic guest.

  15. Novel thrombopoietin mimetic peptides bind c-Mpl receptor: Synthesis, biological evaluation and molecular modeling.

    Science.gov (United States)

    Liu, Yaquan; Tian, Fang; Zhi, Dejuan; Wang, Haiqing; Zhao, Chunyan; Li, Hongyu

    2017-02-01

    Thrombopoietin (TPO) acts in promoting the proliferation of hematopoietic stem cells and by initiating specific maturation events in megakaryocytes. Now, TPO-mimetic peptides with amino acid sequences unrelated to TPO are of considerable pharmaceutical interest. In the present paper, four new TPO mimetic peptides that bind and activate c-Mpl receptor have been identified, synthesized and tested by Dual-Luciferase reporter gene assay for biological activities. The molecular modeling research was also approached to understand key molecular mechanisms and structural features responsible for peptide binding with c-Mpl receptor. The results presented that three of four mimetic peptides showed significant activities. In addition, the molecular modeling approaches proved hydrophobic interactions were the driven positive forces for binding behavior between peptides and c-Mpl receptor. TPO peptide residues in P7, P13 and P7' positions were identified by the analysis of hydrogen bonds and energy decompositions as the key ones for benefiting better biological activities. Our data suggested the synthesized peptides have considerable potential for the future development of stable and highly active TPO mimetic peptides. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Conception and synthesis of the new cryptophane for the applications in xenon NMR molecular imaging

    International Nuclear Information System (INIS)

    Gao, Bo

    2016-01-01

    Among all the imaging techniques, magnetic resonance imaging (MRI) offers several advantages owing to its low invasiveness, its harmlessness and its spatial in-depth resolution but suffers from poor sensitivity. To address this issue, different strategies were proposed, including the utilization of hyper-polarizable species such as "1"2"9Xe. Xenon is an inert gas with a polarizable electronic cloud which leads to an extreme sensitivity to its chemical environment. Its capacity of being hyper-polarized makes it possible to obtain a significant gain of sensitivity. Nevertheless, xenon has no specificity to any biological target therefore it needs to be encapsulated and vectorized. Different molecular cages were proposed and we are particularly interested in cryptophane which is one of the best candidates for xenon encapsulation. In this context, the objective of this thesis is to design new cryptophanes which can be used as molecular platforms to construct novel "1"2"9Xe MRI biosensors usable for in vivo imaging. To meet this demand, these cryptophanes should be mono-functionalizable and enough soluble in water. In this thesis, the polyethylene glycol (PEG) group is used to improve the poor solubility of the hydrophobic molecular cage. And there is a systematic discussion of how to break the symmetry of cryptophanes and different strategies were attempted to synthesize mono-functionalized cryptophanes. As a result, several PEGylated mono-functionalized cryptophanes were obtained and their properties for encapsulating xenon were tested [fr

  17. Molecular pharmacology of human NMDA receptors

    DEFF Research Database (Denmark)

    Hedegaard, Maiken; Hansen, Kasper Bø; Andersen, Karen Toftegaard

    2012-01-01

    N-methyl-d-aspartate (NMDA) receptors are ionotropic glutamate receptors that mediate excitatory neurotransmission. NMDA receptors are also important drug targets that are implicated in a number of pathophysiological conditions. To facilitate the transition from lead compounds in pre-clinical ani...

  18. CLINICAL PHARMACOLOGY OF DIURETICS

    Directory of Open Access Journals (Sweden)

    I. V. Soldatenko

    2014-06-01

    Full Text Available Clinical pharmacology of diuretics in the international system of ATC (anatomic-therapeutic-chemical is presented. Classification of this group by the action mechanism and caused effects is provided. Pharmacokinetics and pharmacodynamics features, indications and principles of diuretics usage in clinics are considered. Contraindications, side effects and interaction with other drugs of this group are discussed in detail.

  19. Developmental paediatric anaesthetic pharmacology

    DEFF Research Database (Denmark)

    Hansen, Tom Giedsing

    2015-01-01

    Safe and effective drug therapy in neonates, infants and children require detailed knowledge about the ontogeny of drug disposition and action as well how these interact with genetics and co-morbidity of children. Recent advances in developmental pharmacology in children follow the increased...

  20. Synthesis and pharmacological characterization of the selective GluK1 radioligand (S)-2-amino-3-(6-[3H]-2,4-dioxo-3,4-dihydrothieno.3,2-d] pyrimidin1(2H)- yl) propanoic acid ([3H]-NF608)

    DEFF Research Database (Denmark)

    Alcaide, Anna; Marconi, Laura; Marek, Ales

    2016-01-01

    The kainic acid receptors belong to the class of ionotropic glutamate receptors and comprise five subunits named GluK1-5. Radioligands are essential tools for use in binding assays aimed at ligand-receptor structure-activity-relationship studies. Previous work has led to the synthesis of GluK1...... radioligands [H-3]SYM2081, [H-3]-UBP310 and [H-3]-ATPA, however all strategies were work-intensive and thus not attractive. Herein, we report the synthesis of [H-3]-NF608 and subsequent pharmacological evaluation at homomeric recombinant rat GluK1 receptors. Binding affinities of a series of standard GluK1...... ligands were shown to be in line with previously reported affinities obtained by use of already reported radioligands....

  1. A comprehensive study of extended tetrathiafulvalene cruciform molecules for molecular electronics: synthesis and electrical transport measurements.

    Science.gov (United States)

    Parker, Christian R; Leary, Edmund; Frisenda, Riccardo; Wei, Zhongming; Jennum, Karsten S; Glibstrup, Emil; Abrahamsen, Peter Bæch; Santella, Marco; Christensen, Mikkel A; Della Pia, Eduardo Antonio; Li, Tao; Gonzalez, Maria Teresa; Jiang, Xingbin; Morsing, Thorbjørn J; Rubio-Bollinger, Gabino; Laursen, Bo W; Nørgaard, Kasper; van der Zant, Herre; Agrait, Nicolas; Nielsen, Mogens Brøndsted

    2014-11-26

    Cruciform-like molecules with two orthogonally placed π-conjugated systems have in recent years attracted significant interest for their potential use as molecular wires in molecular electronics. Here we present synthetic protocols for a large selection of cruciform molecules based on oligo(phenyleneethynylene) (OPE) and tetrathiafulvalene (TTF) scaffolds, end-capped with acetyl-protected thiolates as electrode anchoring groups. The molecules were subjected to a comprehensive study of their conducting properties as well as their photophysical and electrochemical properties in solution. The complex nature of the molecules and their possible binding in different configurations in junctions called for different techniques of conductance measurements: (1) conducting-probe atomic force microscopy (CP-AFM) measurements on self-assembled monolayers (SAMs), (2) mechanically controlled break-junction (MCBJ) measurements, and (3) scanning tunneling microscopy break-junction (STM-BJ) measurements. The CP-AFM measurements showed structure-property relationships from SAMs of series of OPE3 and OPE5 cruciform molecules; the conductance of the SAM increased with the number of dithiafulvene (DTF) units (0, 1, 2) along the wire, and it increased when substituting two arylethynyl end groups of the OPE3 backbone with two DTF units. The MCBJ and STM-BJ studies on single molecules both showed that DTFs decreased the junction formation probability, but, in contrast, no significant influence on the single-molecule conductance was observed. We suggest that the origins of the difference between SAM and single-molecule measurements lie in the nature of the molecule-electrode interface as well as in effects arising from molecular packing in the SAMs. This comprehensive study shows that for complex molecules care should be taken when directly comparing single-molecule measurements and measurements of SAMs and solid-state devices thereof.

  2. Synthesis and photophysical properties of a novel corrole–anthraquinone–corrole molecular system

    International Nuclear Information System (INIS)

    Sudhakar, Kolanu; Kanaparthi, Ravi Kumar; Kumar, Challa Kiran; Giribabu, Lingamallu

    2014-01-01

    A novel molecular triad (AQ-(H 3 ) 2 ) based on tritolylcorrole and anthraquinone having azomethine-bridge at the pyrrole-β position has been designed and synthesized by following a facile one step reaction. The molecular system, AQ-(H 3 ) 2 is characterized by elemental analysis, MALDI-MS, 1 H-NMR, UV–Visible and fluorescence spectroscopy (steady-state and time-resolved) as well as electrochemical methods. In absorption spectra, prominent changes such as red-shift (∼7 nm) and broadening of the both Soret and Q-bands with respect to their monomer units were observed. The present study supported by density functional theory calculations manifest that there exists a negligible electronic communication in the ground state between the donor tritolylcorrole and acceptor anthraquinone of the triad. However, interestingly, in the triad AQ-(H 3 ) 2 , fluorescence emission of the tritolylcorrole quenched significantly (17–80%) compared to their monomeric units. The emission quenching is attributed to the excited state intramolecular photoinduced electron transfer from donor tritolylcorrole to acceptor anthraquinone and the electron transfer rates (k ET ) are found in the range 4.1×10 8 to 2.4×10 9 s −1 and are found to be solvent dependent. - Highlights: • Molecular triad based on corrole and anthraquinone having azomethine-bridge at pyrrole-β position. • Ground state properties showed that there exist minimum π–π interactions. • Excited state properties showed intramolecular photoinduced electron transfer from corrole to anthraquinone

  3. Synthesis and photophysical properties of a novel corrole–anthraquinone–corrole molecular system

    Energy Technology Data Exchange (ETDEWEB)

    Sudhakar, Kolanu [Inorganic and Physical Chemistry Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500007, Andhra Pradesh (India); Kanaparthi, Ravi Kumar [Inorganic and Physical Chemistry Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500007, Andhra Pradesh (India); Department of Chemistry, Central University of Kerala, Reverside Transit Campus, Padanakkad, Nileshwar Kasaragod District - 671 314 Kerala (India); Kumar, Challa Kiran [Inorganic and Physical Chemistry Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500007, Andhra Pradesh (India); Giribabu, Lingamallu, E-mail: giribabu@iict.res.in [Inorganic and Physical Chemistry Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500007, Andhra Pradesh (India)

    2014-09-15

    A novel molecular triad (AQ-(H{sub 3}){sub 2}) based on tritolylcorrole and anthraquinone having azomethine-bridge at the pyrrole-β position has been designed and synthesized by following a facile one step reaction. The molecular system, AQ-(H{sub 3}){sub 2} is characterized by elemental analysis, MALDI-MS, {sup 1}H-NMR, UV–Visible and fluorescence spectroscopy (steady-state and time-resolved) as well as electrochemical methods. In absorption spectra, prominent changes such as red-shift (∼7 nm) and broadening of the both Soret and Q-bands with respect to their monomer units were observed. The present study supported by density functional theory calculations manifest that there exists a negligible electronic communication in the ground state between the donor tritolylcorrole and acceptor anthraquinone of the triad. However, interestingly, in the triad AQ-(H{sub 3}){sub 2}, fluorescence emission of the tritolylcorrole quenched significantly (17–80%) compared to their monomeric units. The emission quenching is attributed to the excited state intramolecular photoinduced electron transfer from donor tritolylcorrole to acceptor anthraquinone and the electron transfer rates (k{sub ET}) are found in the range 4.1×10{sup 8} to 2.4×10{sup 9} s{sup −1} and are found to be solvent dependent. - Highlights: • Molecular triad based on corrole and anthraquinone having azomethine-bridge at pyrrole-β position. • Ground state properties showed that there exist minimum π–π interactions. • Excited state properties showed intramolecular photoinduced electron transfer from corrole to anthraquinone.

  4. Synthesis of 2-acylated and sulfonated 4-hydroxycoumarins: In vitro urease inhibition and molecular docking studies.

    Science.gov (United States)

    Rashid, Umer; Rahim, Fazal; Taha, Muhammad; Arshad, Muhammad; Ullah, Hayat; Mahmood, Tariq; Ali, Muhammad

    2016-06-01

    Sixteen 4-hydroxycoumarin derivatives were synthesized, characterized through EI-MS and (1)H NMR and screened for urease inhibitory potential. Three compounds exhibited better urease inhibition than the standard inhibitor thiourea (IC50=21±0.11μM) while other four compounds exhibited good to moderate inhibition with IC50 values between 29.45±1.1μM and 69.53±0.9μM. Structure activity relationship was established on the basis of molecular docking studies, which helped to predict the binding interactions of the most active compounds. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Synthesis and characterization of curcumin-sulfonamide hybrids: Biological evaluation and molecular docking studies

    Science.gov (United States)

    Banuppriya, Govindharasu; Sribalan, Rajendran; Padmini, Vediappen

    2018-03-01

    Curcumin-sulfonamide hybrids (4a-e) were synthesized and their in vitro antioxidant, anti-inflammatory and anticancer activities were studied. The synthesized compounds showed a very good potent activity towards antioxidant and anti-inflammatory studies rather than its parent as well as standard. These compounds have exhibited an excellent toxicity effect to the cancer cell lines such as A549 and AGS. The compounds 4a and 4c have showed good anticancer activity than curcumin. The molecular docking studies were also performed against various Epidermal Growth Factor Receptor (EGFR) enzymes. The DFT calculations were also done in order to support the docking results.

  6. Synthesis and evaluation of chloramphenicol homodimers: molecular target, antimicrobial activity, and toxicity against human cells.

    Directory of Open Access Journals (Sweden)

    Ourania N Kostopoulou

    Full Text Available As fight against antibiotic resistance must be strengthened, improving old drugs that have fallen in reduced clinical use because of toxic side effects and/or frequently reported resistance, like chloramphenicol (CAM, is of special interest. Chloramphenicol (CAM, a prototypical wide-spectrum antibiotic has been shown to obstruct protein synthesis via binding to the bacterial ribosome. In this study we sought to identify features intensifying the bacteriostatic action of CAM. Accordingly, we synthesized a series of CAM-dimers with various linker lengths and functionalities and compared their efficiency in inhibiting peptide-bond formation in an Escherichia coli cell-free system. Several CAM-dimers exhibited higher activity, when compared to CAM. The most potent of them, compound 5, containing two CAM bases conjugated via a dicarboxyl aromatic linker of six successive carbon-bonds, was found to simultaneously bind both the ribosomal catalytic center and the exit-tunnel, thus revealing a second, kinetically cryptic binding site for CAM. Compared to CAM, compound 5 exhibited comparable antibacterial activity against MRSA or wild-type strains of Staphylococcus aureus, Enterococcus faecium and E. coli, but intriguingly superior activity against some CAM-resistant E. coli and Pseudomonas aeruginosa strains. Furthermore, it was almost twice as active in inhibiting the growth of T-leukemic cells, without affecting the viability of normal human lymphocytes. The observed effects were rationalized by footprinting tests, crosslinking analysis, and MD-simulations.

  7. Mannich-Benzimidazole Derivatives as Antioxidant and Anticholinesterase Inhibitors: Synthesis, Biological Evaluations, and Molecular Docking Study.

    Science.gov (United States)

    Alpan, Ayşe Selcen; Sarıkaya, Görkem; Çoban, Güneş; Parlar, Sülünay; Armagan, Güliz; Alptüzün, Vildan

    2017-07-01

    A series of Mannich bases of benzimidazole derivatives having a phenolic group were designed to assess their anticholinesterase and antioxidant activities. The acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities were evaluated in vitro by using Ellman's method. According to the activity results, all of the compounds exhibited moderate to good AChE inhibitory activity (except for 2a), with IC 50 values ranging from 0.93 to 10.85 μM, and generally displayed moderate BuChE inhibitory activity. Also, most of the compounds were selective against BuChE. Compound 4b was the most active molecule on the AChE enzyme and also selective. In addition, we investigated the antioxidant effects of the synthesized compounds against FeCl 2 /ascorbic acid-induced oxidative stress in the rat brain in vitro, and the activity results showed that most of the compounds are effective as radical scavengers. Molecular docking studies and molecular dynamics simulations were also carried out. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Synthesis and molecular modelling studies of phenyl linked oxadiazole-phenylhydrazone hybrids as potent antileishmanial agents.

    Science.gov (United States)

    Taha, Muhammad; Ismail, Nor Hadiani; Imran, Syahrul; Anouar, El Hassane; Selvaraj, Manikandan; Jamil, Waqas; Ali, Muhammad; Kashif, Syed Muhammad; Rahim, Fazal; Khan, Khalid Mohammed; Adenan, Mohd Ilham

    2017-01-27

    Molecular hybridization yielded phenyl linked oxadiazole-benzohydrazones hybrids 6-35 and were evaluated for their antileishmanial potentials. Compound 10, a 3,4-dihydroxy analog with IC 50 value of 0.95 ± 0.01 μM, was found to be the most potent antileishmanial agent (7 times more active) than the standard drug pentamidine (IC 50  = 7.02 ± 0.09 μM). The current series 6-35 conceded in the identification of thirteen (13) potent antileishmanial compounds with the IC 50 values ranging between 0.95 ± 0.01-78.6 ± 1.78 μM. Molecular docking analysis against pteridine reductase (PTR1) were also performed to probe the mode of action. Selectivity index showed that compounds with higher number of hydroxyl groups have low selectivity index. Theoretical stereochemical assignment was also done for certain derivatives by using density functional calculations. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  9. Synthesis and characterization of high molecular weight hydrophobically modified polyacrylamide nanolatexes using novel nonionic polymerizable surfactants

    Directory of Open Access Journals (Sweden)

    A.M. Al-Sabagh

    2013-12-01

    Full Text Available In this article, nine hydrophobically modified polyacrylamides (HM-PAM nanolatexes, were synthesized by copolymerizing the acrylamide monomer and novel polymerizable surfactants (surfmers. The reaction was carried out by inverse microemulsion copolymerization technique. The copolymerization was initiated by redox initiators composed of potassium peroxodisulphate and sodium bisulfite. The emulsion was stabilized using mixed tween 85 and span 80 as nonionic emulsifiers. The prepared HM-PAMs were classified into three groups according to the surfmers used in the copolymerization. The chemical structures of the prepared HM-PAMs were confirmed by FT-IR, 1H NMR and 13C NMR. The thermal properties were estimated with the thermal gravimetric analysis (TGA. The size and morphology of the prepared latexes were investigated by the dynamic light scattering (DLS and the High Resolution Transmission Electron Microscope (HRTEM. Finally, the molecular weights of the prepared copolymers were determined by the GPC and the viscosity average molecular weight method. They were situated between 1.58 × 106 and 0.89 × 106.

  10. Synthesis of Molecularly Imprinted Polymers for Amino Acid Derivates by Using Different Functional Monomers

    Directory of Open Access Journals (Sweden)

    Sonia Scorrano

    2011-03-01

    Full Text Available Fmoc-3-nitrotyrosine (Fmoc-3-NT molecularly imprinted polymers (MIPs were synthesized to understand the influence of several functional monomers on the efficiency of the molecular imprinting process. Acidic, neutral and basic functional monomers, such as acrylic acid (AA, methacrylic acid (MAA, methacrylamide (MAM, 2-vinylpyridine (2-VP, 4-vinylpyridine (4-VP, have been used to synthesize five different polymers. In this study, the MIPs were tested in batch experiments by UV-visible spectroscopy in order to evaluate their binding properties. The MIP prepared with 2-VP exhibited the highest binding affinity for Fmoc-3NT, for which Scatchard analysis the highest association constant (2.49 × 104 M−1 was obtained. Furthermore, titration experiments of Fmoc-3NT into acetonitrile solutions of 2-VP revealed a stronger bond to the template, such that a total interaction is observed. Non-imprinted polymers as control were prepared and showed no binding affinities for Fmoc-3NT. The results are indicative of the importance of ionic bonds formed between the –OH residues of the template molecule and the pyridinyl groups of the polymer matrix. In conclusion, 2-VP assists to create a cavity which allows better access to the analytes.

  11. Electric discharge microplasmas generated in highly fluctuating fluids: Characteristics and application to the synthesis of molecular diamond

    Science.gov (United States)

    Stauss, Sven

    2014-10-01

    Plasma-based fabrication of novel nanomaterials and nanostructures is paramount for the development of next-generation electronic devices and for green energy applications. In particular, controlling the interactions between plasmas and materials interfaces, and the plasma fluctuations are crucial for further development of plasma-based processes and bottom-up growth of nanomaterials. Discharge microplasmas generated in supercritical fluids represent a special class of high-pressure plasmas, where fluctuations on the molecular scale influence the discharge properties and the possible bottom-up growth of nanomaterials. In the first part of the talk, we will discuss an anomaly observed for microplasmas generated near the critical point, a local decrease in the breakdown voltage, which has been observed for both molecular and monoatomic gases. This anomalous behavior is suggested to be caused by the concomitant decrease of the ionization potential due to the formation of clusters near the critical point, and the formation of extended electron mean free paths induced by the high-density fluctuation near the critical point. We will also show that when generating microplasma discharges close to the critical point, that the high-density fluctuation of the supercritical fluid persists. In the second part of the presentation, we will first introduce the basic properties of diamondoids and their potential for application in many different fields - biotechnology, medicine, opto- and nanoelectronics - before discussing their synthesis by microplasmas generated inside both conventional batch-type and continuous flow reactors, using the smallest diamondoid, adamantane, as a precursor and seed. Finally we show that one possible growth mechanism of larger diamondoids from smaller ones consists in the repeated abstraction of hydrogen terminations and the addition of methyl radicals. Supported financially in part by Grant No. 23760688 and Grant No. 21110002 from the Ministry of

  12. Synthesis and molecular structure of (monoaqua) oxovanadium (IV) thiosemicarbazide-diacetate monohydrate

    International Nuclear Information System (INIS)

    Gerbeleu, N.V.; Bologa, A.O.; Burshtein, I.F.; Filippova, I.G.; Kiosse, G.A.

    1986-01-01

    This paper describes the structure for a new complex of oxovanadium (IV) with H 2 L. This compound was obtained by mixing warm aqueous solutions containing 1.0 g VOSO 4 .2H 2 O and H 2 L at room temperature. The coordinates and the individual temperature factors of the basis atoms in the structure VOLH 2 O .H 2 O are presented. It is shown that the vanadium atom in both complexes has a distorted octahedral environment. The geometrical isomerism is accompanied by differences in the conformations of the molecular ligand. Two geometrical isomers of a previously unknown type are concurrently present in the VOLH 2 O structure. The formation of these isomers is made possible by the different arrangement of inequivalent branches of the organic ligand. This type of isomerism should be expected in the complexes of other metals with H 2 L and in the coordination compounds of metals with other B-type tripod ligands

  13. Seeking for Non-Zinc-Binding MMP-2 Inhibitors: Synthesis, Biological Evaluation and Molecular Modelling Studies

    Directory of Open Access Journals (Sweden)

    Alessandra Ammazzalorso

    2016-10-01

    Full Text Available Matrix metalloproteinases (MMPs are an important family of zinc-containing enzymes with a central role in many physiological and pathological processes. Although several MMP inhibitors have been synthesized over the years, none reached the market because of off-target effects, due to the presence of a zinc binding group in the inhibitor structure. To overcome this problem non-zinc-binding inhibitors (NZIs have been recently designed. In a previous article, a virtual screening campaign identified some hydroxynaphtyridine and hydroxyquinoline as MMP-2 non-zinc-binding inhibitors. In the present work, simplified analogues of previously-identified hits have been synthesized and tested in enzyme inhibition assays. Docking and molecular dynamics studies were carried out to rationalize the activity data.

  14. Synthesis, molecular modeling and structural characterization of vanillin derivatives as antimicrobial agents

    Science.gov (United States)

    Sun, Juan; Yin, Yong; Sheng, Gui-Hua; Yang, Zhi-Bo; Zhu, Hai-Liang

    2013-05-01

    Two vanillin derivatives have been designed and synthesized and their biological activities were also evaluated for antimicrobial activity. Their chemical structures are characterized by single crystal X-ray diffraction studies, 1H NMR, MS, and elemental analysis. Structural stabilization of them followed by intramolecular as well as intermolecular H-bonds makes these molecules as perfect examples in molecular recognition with self-complementary donor and acceptor units within a single molecule. Docking simulations have been performed to position compounds into the FtsZ active site to determine their probable binding model. Compound 3a shows the most potent biological activity, which may be a promising antimicrobial leading compound for the further research.

  15. Bisindolylmethane thiosemicarbazides as potential inhibitors of urease: Synthesis and molecular modeling studies.

    Science.gov (United States)

    Taha, Muhammad; Ullah, Hayat; Al Muqarrabun, Laode Muhammad Ramadhan; Khan, Muhammad Naseem; Rahim, Fazal; Ahmat, Norizan; Javid, Muhammad Tariq; Ali, Muhammad; Khan, Khalid Mohammed

    2018-01-01

    Bisindolylmethane thiosemicarbazides 1-18 were synthesized, characterized by 1 H NMR and ESI MS and evaluated for urease inhibitory potential. All analogs showed outstanding urease inhibitory potentials with IC 50 values ranging between 0.14 ± 0.01 to 18.50 ± 0.90 μM when compared with the standard inhibitor thiourea having IC 50 value 21.25 ± 0.90 μM. Among the series, analog 9 (0.14 ± 0.01 μM) with di-chloro substitution on phenyl ring was identified as the most potent inhibitor of urease. The structure activity relationship has been also established on the basis of binding interactions of the active analogs. These binding interactions were identified by molecular docking studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Synthesis, Biological Evaluation and Molecular Modelling of 2′-Hydroxychalcones as Acetylcholinesterase Inhibitors

    Directory of Open Access Journals (Sweden)

    Sri Devi Sukumaran

    2016-07-01

    Full Text Available A series of 2′-hydroxy- and 2′-hydroxy-4′,6′-dimethoxychalcones was synthesised and evaluated as inhibitors of human acetylcholinesterase (AChE. The majority of the compounds were found to show some activity, with the most active compounds having IC50 values of 40–85 µM. Higher activities were generally observed for compounds with methoxy substituents in the A ring and halogen substituents in the B ring. Kinetic studies on the most active compounds showed that they act as mixed-type inhibitors, in agreement with the results of molecular modelling studies, which suggested that they interact with residues in the peripheral anionic site and the gorge region of AChE.

  17. [Synthesis and Study on Adsorption Property of Congo Red Molecularly Imprinted Polymer Nanospheres].

    Science.gov (United States)

    Chang, Zi-qiang; Chen, Fu-bin; Zhang, Yu; Shi, Zuo-long; Yang, Chun-yan; Zhang, Zhu-jun

    2015-07-01

    Molecularly imprinted polymer nanospheres (MIP) were prepared with Congo red as the template, methacrylic acid (MAA) as a functional monomer, ethylene glycol dimethacrylate (EGDMA) as the cross linker, azodiisobutyronitrile (AIBN) as an initiator, and acetonitrile as the porogen by precipitation polymerization. The morphology of MIP was characterized by SEM and TEM which showed that the diameter of MIP was nanometer grade (90 nm) and the shape was homogeneous. The specific surface area and pore volumes of MIP and NIP were examined through Brunauer-Emett-Teller method of nitrogen adsorption experiments. Then, the adsorption and selective recognition ability of MIPs were evaluated using the equilibrium rebinding experiments. The results indicated that the prepared MIP showed a good selectivity recognition ability to its template. It concluded that MIP could be employed as an effective material for removing Congo red from waste water.

  18. Synthesis, solid and solution studies of paraquat dichloride calixarene complexes. Molecular modelling

    International Nuclear Information System (INIS)

    Garcia S, I.; Ramirez, F. M.

    2010-01-01

    The interaction of the herbicide paraquat dichloride (P Q, substrate) with p-tert-butylcalix arenas (L, receptor) was investigated in both the solution and solid states. The isolated paraquat calixarene complexes were characterised by UV-visible, 1 H NMR, ESI-Ms, Luminescence and IR spectroscopies and elemental analysis. The stoichiometry of complexes 1 and 2 was 1:1 (1 herbicide: 1 calixarene) and both revealed a biexponential luminescence decay with lifetimes depending on the size and the conformational particularity of the calixarenes. Molecular modelling suggested that both calixarenes interact with the herbicide through cation-π interaction. P Q in included in the p-tert butylcalix a rene cavity, a situation favoured by its pinched conformation in polar solvent while it is partially included in the p-tert butylcalix a rene cavity because of its in-out cone conformation. The theoretical results, in particular using Mopac procedures, were in agreement with the experimental findings. (Author)

  19. Synthesis, solid and solution studies of paraquat dichloride calixarene complexes. Molecular modelling

    Energy Technology Data Exchange (ETDEWEB)

    Garcia S, I.; Ramirez, F. M., E-mail: flor.ramirez@inin.gob.m [ININ, Departamento de Quimica, Carretera Mexico-Toluca s/n, 52750 Ocoyoacac, Estado de Mexico (Mexico)

    2010-07-01

    The interaction of the herbicide paraquat dichloride (P Q, substrate) with p-tert-butylcalix arenas (L, receptor) was investigated in both the solution and solid states. The isolated paraquat calixarene complexes were characterised by UV-visible, {sup 1}H NMR, ESI-Ms, Luminescence and IR spectroscopies and elemental analysis. The stoichiometry of complexes 1 and 2 was 1:1 (1 herbicide: 1 calixarene) and both revealed a biexponential luminescence decay with lifetimes depending on the size and the conformational particularity of the calixarenes. Molecular modelling suggested that both calixarenes interact with the herbicide through cation-{pi} interaction. P Q in included in the p-tert butylcalix a rene cavity, a situation favoured by its pinched conformation in polar solvent while it is partially included in the p-tert butylcalix a rene cavity because of its in-out cone conformation. The theoretical results, in particular using Mopac procedures, were in agreement with the experimental findings. (Author)

  20. Novel α, β-Unsaturated Sophoridinic Derivatives: Design, Synthesis, Molecular Docking and Anti-Cancer Activities

    Directory of Open Access Journals (Sweden)

    Yiming Xu

    2017-11-01

    Full Text Available Using sophoridine 1 and chalcone 3 as the lead compounds, a series of novel α, β-unsaturated sophoridinic derivatives were designed, synthesized, and evaluated for their in vitro cytotoxicity. Structure-activity relationship (SAR analysis indicated that introduction of α, β-unsaturated ketone moiety and heterocyclic group might significantly enhance anticancer activity. Among the compounds, 2f and 2m exhibited potential effects against HepG-2 and CNE-2 human cancer cell lines. Furthermore, molecular docking studies were performed to understand possible docking sites of the molecules on the target proteins and the mode of binding. This work provides a theoretical basis for structural optimizations and exploring anticancer pathways of this kind of compound.

  1. Synthesis and catalytic performance of ZSM-5/MCM-41 composite molecular sieve from palygorskite

    Science.gov (United States)

    Jiang, Jinlong; Wu, Mei; Yang, Yong; Duanmu, Chuansong; Chen, Jing; Gu, Xu

    2017-10-01

    ZSM-5/MCM-41 composite molecular sieve has been hydrothermally synthesized through a two-step crystallization process using palygorskite (PAL) as silicon and aluminum source. The products were characterized by various means and their catalytic properties for acetalization of cyclohexanone and esterification of acetic acid and n-butanol were also investigated. In the first step ZSM-5 zeolite could be formed from the acid-treated PAL after hydrothermal treatment using tetrapropylammonium bromide as template. XRD patterns, N2 adsorption and desorption data, and TEM images show that the composite obtained in the secondary step had a well-ordered mesoporous MCM-41 phase and a microporous ZSM-5 zeolite phase. Compared with ZSM-5, ZSM-5/MCM-41 composite possessed more total acid amount, weak acid sites and large pore structure due to the formation of MCM-41 and exhibited higher catalytic activity for the acetalization and esterification reaction.

  2. Synthesis of Norbornene Derived Helical Copolymer by Simple Molecular Marriage Approach to Produce Smart Nanocarrier.

    Science.gov (United States)

    Mane, Shivshankar R; Sathyan, Ashlin; Shunmugam, Raja

    2017-03-22

    A novel library of norbornene derived helical copolymer has been synthesized through the coupling of two homopolymers via Molecular Marriage Approach. The helicity is governed by the non-covalent interactions like hydrogen bonding, π-π stacking and the influence of hydrophobic and hydrophilic motifs. The detailed characterization of the copolymer (Copoly 1) has been provided and the super structures are confirmed through dynamic light scattering (DLS), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The observed size of the aggregates was about 200 nm. The density functional theory (DFT) is favorably supported for the formation of proposed structure of Copoly 1. Circular dichroism (CD) measurement has confirmed the one handed helical structure of the copolymer. Reservoir capability of this pH responsive polymer (Copoly 1) to encapsulate anti-cancer drug doxorubicin (DOX) warrants its potential applications in the field of bio-medical sciences.

  3. Synthesis and characterization of arylamine derivatives of rauwolscine as molecular probes for alpha 2-adrenergic receptors

    International Nuclear Information System (INIS)

    Lanier, S.M.; Graham, R.M.; Hess, H.J.; Grodski, A.; Repaske, M.G.; Nunnari, J.M.; Limbird, L.E.; Homcy, C.J.

    1987-01-01

    The selective alpha 2-adrenergic receptor antagonist rauwolscine was structurally modified to yield a series of arylamine carboxamide derivatives, which were investigated as potential molecular probes for the localization and structural characterization of alpha 2-adrenergic receptors. The arylamine carboxamides differ in the number of carbon atoms separating the reactive phenyl moiety from the fused ring structure of the parent compound, rauwolscine carboxylate. Competitive inhibition studies with [ 3 H]rauwolscine in rat kidney membranes indicate that the affinity for the carboxamide derivatives is inversely related to the length of the carbon spacer arm with rauwolscine 4-aminophenyl carboxamide exhibiting the highest affinity (Kd = 2.3 +/- 0.2 nM). Radioiodination of rau-AMPC yields a ligand, 125 I-rau-AMPC, which binds to rat kidney alpha 2-adrenergic receptors with high affinity, as determined by both kinetic analysis (Kd = k2/k1 = 0.016 min-1/2.1 X 10(7) M-1 min-1 = 0.76 nM) and equilibrium binding studies (Kd = 0.78 +/- 0.16 nM). 125 I-rau-AMPC was quantitatively converted to the photolabile arylazide derivative 17 alpha-hydroxy-20 alpha-yohimban-16 beta-(N-4-azido-3-[ 125 I]iodophenyl) carboxamide ( 125 I-rau-AZPC). In a partially purified receptor preparation from porcine brain, this compound photolabels a major (Mr = 62,000) peptide. The labeling of this peptide is inhibited by adrenergic agonists and antagonists with a rank order of potency consistent with an alpha 2-adrenergic receptor binding site. Both 125 I-rau-AMPC and the photolabile arylazide derivative, 125 I-rau-AZPC, should prove useful as molecular probes for the structural and biochemical characterization of alpha 2-adrenergic receptors

  4. Synthesis and properties of functionalized 4 nm scale molecular wires with thiolated termini for self-assembly onto metal surfaces.

    Science.gov (United States)

    Wang, Changsheng; Bryce, Martin R; Gigon, Joanna; Ashwell, Geoffrey J; Grace, Iain; Lambert, Colin J

    2008-07-04

    We report the synthesis of new oligo(aryleneethynylene) molecular wires of ca. 4 nm length scale by palladium-catalyzed Sonogashira cross-coupling methodology. Key structural features are the presence of electron donor 9-(1,3-dithiol-2-ylidene)fluorene (compounds 13 and 14) and electron acceptor 9-[di(4-pyridyl)methylene]fluorene units (compound 16) at the core of the molecules. Terminal thiolate substituents are protected as cyanoethylsulfanyl (13 and 16) or thioacetate derivatives (14). The molecules display well-defined redox processes in solution electrochemical studies. The optical properties in solution are similar to those of the fluorenone analog 6: the strongest absorptions for 6, 13 and 16 are in the region lambda(max) = 387-393 nm, with 13 showing an additional shoulder at 415 nm which is not present for 6 and 16; this shoulder is assigned to a HOMO-LUMO transition from the dithiole to the fluorene unit. Molecules 6, 13, 14 and 16 form self-assembled monolayers on gold substrates which exhibit essentially symmetrical current-voltage (I-V) characteristics when contacted by a gold scanning tunelling microscope (STM) tip. The effects of the chemical modifications at the central unit of 6, 14 and 16 on the HOMO-LUMO levels and electron transport through the molecules in vacuum have been computed by an ab initio approach.

  5. Hybrid Pharmacophoric Approach in the Design and Synthesis of Coumarin Linked Pyrazolinyl as Urease Inhibitors, Kinetic Mechanism and Molecular Docking.

    Science.gov (United States)

    Saeed, Aamer; Mahesar, Parvez Ali; Channar, Pervaiz Ali; Larik, Fayaz Ali; Abbas, Qamar; Hassan, Mubashir; Raza, Hussain; Seo, Sung-Yum

    2017-08-01

    The current research article reports the synthesis of coumarinyl pyrazolinyl thioamide derivatives and their biological activity as inhibitors of jack bean urease. The coumarinyl pyrazolinyl thioamides were synthesized by reacting thiosemicarbazide with newly synthesized chalcones to afford the products in good yields and the synthesized compounds were purified by recrystallization. Coumarinyl pyrazolinyl thioamide derivatives 5a - 5q showed significant activity against Urease enzyme and also exhibited good antioxidant potential. The compound 3-(2-oxo-2H-chromen-3-yl)-5-phenyl-4,5-dihydro-1H-pyrazole-1-carbothioamide (5n) was found to be superior agent in the series with an IC 50  = 0.358 ± 0.017 μm compared to standard thiourea with an IC 50  = 4720 ± 174 μm. To undermine the binding mode of inhibition kinetic studies were performed for most potent derivative and it was found that compound 5n inhibits urease enzyme by non-competitive mode of inhibition. Molecular docking studies were carried out to delineate the binding affinity of the synthesized derivatives. © 2017 Wiley-VHCA AG, Zurich, Switzerland.

  6. Synthesis of Ruthenium(III Phthalocyanine with Di-axial Bromo Ligands - A Promising Molecular Conductor with Giant Negative Magnetoresistance

    Directory of Open Access Journals (Sweden)

    Mario A.V. Gamboa

    2015-01-01

    Full Text Available The electron transport of Phthalocyanines (Pc with central metal and di-axial ligands (such as FeIII(PcL2; where L = CN, Cl, Br originates from its intermolecular Pc π-π orbital overlap while its giant negative magnetoresistance (GNMR arises from its intramolecular Pc-π(HOMO and Fe-d (s=1/2 interaction. However, the π-d interaction tends to localize itinerant electrons resulting in the decrease in the conductivity of the FeIII(PcL2 series compared to the non-magnetic CoIII(PcL2 where π-d interaction is absent. More so, the axial ligand field energy of the FeIII(PcL2 system is found to have the ability to proportionally modulate the π-d interaction. In reference thereof, theoretical calculations point that isostructural RuIII(PcBr2 would provide the best balance of π-d orbital energy interplay. That is, RuIII(PcBr2 is expected to be a molecule with high electrical conductivity and GNMR which would make it an ideal magnetic molecular conductor. This paper reports on the synthesis of RuIII(PcBr2.

  7. Design, synthesis and photochemical properties of the first examples of iminosugar clusters based on fluorescent cores

    Directory of Open Access Journals (Sweden)

    Mathieu L. Lepage

    2015-05-01

    Full Text Available The synthesis and photophysical properties of the first examples of iminosugar clusters based on a BODIPY or a pyrene core are reported. The tri- and tetravalent systems designed as molecular probes and synthesized by way of Cu(I-catalysed azide–alkyne cycloadditions are fluorescent analogues of potent pharmacological chaperones/correctors recently reported in the field of Gaucher disease and cystic fibrosis, two rare genetic diseases caused by protein misfolding.

  8. Biopolymeric receptor for peptide recognition by molecular imprinting approach—Synthesis, characterization and application

    International Nuclear Information System (INIS)

    Singh, Lav Kumar; Singh, Monika; Singh, Meenakshi

    2014-01-01

    The present work is focused on the development of a biocompatible zwitterionic hydrogel for various applications in analytical chemistry. Biopolymer chitosan was derivatized to obtain a series of zwitterionic hydrogel samples. Free amino groups hanging on the biopolymeric chain were reacted with γ-butyrolactone to quaternize the N-centers of polymeric chain. N,N-methylene-bis-acrylamide acts as a crosslinker via Michael-type addition in the subsequent step and facilitated gelation of betainized chitosan. These biopolymeric hydrogel samples were fully characterized by FTIR, 1 H NMR, 13 C NMR spectra, SEM and XRD. Hydrogels were further characterized for their swelling behavior at varying parameters. The extent of swelling was perceived to be dictated by solvent composition such as pH, ionic strength and temperature. This valuable polymeric format is herein chosen to design an artificial receptor for dipeptide ‘carnosine’, which has adequate societal significance to be analytically determined, by molecular imprinting. Electrostatic interactions along with complementary H-bonding and other hydrophobic interactions inducing additional synergetic effect between the template (carnosine) and the imprinted polymer led to the formation of imprinted sites. The MIP was able to selectively and specifically take up carnosine from aqueous solution quantitatively. Thus prepared MIPs were characterized by FTIR spectroscopy, SEM providing evidence for the quality and quantity of imprinted gels. The binding studies showed that the MIP illustrated good recognition for carnosine as compared to non-imprinted polymers (NIPs). Detection limit was estimated as 3.3 μg mL −1 . Meanwhile, selectivity experiments demonstrated that imprinted gel had a high affinity to carnosine in the presence of close structural analogues (interferrants). - Highlights: • Development of a biocompatible zwitterionic hydrogel • A series of chitosan-derived zwitterionic hydrogel samples • Polymeric

  9. Pharmacological interactions of vasoconstrictors.

    Science.gov (United States)

    Gómez-Moreno, Gerardo; Guardia, Javier; Cutando, Antonio; Calvo-Guirado, José Luis

    2009-01-01

    This article is the first of a series on pharmacological interactions involving medicaments commonly prescribed and/or used in odontology: vasoconstrictors in local anaesthetics and anti-inflammatory and anti-microbial analgesics. The necessity for the odontologist to be aware of adverse reactions as a result of the pharmacological interactions is due to the increase in medicament consumption by the general population. There is a demographic change with greater life expectancy and patients have increased chronic health problems and therefore have increased medicament intake. The presence of adrenaline (epinephrine) and other vasoconstrictors in local odontological anaesthetics is beneficial in relation to the duration and depth of anaesthesia and reduces bleeding and systemic toxicity of the local anaesthetic. However, it might produce pharmacological interactions between the injected vasoconstrictors and the local anaesthetic and adrenergic medicament administered exogenically which the odontologist should be aware of, especially because of the risk of consequent adverse reactions. Therefore the importance of conducting a detailed clinical history of the general state of health and include all medicaments, legal as well as illegal, taken by the patient.

  10. Clinical Pharmacology of Kinase Inhibitors in Oncology : Personalized and Optimzed Dosing

    NARCIS (Netherlands)

    Verheijen, Remy B.

    2017-01-01

    Kinase inhibitors are an important category of molecularly targeted therapies used for cancer. Verheijen’s doctoral thesis describes several clinical pharmacological studies to optimize and personalize the treatment of cancer with kinase inhibitors, using pharmacokinetics, molecular imaging and

  11. Synthesis of polymer gel electrolyte with high molecular weight poly(methyl methacrylate)-clay nanocomposite

    International Nuclear Information System (INIS)

    Meneghetti, Paulo; Qutubuddin, Syed; Webber, Andrew

    2004-01-01

    Polymer nanocomposite gel electrolytes consisting of high molecular weight poly(methyl methacrylate) PMMA-clay nanocomposite, ethylene carbonate (EC)/propylene carbonate (PC) as plasticizer, and LiClO 4 electrolyte are reported. Montmorillonite clay was ion exchanged with a zwitterionic surfactant (octadecyl dimethyl betaine) and dispersed in methyl methacrylate, which was then polymerized to synthesize PMMA-clay nanocomposites. The nanocomposite was dissolved in a mixture of EC/PC with LiClO 4 , heated and pressed to obtain polymer gel electrolyte. X-ray diffraction (XRD) of the gels indicated intercalated clay structure with d-spacings of 2.85 and 1.40 nm. In the gel containing plasticizer, the clay galleries shrink suggesting intercalation rather than partial exfoliation observed in the PMMA-clay nanocomposite. Ionic conductivity varied slightly and exhibited a maximum value of 8 x 10 -4 S/cm at clay content of 1.5 wt.%. The activation energy was determined by modeling the conductivity with a Vogel-Tamman-Fulcher expression. The clay layers are primarily trapped inside the polymer matrix. Consequently, the polymer does not interact significantly with LiClO 4 electrolyte as shown by FTIR. The presence of the clay increased the glass transition temperature (Tg) of the gel as determined by differential scanning calorimetry. The PMMA nanocomposite gel electrolyte shows a stable lithium interfacial resistance over time, which is a key factor for use in electrochemical applications

  12. Synthesis and Characterization of Molecular Imprinting Polymer Microspheres of Piperine: Extraction of Piperine from Spiked Urine

    Directory of Open Access Journals (Sweden)

    Rachel Marcella Roland

    2016-01-01

    Full Text Available Molecularly imprinted polymer (MIP microspheres for Piperine were synthesized by precipitation polymerization with a noncovalent approach. In this research Piperine was used as a template, acrylic acid as a functional monomer, ethylene glycol dimethacrylate as a cross-linker, and 2,2′-azobisisobutyronitrile (AIBN as an initiator and acetonitrile as a solvent. The imprinted and nonimprinted polymer particles were characterized by using Fourier transform infrared spectroscopy (FT-IR and Scanning Electron Microscopy (SEM. The synthesized polymer particles were further evaluated for their rebinding efficiency by batch binding assay. The highly selected imprinted polymer for Piperine was MIP 3 with a composition (molar ratio of 0.5 : 3 : 8, template : monomer : cross-linker, respectively. The MIP 3 exhibits highest binding capacity (84.94% as compared to other imprinted and nonimprinted polymers. The extraction efficiency of highly selected imprinted polymer of Piperine from spiked urine was above 80%.

  13. Synthesis, properties, and molecular structure of a trivalent organouranium diphosphine hydride

    International Nuclear Information System (INIS)

    Duttera, M.R.; Fagan, P.J.; Marks, T.J.; Day, V.W.

    1982-01-01

    Hydrogenolysis of U[(CH 3 ) 5 C 5 ] 2 R 2 , [R = CH 3 Ch 2 Si(CH 3 ) 3 ], proceeds at -20 0 C in the presence of excess bis(2 dimethylphosphino)ethane(dmpe) according to this reaction: U[(CH 3 ) 3 C 5 ] 2 R 2 + 1.5H 2 + dmpe → (toluene, 18h) U[(CH 3 ) 5 C 5 ] 2 (dmpe) H + 2RH. Black microcrystals can be purified by vacuum Soxhlet extraction with toluene. All processes involving this compound must be performed under argon or helium atmospheres, since it reacts with nitrogen. The structure was studied by NMR, ir spectra. The molar magnetic suceptibility was measured at 295 K, 5120 x 10 -4 emu and is consistent with a U (III) formulation. Crystals are orthorhombic. X-ray diffraction data were collected. Structural parameters were refined to convergence. X-ray structural analysis reveals monocrystals of discrete mononuclear U[eta 5 -(CH 3 ) 5 C 5 ] 2 (dmpe)H molecules. The molecular structure is evaluated. 1 figure

  14. Synthesis and properties of large crystal of aluminum-deficient ultrasil molecular sieve materials

    International Nuclear Information System (INIS)

    Durrani, J.; Akhtar, J.; Chughtai, N.A.; Arif, M.; Saeed, K.; Ahmed, M.; Siddique, M.

    2003-01-01

    Large crystals of aluminum-deficient and silica rich molecular sieve materials such as Silicalite-I, Silicalite-II ZSM11-B and ZSM11-Fe have been synthesized hydro thermally from the aqueous silicate gel of (R/sub 2/O -SiO/sub 2/- B/sub 2/O/sub 3/ -Fe/sub 2/O/ sub 3/ -H/sub 2/O) using PTFE-lined stainless digestion bomb. The term R is a alkyl group. The synthesized materials were identified for crystallinity, thermal stability, phase, crystal structure, morphology and unit cell dimensions using thermogravimetry (TG/DTA), differential scanning calorimetric(DSC), X-ray diffraction (XRD), scanning electron microscopy (SEM) and other analytical techniques. All product materials were found to be white crystalline and crysto-graphically pure. Surface area and particle size distribution of materials were also ascertained. /sup 57/Fe Mossbauer spectroscopic studies on as-synthesized and calcined samples have confirmed the uniform dispersion of Fe/sup 3+/ ions in the tetrahedral framework of ZSM11-Fe material. (author)

  15. Synthesis and Characterization of Molecularly Imprinted Polymer Membrane for the Removal of 2,4-Dinitrophenol

    Directory of Open Access Journals (Sweden)

    Md. Jelas Haron

    2013-02-01

    Full Text Available Molecularly imprinted polymers (MIPs were prepared by bulk polymerization in acetonitrile using 2,4-dinitrophenol, acrylamide, ethylene glycol dimethacrylate, and benzoyl peroxide, as the template, functional monomer, cross-linker, and initiator, respectively. The MIP membrane was prepared by hybridization of MIP particles with cellulose acetate (CA and polystyrene (PS after being ground and sieved. The prepared MIP membrane was characterized using Fourier transform infrared spectroscopy and scanning electron microscopy. The parameters studied for the removal of 2,4-dinitrophenol included the effect of pH, sorption kinetics, and the selectivity of the MIP membrane. Maximum sorption of 2,4-nitrophenol by the fabricated CA membrane with MIP (CA-MIP and the PS membrane with MIP (PS-MIP was observed at pH 7.0 and pH 5.0, respectively. The sorption of 2,4-dinitrophenol by CA-MIP and PS-MIP followed a pseudo–second-order kinetic model. For a selectivity study, 2,4-dichlorophenol, 3-chlorophenol, and phenol were selected as potential interferences. The sorption capability of CA-MIP and PS-MIP towards 2,4-dinitrophenol was observed to be higher than that of 2,4-dichlorophenol, 3-chlorophenol, or phenol.

  16. Synthesis, antimicrobial, anti-biofilm evaluation, and molecular modelling study of new chalcone linked amines derivatives.

    Science.gov (United States)

    El-Messery, Shahenda M; Habib, El-Sayed E; Al-Rashood, Sarah T A; Hassan, Ghada S

    2018-12-01

    A series of amide chalcones conjugated with different secondary amines were synthesised and characterised by different spectroscopic techniques 1 H NMR, 13 C NMR, and ESI-MS. They were screened for in vitro antibacterial activity. Compounds 36, 37, 38, 42, and 44 are the most active among the synthesised series exhibiting MIC value of 2.0-10.0 µg/ml against different bacterial strains. Compound 36 was equipotent to the standard drug Ampicillin displaying MBC value of 2.0 µg/ml against the bacterial strain Staphylococcus aureus. The products were screened for anti-biofilm activity. Compounds 36, 37, and 38 exhibited promising anti-biofilm activity with IC 50 value ranges from 2.4 to 8.6 µg. Molecular modelling was performed suggesting parameters of signalling anti-biofilm mechanism. AspB327 HisB340 (arene-arene interaction) and IleB328 amino acid residues seemed of higher importance to inhibit c-di-GMP. Hydrophobicity may be crucial for activity. ADME calculations suggested that compounds 36, 37, and 38 could be used as good orally absorbed anti-biofilm agents.

  17. Synthesis, α-glucosidase inhibition and molecular docking study of coumarin based derivatives.

    Science.gov (United States)

    Taha, Muhammad; Shah, Syed Adnan Ali; Afifi, Muhammad; Imran, Syahrul; Sultan, Sadia; Rahim, Fazal; Khan, Khalid Mohammed

    2018-04-01

    We have synthesized seventeen Coumarin based derivatives (1-17), characterized by 1 HNMR, 13 CNMR and EI-MS and evaluated for α-glucosidase inhibitory potential. Among the series, all derivatives exhibited outstanding α-glucosidase inhibition with IC 50 values ranging between 1.10 ± 0.01 and 36.46 ± 0.70 μM when compared with the standard inhibitor acarbose having IC 50 value 39.45 ± 0.10 μM. The most potent derivative among the series is derivative 3 having IC 50 value 1.10 ± 0.01 μM, which are many folds better than the standard acarbose. The structure activity relationship (SAR) was mainly based upon by bring about difference of substituent's on phenyl part. Molecular docking studies were carried out to understand the binding interaction of the most active compounds. Copyright © 2018 Elsevier Inc. All rights reserved.

  18. Synthesis and molecular docking study of piperazine derivatives as potent urease inhibitors.

    Science.gov (United States)

    Taha, Muhammad; Wadood, Abdul

    2018-04-13

    Urease is known to be one of the major causes of diseases induced by Helicobacter pylori, thus allow them to survive at low pH inside the stomach and thereby, play an important role in the pathogenesis of gastric and peptic ulcer, apart from cancer as well. Keeping in view the great importance of urease inhibitors, here in this study we have synthesized piperazine derivatives (1-15) and evaluated for their urease inhibitory activity. All analogs showed excellent inhibitory potential with IC 50 values ranging between 1.1 ± 0.01 and 33.40 ± 1.50 µM when compared with the standard inhibitor thiourea (IC 50  = 21.30 ± 1.10 µM). Structure activity relationship has been established for all compounds which are mainly based upon the substitution on phenyl ring. Molecular docking study was performed in order to understand the binding interaction of the compounds in the active site of enzyme. Copyright © 2018 Elsevier Inc. All rights reserved.

  19. Synthesis of piperazine sulfonamide analogs as diabetic-II inhibitors and their molecular docking study.

    Science.gov (United States)

    Taha, Muhammad; Irshad, Maryam; Imran, Syahrul; Chigurupati, Sridevi; Selvaraj, Manikandan; Rahim, Fazal; Ismail, Nor Hadiani; Nawaz, Faisal; Khan, Khalid Mohammed

    2017-12-01

    Piperazine Sulfonamide analogs (1-19) have been synthesized, characterized by different spectroscopic techniques and evaluated for α-amylase Inhibition. Analogs 1-19 exhibited a varying degree of α-amylase inhibitory activity with IC 50 values ranging in between 1.571 ± 0.05 to 3.98 ± 0.397 μM when compared with the standard acarbose (IC 50  = 1.353 ± 0.232 μM). Compound 1, 2, 3 and 7 showed significant inhibitory effects with IC 50 value 2.348 ± 0.444, 2.064 ± 0.04, 1.571 ± 0.05 and 2.118 ± 0.204 μM, respectively better than the rest of the series. Structure activity relationships were established. Molecular docking studies were performed to understand the binding interaction of the compounds. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  20. Synthesis, molecular docking study and thymidine phosphorylase inhibitory activity of 3-formylcoumarin derivatives.

    Science.gov (United States)

    Taha, Muhammad; Adnan Ali Shah, Syed; Afifi, Muhammad; Imran, Syahrul; Sultan, Sadia; Rahim, Fazal; Hadiani Ismail, Nor; Mohammed Khan, Khalid

    2018-03-01

    Thymidine phosphorylase (TP) over expression plays role in several pathological conditions, such as rheumatoid arthritis, chronic inflammatory diseases, psoriasis, and tumor angiogenesis. The inhibitor of this enzyme plays an important role in preventing the serious threat due to over expression of TP. In this regard, a series of seventeenanalogs of 3-formylcoumarin (1-17) were synthesized, characterized by 1 HNMR and EI-MS and screened for thymidine phosphorylaseinhibitory activity. All analogs showed a variable degree of thymidine phosphorylase inhibition with IC 50 values ranging between 0.90 ± 0.01 and 53.50 ± 1.20 μM when compared with the standard inhibitor 7-Deazaxanthine having IC 50 value 38.68 ± 1.12 μM. Among the series, fifteenanalogs such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 16 and 17 showed excellent inhibition which is many folds better than the standard 7-Deazaxanthine whiletwo analogs 13 and 14 showed good inhibition. The structure activity relationship (SAR) was mainly based upon by bring about difference of substituents on phenyl ring. Molecular docking study was carried out to understand the binding interaction of the most active analogs. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. Synthesis, β-glucuronidase inhibition and molecular docking studies of hybrid bisindole-thiosemicarbazides analogs.

    Science.gov (United States)

    Taha, Muhammad; Ismail, Nor Hadiani; Imran, Syahrul; Rahim, Fazal; Wadood, Abdul; Khan, Huma; Ullah, Hayat; Salar, Uzma; Khan, Khalid Mohammed

    2016-10-01

    Hybrid bisindole-thiosemicarbazides analogs (1-18) were synthesized and screened for β-glucuronidase activity. All compounds showed varied degree of β-glucuronidase inhibitory potential when compared with standard d-saccharic acid 1,4-lactone (IC50=48.4±1.25μM). Compounds 4, 7, 9, 6, 5, 12, 17 and 18 showed exceptional β-glucuronidase inhibition with IC50 values ranging from 0.1 to 5.7μM. Compounds 1, 3, 8, 16, 13, 2 and 14 also showed better activities than standard with IC50 values ranging from 7.12 to 15.0μM. The remaining compounds 10, 11, and 15 showed good inhibitory potential with IC50 values 33.2±0.75, 21.4±0.30 and 28.12±0.25μM respectively. Molecular docking studies were carried out to confirm the binding interaction of the compounds. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Synthesis, antioxidant, antifungal, molecular docking and ADMET studies of some thiazolyl hydrazones.

    Science.gov (United States)

    Kauthale, Sushama; Tekale, Sunil; Damale, Manoj; Sangshetti, Jaiprakash; Pawar, Rajendra

    2017-08-15

    Some thiazolyl hydrazones were synthesized by one pot reaction of thiophene-2-carbaldehyde or 2, 4-dichlorobenzaldehyde, thiosemicarbazide and various phenacyl bromides which were preliminarily screened for in vitro antioxidant and antifungal activities. Excellent DPPH and H 2 O 2 radical scavenged antioxidant activities were observed with almost all the tested compounds. Compounds 4a, 4b, 4c, 4e, 4f and 4i showed comparable DPPH scavenged antioxidant potential (90.26-96.56%) whereas H 2 O 2 scavenged antioxidant activity (90.98-92.08%) was noticeable in case of 4a and 4f; showing significant antioxidant potential comparable with the standard ascorbic acid (95.3%). In vitro antifungal activity of synthesized compounds against fungal species Candida albicance, Aspergillus niger and Aspergillus flavus was found to be moderate to good as compared with the standard fluconazole and MIC values were found in the range of 3.12-25μg/mL. Molecular docking studies revealed that the compounds 4a, 4b and 4c have a potential to become lead molecules in drug discovery process. In silico ADMET study was also performed for predicting pharmacokinetic and toxicity profile of the synthesized antioxidants which expressed good oral drug like behaviour and non-toxic nature. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Synthesis of Fe–Li–Cr Multinuclear Complexes as Molecular Magnet Materials

    Directory of Open Access Journals (Sweden)

    Iis Siti Jahro

    2008-03-01

    Full Text Available Multinuclear complexes have received considerable interest as molecular magnet materials. Up to now, several complex compounds based on bidentate ligand 2,2’ bipyridine have been synthesized. In this research, the Fe-Li-Cr multinuclear complexes with derivative 2’2- bipyridine ligands: 2-(2’-pyridylquinoline(pq, 2,2’-Pyridil(pdl have been synthesized. The oxalate (ox ligand has also been used as a bridging ligand in these multinuclear complexes. The chemical formula of Li[FeCr(ox2(pq(BF42(H2O2] and [Fe(pdln][LiCr(ox3] complexes have been verified using metal and C, H, N elemental analysis data. The IR spectra in 350 – 4000 cm-1 range exhibit characteristic absorptions, which support the proposed structure of complex. The plausible structure of the compounds has been drawn based on complex formation mechanism. The magnetic susceptibility at room temperature of the pq-complex is about 5.7 BM and of the pdl- complexes are 4.8 and 5.5 BM. These indicated that both spin states of iron(II exist in the multinuclear complexes.

  4. Transformation from layered to tunnel structures: Synthesis, characterization, and applications of manganese oxide octahedral molecular sieves

    Science.gov (United States)

    Xia, Guan-Guang

    Manganese oxide based octahedral molecular sieves (OMS) have been found to have a wide variety of applications as catalysts, absorbents, and battery materials due to their unique structures and physical and chemical properties. OMS materials are made up of manganese oxide octahedral building blocks sharing comers and edges to form tunnel structures. Manganese species in the framework of OMS materials are mixed valent with various ion-exchangeable cations residing in the tunnels playing important roles in charge balancing and special chemical activities. With different synthetic parameters such as the template used, temperature, pressure, and the pH of the synthetic media, layered birnessite materials were hydrothermally transformed into distinct tunnel structures with different tunnel sizes, including Mg-3x3 (OMS-1), NH4-2x2 (NH4-OMS-2), Na-2x4 (OMS-5), and other manganese oxides. Characterization of the OMS materials with a wide variety of instruments has revealed that most of them are nano-fibrous hollow crystals ith large surface areas, high ion-exchange capabilities, and relatively high thermal stabilities. The Na-2x4 tunnel structure sodium MnOx has been synthesized for the first time and studied in detail, including synthetic strategies, structural analyses, and other physical and chemical property analyses. As catalysts, the synthetic OMS materials show high catalytic activities and shape-selective properties. For example, the results of the competitive oxidation of cycloalkanes with tertiary butyl hydrogen peroxide (TBHP) over different tunnel sized ONIS materials have proven that the OMS materials with larger tunnels are more favorable for the oxidation of the biggest molecule, cyclooctane, than the smallest one, cyclohexane. Besides the tunnel size effects, tunnel cations in the OMS materials also have influences on their catalytic activities. The study of carbon monoxide cleanup for fuel cell applications demonstrates that Ag-OMS-2 (a hollandite

  5. Multicomponent synthesis, biological evaluation and molecular docking of new spiro-oxindole derivatives

    Directory of Open Access Journals (Sweden)

    M. Sapnakumari

    2017-11-01

    Full Text Available A new series of spiro-oxindoles that were identified based upon their ability to inhibit methionine tRNA synthase (PDB ID: 1PFV and glucosamine-6-phosphate synthase (PDB ID: 1JXA enzymes in virtual screening was synthesized by a three-component 1,3-dipolar cycloaddition method. The reaction proceeds through the formation of azomethine ylides generated in situ by the decarboxylative condensation of isatin and amino acids with dipolarophile chalcones. These compounds are active against Staphylococcus aureus, Escherichia coli, Aspergillus niger and Aspergillus flavus, supporting the in silico screening. In addition, their antitubercular activity was assessed using the MABA method. The compounds 3′-[(4-fluorophenylcarbonyl]-4′-phenylspiro[indole-3,2′-pyrrolidin]-2(1H-one 3a, 4′-(4-bromophenyl-3′-[(4-fluorophenylcarbonyl]-5′-(hydroxymethyl spiro[indole-3,2′-pyrrolidin]-2(1H-one 3e and 4′-(4-chlorophenyl-3′-[(4-fluorophenylcarbonyl]-5′-(2-methylpropylspiro[indole-3,2′-pyrrolidin]-2(1H-one 3g are potent molecules with MIC of 0.8 μg/mL. In the DPPH radical scavenging assay, compounds 4′-(4-chlorophenyl-3′-[(4-fluorophenylcarbonyl]spiro[indole-3,2′-pyrrolidin]-2(1H-one 3b, 4′-(4-chlorophenyl-3′-[(4-fluorophenylcarbonyl]-5′-(hydroxymethylspiro[indole-3,2′-pyrrolidin]-2(1H-one 3d and 4′-(4-bromophenyl-3′-[(4-fluorophenylcarbonyl]-5′-(hydroxymethylspiro[indole-3,2′-pyrrolidin]-2(1H-one 3e exhibited significant radical scavenging capacity. Keywords: Chalcone, Spiro-oxindole, Azomethine ylide, Antimicrobial activity, Molecular docking

  6. Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology.

    Science.gov (United States)

    Pirazzini, Marco; Rossetto, Ornella; Eleopra, Roberto; Montecucco, Cesare

    2017-04-01

    The study of botulinum neurotoxins (BoNT) is rapidly progressing in many aspects. Novel BoNTs are being discovered owing to next generation sequencing, but their biologic and pharmacological properties remain largely unknown. The molecular structure of the large protein complexes that the toxin forms with accessory proteins, which are included in some BoNT type A1 and B1 pharmacological preparations, have been determined. By far the largest effort has been dedicated to the testing and validation of BoNTs as therapeutic agents in an ever increasing number of applications, including pain therapy. BoNT type A1 has been also exploited in a variety of cosmetic treatments, alone or in combination with other agents, and this specific market has reached the size of the one dedicated to the treatment of medical syndromes. The pharmacological properties and mode of action of BoNTs have shed light on general principles of neuronal transport and protein-protein interactions and are stimulating basic science studies. Moreover, the wide array of BoNTs discovered and to be discovered and the production of recombinant BoNTs endowed with specific properties suggest novel uses in therapeutics with increasing disease/symptom specifity. These recent developments are reviewed here to provide an updated picture of the biologic mechanism of action of BoNTs, of their increasing use in pharmacology and in cosmetics, and of their toxicology. Copyright © 2017 by The Author(s).

  7. [Pharmacological approaches for correction of thyroid dysfunctions in diabetes mellitus].

    Science.gov (United States)

    Shpakov, A O

    2017-05-01

    Thyroid diseases are closely associated with the development of types 1 and 2 diabetes mellitus (DM), and as a consequence, the development of effective approaches for their treatment is one of the urgent problems of endocrinology. Traditionally, thyroid hormones (TH) are used to correct functions of the thyroid system. However, they are characterized by many side effects, such as their negative effect on the cardiovascular system as well as the ability of TH to enhance insulin resistance and to disturb insulin-producing function of pancreas, exacerbating thereby diabetic pathology. Therefore, the analogues of TH, selective for certain types of TH receptors, that do not have these side effects, are being developed. The peptide and low-molecular weight regulators of thyroid-stimulating hormone receptor, which regulate the activity of the thyroid axis at the stage of TH synthesis and secretion in thyrocytes, are being created. Systemic and intranasal administration of insulin, metformin therapy and drugs with antioxidant activity are effective for the treatment of thyroid pathology in types 1 and 2 DM. In the review, the literature data and the results of own investigations on pharmacological approaches for the treatment and prevention of thyroid diseases in patients with types 1 and 2 DM are summarized and analyzed.

  8. Cough: neurophysiology, methods of research, pharmacological therapy and phonoaudiology

    Directory of Open Access Journals (Sweden)

    Balbani, Aracy Pereira Silveira

    2012-01-01

    Full Text Available Introduction: The cough is the more common respiratory symptom in children and adults. Objective: To present a revision on the neurophysiology and the methods for study of the consequence of the cough, as well as the pharmacotherapy and phonoaudiology therapy of the cough, based on the works published between 2005 and 2010 and indexed in the bases Medline, Lilacs and Library Cochrane under them to keywords "cough" or "anti-cough". Synthesis of the data: The consequence of the cough involves activation of receiving multiples becomes vacant in the aerial ways and of neural projections of the nucleus of the solitary treatment for other structures of the central nervous system. Experimental techniques allow studying the consequence of the cough to the cellular and molecular level to develop new anti-cough agents. It does not have evidences of that anti-cough exempt of medical lapsing they have superior effectiveness to the one of placebo for the relief of the cough. The phonoaudiology therapy can benefit patients with refractory chronic cough to the pharmacological treatment, over all when paradoxical movement of the vocal folds coexists. Final Comments: The boarding to multidiscipline has basic paper in the etiological diagnosis and treatment of the cough. The otolaryngologist must inform the patients on the risks of the anti-cough of free sales in order to prevent adverse poisonings and effect, especially in children.

  9. Comparative studies of Zr-based MCM-41 and MCM-48 mesoporous molecular sieves: Synthesis and physicochemical properties

    Energy Technology Data Exchange (ETDEWEB)

    Chen, L.F. [Departamento de Ciencias Basicas, Universidad Autonoma Metropolitana-A, Av. San Pablo 180, Col. Reynosa-Tamaulipas, 02200 Mexico D.F. (Mexico)]. E-mail: chenlf2001@yahoo.com; Zhou, X.L. [Petroleum Processing Research Center, East China University of Science and Technology, 200237 Shanghai (China); Norena, L.E. [Departamento de Ciencias Basicas, Universidad Autonoma Metropolitana-A, Av. San Pablo 180, Col. Reynosa-Tamaulipas, 02200 Mexico D.F. (Mexico)]. E-mail: lnf@correo.azc.uam.mx; Wang, J.A. [Laboratorio de Catalisis y Materiales, SEPI-ESIQIE, Instituto Politecnico Nacional, Av. Politecnico S/N, Col. Zacatenco, 07738 Mexico D.F. (Mexico); Navarrete, J. [Grupo de Molecular Ingenieria, Instituto Mexicano del Petroleo, Eje Lazaro Cardenas 152, 07730 Mexico D.F. (Mexico); Salas, P. [Grupo de Molecular Ingenieria, Instituto Mexicano del Petroleo, Eje Lazaro Cardenas 152, 07730 Mexico D.F. (Mexico); Montoya, A. [Grupo de Molecular Ingenieria, Instituto Mexicano del Petroleo, Eje Lazaro Cardenas 152, 07730 Mexico D.F. (Mexico); Del Angel, P. [Grupo de Molecular Ingenieria, Instituto Mexicano del Petroleo, Eje Lazaro Cardenas 152, 07730 Mexico D.F. (Mexico); Llanos, M.E. [Grupo de Molecular Ingenieria, Instituto Mexicano del Petroleo, Eje Lazaro Cardenas 152, 07730 Mexico D.F. (Mexico)

    2006-12-30

    Two surfactant-templated synthetic routes are developed for the preparation of new types of mesoporous molecular sieves, Zr-MCM-41 and Zr-MCM-48, using different Si sources but keeping the same zirconium precursor (zirconium-n-propoxide). When fumed silica was used as Si precursor, a Zr-MCM-48 material of cubic structure was formed with a surface area of 654.8 m{sup 2}/g and an unimodal pore diameter distribution. It shows low stability: after calcination at 600 deg. C, the ordered structure was transformed into a relatively disordered worm-like mesostructure with many defects and silanol groups. The use of tetraethyl orthosilicate as Si source led to the formation of a Zr-MCM-41 mesoporous solid, which had good thermal stability and a highly ordered hexagonal arrangement, with a surface area 677.9 m{sup 2}/g and an uniform pore diameter distribution. Fourier transform infrared (FT-IR) characterization and {sup 29}Si NMR analysis confirm that zirconium ions indeed incorporated into the framework of the solid. The in situ FT-IR spectroscopy of pyridine adsorption reveals that both, Lewis and Broensted acid sites, were formed on the surface of these mesoporous materials. The strength and number of the Broensted acid sites of the Zr-MCM-48 solid were greater than those of the Zr-MCM-41, due to a lower degree of condensation reaction during the synthesis that led to more structural defects in the framework and more silanol groups stretching from the solid surface.

  10. Comparative studies of Zr-based MCM-41 and MCM-48 mesoporous molecular sieves: Synthesis and physicochemical properties

    International Nuclear Information System (INIS)

    Chen, L.F.; Zhou, X.L.; Norena, L.E.; Wang, J.A.; Navarrete, J.; Salas, P.; Montoya, A.; Del Angel, P.; Llanos, M.E.

    2006-01-01

    Two surfactant-templated synthetic routes are developed for the preparation of new types of mesoporous molecular sieves, Zr-MCM-41 and Zr-MCM-48, using different Si sources but keeping the same zirconium precursor (zirconium-n-propoxide). When fumed silica was used as Si precursor, a Zr-MCM-48 material of cubic structure was formed with a surface area of 654.8 m 2 /g and an unimodal pore diameter distribution. It shows low stability: after calcination at 600 deg. C, the ordered structure was transformed into a relatively disordered worm-like mesostructure with many defects and silanol groups. The use of tetraethyl orthosilicate as Si source led to the formation of a Zr-MCM-41 mesoporous solid, which had good thermal stability and a highly ordered hexagonal arrangement, with a surface area 677.9 m 2 /g and an uniform pore diameter distribution. Fourier transform infrared (FT-IR) characterization and 29 Si NMR analysis confirm that zirconium ions indeed incorporated into the framework of the solid. The in situ FT-IR spectroscopy of pyridine adsorption reveals that both, Lewis and Broensted acid sites, were formed on the surface of these mesoporous materials. The strength and number of the Broensted acid sites of the Zr-MCM-48 solid were greater than those of the Zr-MCM-41, due to a lower degree of condensation reaction during the synthesis that led to more structural defects in the framework and more silanol groups stretching from the solid surface

  11. Synthesis, characterization, and molecular structure of tetraethylammonium pentakis(isothiocyanato)bis(2,2'-bipyridine)uranate(IV)

    International Nuclear Information System (INIS)

    Wiley, R.O.; Von Dreele, R.B.; Brown, T.M.

    1980-01-01

    The synthesis of tetraethylammonium pentakis(isothiocyanato)bis(2,2'-bipyridine)uranate(IV) has been accomplished, and it was characterized by classical physical methods. The crystal and molecular structure was determined from single-crystal x-ray data collected by the theta-2theta technique on an automated diffractometer. The compound consists of pentakis(isothiocyanato)bis (2,2'-bipyridine)uranate(IV) anions and disordered tetraethylammonium cations. Uranium is bound to nine nitrogen atoms in a highly distorted monocapped square antiprism in which one bipyridine occupies a position bridging the cap and the near square while the other bipyridine spans the opposite edge of the far square. Distortion from the ideal geometry is caused by the small ligand bite of the bipyridine ligand. An alternative description of the coordination geometry is derived from the seven-coordinate pentagonal bipyramid in which each bipyridine ligand is assumed to occupy an axial position with the five thiocyanato ligands forming the pentagonal girdle. The U-N bond distances vary from 2.35 to 2.47 A for the thiocyanato ligands and from 2.61 to 2.65 A for the bipyridine ligands. The structure was solved by standard heavy-atom techniques and refined by large-block matrix least squares to a final R value of 0.083 for 3878 independent observed reflections. The compound crystallized in the monoclinic space group P2 1 /c, Z = 4, with lattice parameters a = 14.427 (10) A, b = 18.612 (17) A, c = 15.710 (10) A, and β = 105.17 (7) 0 , rho/sub obsd/ = 1.57 g cm -3

  12. Synthesis and application of molecularly imprinted polymers for the selective extraction of organophosphorus pesticides from vegetable oils.

    Science.gov (United States)

    Boulanouar, Sara; Combès, Audrey; Mezzache, Sakina; Pichon, Valérie

    2017-09-01

    The increasing use of pesticides in agriculture causes environmental issues and possible serious health risks to humans and animals. Their determination at trace concentrations in vegetable oils constitutes a significant analytical challenge. Therefore, their analysis often requires both an extraction and a purification step prior to separation with liquid chromatography (LC) and mass spectrometry (MS) detection. This work aimed at developing sorbents that are able to selectively extract from vegetable oil samples several organophosphorus (OPs) pesticides presenting a wide range of physico-chemical properties. Therefore, different conditions were screened to prepare molecularly imprinted polymers (MIPs) by a non-covalent approach. The selectivity of the resulting polymers was evaluated by studying the OPs retention in pure media on both MIPs and non-imprinted polymers (NIP) used as control. The most promising MIP sorbent was obtained using monocrotophos (MCP) as the template, methacrylic acid (MAA) as the monomer and ethylene glycol dimethacrylate (EGDMA) as the cross-linker with a molar ratio of 1/4/20 respectively. The repeatability of the extraction procedure and of the synthesis procedure was demonstrated in pure media. The capacity of this MIP was 1mg/g for malathion. This MIP was also able to selectively extract three OPs from almond oil by applying the optimized SPE procedure. Recoveries were between 73 and 99% with SD values between 4 and 6% in this oil sample. The calculated LOQs (between 0.3 and 2μg/kg) in almond seeds with a SD between 0.1 and 0.4μg/kg were lower than the Maximum Residue Levels (MRLs) established for the corresponding compounds in almond seed. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Synthesis of Mesoporous Carbons from Date Pits for the Adsorption of Large Molecular Weight Micropollutants in Wastewater

    KAUST Repository

    Al Jeffrey, Ahmed

    2013-07-01

    Efficient reuse of waste water requires removal of micro-pollutants from waste water streams by affordable and sustainable methods. Activated carbon is considered a powerful adsorbent due to its high surface area and low cost of treatment, compared to other expensive methods such as membrane filtration. Producing activated carbon with larger mesoporosity (>2nm) is of particular interest in industry in the removal of larger molecular sized pollutants. This study reports the synthesis of mesoporous activated carbons from a nonsoluble biomass precursor (date-pits) along with chemical activation using ZnCl2. Thus, produced activated carbon showed high surface area and large mesopore volume up to 1571 m2/g and 2.00 cm3/g respectively. In addition, the pore size of the product was as high as 9.30 nm. As a method of verification, HRTEM (Highresolution transmission electron microscopy) was used to directly authenticate the pore size of the synthesized activated carbons. Tannic acid and atrazine were used as model waste water pollutants and the adsorption capability of the produced activated carbon for these pollutants were evaluated and compared to a commercial mesoporous carbon: G60 from Norit. The results showed that the sorption capacity of produced activated carbon for tannic acid was 2 times that of G60 while the sorption capacity of produced activated carbon for atrazine was lower than that of G60. The activated carbon was also evaluated for adsorption of real secondary effluent municipal wastewater and the results suggest that the produced activated carbon was able to sorb a greater amount of biopolymers than G60. These results demonstrate that the thus-produced activated carbon may be a promising sorbent for waste water treatment.

  14. Synthesis of new molecular probes radiolabelled with fluorine-18 for imaging neuro-inflammation with Positon Emission Tomography

    International Nuclear Information System (INIS)

    Medran-Navarrete, Vincent

    2014-01-01

    The work presented in this manuscript aims to describe the synthesis of new ligands of the translocation protein 18 kDa (TSPO), their in vitro evaluation and, for the most promising candidates, their isotopic radiolabelling with the short-lived positron emitter fluorine-18 (t 1/2 : 109.8 minutes). The ultimate goal of this work consists in developing new molecular probes, or bio-markers, for imaging neuro-inflammation in a non-invasive and atraumatic manor using Positron Emission Tomography (PET). Neuro-inflammatory processes have been identified in Alzheimer and Parkinson diseases, MS and various psychiatric pathologies. The radioligand of choice for imaging TSPO is currently [ 18 F]DPA-714, a pyr-azolo[1,5-a]pyrimidine radiolabelled with fluorine-18 which has been recently prepared in our laboratories. However, [ 18 F]DPA-714 undergoes a rapid in vivo loss of the radioactive fluorine by cleavage of the fluoro-alkoxy chain as demonstrated in metabolic studies. Therefore, my PhD project aimed to design and develop new structurally related analogues of DPA-714 where the linkage between the main backbone and the fluorine-18 would be reinforced. To this extent, nineteen compounds were prepared and their affinity towards the TSPO was evaluated. Two promising candidates, coded DPA-C5yne and CfO-DPA-714, were radiolabelled with fluorine-18 with good radiochemical yields (20-30 %) and high specific radioactivities (50-90 GBq/μmol). These radioligands were also evaluated by PET imaging at the preclinical stage and displayed equivalent or slightly improved results when compared to [ 18 F]DPA- 714. (author) [fr

  15. Process Pharmacology: A Pharmacological Data Science Approach to Drug Development and Therapy.

    Science.gov (United States)

    Lötsch, Jörn; Ultsch, Alfred

    2016-04-01

    A novel functional-genomics based concept of pharmacology that uses artificial intelligence techniques for mining and knowledge discovery in "big data" providing comprehensive information about the drugs' targets and their functional genomics is proposed. In "process pharmacology", drugs are associated with biological processes. This puts the disease, regarded as alterations in the activity in one or several cellular processes, in the focus of drug therapy. In this setting, the molecular drug targets are merely intermediates. The identification of drugs for therapeutic or repurposing is based on similarities in the high-dimensional space of the biological processes that a drug influences. Applying this principle to data associated with lymphoblastic leukemia identified a short list of candidate drugs, including one that was recently proposed as novel rescue medication for lymphocytic leukemia. The pharmacological data science approach provides successful selections of drug candidates within development and repurposing tasks. © 2016 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  16. Increased synthesis of high-molecular-weight cPLA2 mediates early UV-induced PGE2 in human skin.

    Science.gov (United States)

    Gresham, A; Masferrer, J; Chen, X; Leal-Khouri, S; Pentland, A P

    1996-04-01

    Ultraviolet light (UV) B-induced inflammation is characterized by dramatic increases in prostaglandin E2 (PGE2) synthesis due to enhanced arachidonate deacylation from the membrane. Therefore, the effect of UV on sythesis, mass, and distribution of the high-molecular-weight phospholipase A2 (cPLA2) in cultured human keratinocytes and human skin was studied. The 105-kDa cPLA2 was demonstrated to be the critical enzyme in UV-induced PGE2 synthesis and erythema in the first 6 h postirradiation. Immunoprecipitation of 35S-labeled protein showed cPLA2 synthesis increased three- to fourfold 6 h after irradiation. Immunoprecipitated 32P-labeled cPLA2 demonstrated phosphorylation of cPLA2 was concurrently induced, suggesting that UV also activates cPLA2. This increase in cPLA2 synthesis and activation also closely correlated with increased PGE2 synthesis and [3H]arachidonic acid release and was effectively blocked by both an S-oligonucleotide antisense to cPLA2 and methyl arachidonate fluorophosphate, a specific inhibitor of cPLA2. Biopsy and histochemical examination of erythematous sites expressed increased amounts of cPLA2 whereas nonerythematous irradiated sites did not. In contrast, cyclooxygenase-1 and -2 in cultures and skin explants were unaffected 6 h post-UV, and no change in cyclooxygenase activity was observed at this time. These results suggest that increased cPLA2 synthesis occurs only when skin is exposed to UV doses that are sufficient to cause erythema and indicate expression of cPLA2 participates in acute UV inflammation.

  17. Development of a Bifunctional Andrographolide-Based Chemical Probe for Pharmacological Study.

    Science.gov (United States)

    Hsu, Ya-Hsin; Hsu, Yu-Ling; Liu, Sheng-Hung; Liao, Hsin-Chia; Lee, Po-Xuan; Lin, Chao-Hsiung; Lo, Lee-Chiang; Fu, Shu-Ling

    2016-01-01

    Andrographolide (ANDRO) is a lactone diterpenoid compound present in the medicinal plant Andrographis paniculata which is clinically applied for multiple human diseases in Asia and Europe. The pharmacological activities of andrographolide have been widely demonstrated, including anti-inflammation, anti-cancer and hepatoprotection. However, the pharmacological mechanism of andrographolide remains unclear. Therefore, further characterization on the kinetics and molecular targets of andrographolide is essential. In this study, we described the synthesis and characterization of a novel fluorescent andrographolide derivative (ANDRO-NBD). ANDRO-NBD exhibited a comparable anti-cancer spectrum to andrographolide: ANDRO-NBD was cytotoxic to various types of cancer cells and suppressed the migration activity of melanoma cells; ANDRO-NBD treatment induced the cleavage of heat shock protein 90 (Hsp90) and the downregulation of its client oncoproteins, v-Src and Bcr-abl. Notably, ANDRO-NBD showed superior inhibitory effects to andrographolide in all anticancer assays we have performed. In addition, ANDRO-NBD was further used as a fluorescent probe to investigate the uptake kinetics, cellular distribution and molecular targets of andrographolide. Our data revealed that ANDRO-NBD entered cells rapidly and its fluorescent signal could be detected in nucleus, cytoplasm, mitochondria, and lysosome. Moreover, we demonstrated that ANDRO-NBD was covalently bound to several putative target proteins of andrographolide, including NF-κB and hnRNPK. In summary, we developed a fluorescent andrographolide probe with comparable bioactivity to andrographolide, which serves as a powerful tool to explore the pharmacological mechanism of andrographolide.

  18. Development of a Bifunctional Andrographolide-Based Chemical Probe for Pharmacological Study.

    Directory of Open Access Journals (Sweden)

    Ya-Hsin Hsu

    Full Text Available Andrographolide (ANDRO is a lactone diterpenoid compound present in the medicinal plant Andrographis paniculata which is clinically applied for multiple human diseases in Asia and Europe. The pharmacological activities of andrographolide have been widely demonstrated, including anti-inflammation, anti-cancer and hepatoprotection. However, the pharmacological mechanism of andrographolide remains unclear. Therefore, further characterization on the kinetics and molecular targets of andrographolide is essential. In this study, we described the synthesis and characterization of a novel fluorescent andrographolide derivative (ANDRO-NBD. ANDRO-NBD exhibited a comparable anti-cancer spectrum to andrographolide: ANDRO-NBD was cytotoxic to various types of cancer cells and suppressed the migration activity of melanoma cells; ANDRO-NBD treatment induced the cleavage of heat shock protein 90 (Hsp90 and the downregulation of its client oncoproteins, v-Src and Bcr-abl. Notably, ANDRO-NBD showed superior inhibitory effects to andrographolide in all anticancer assays we have performed. In addition, ANDRO-NBD was further used as a fluorescent probe to investigate the uptake kinetics, cellular distribution and molecular targets of andrographolide. Our data revealed that ANDRO-NBD entered cells rapidly and its fluorescent signal could be detected in nucleus, cytoplasm, mitochondria, and lysosome. Moreover, we demonstrated that ANDRO-NBD was covalently bound to several putative target proteins of andrographolide, including NF-κB and hnRNPK. In summary, we developed a fluorescent andrographolide probe with comparable bioactivity to andrographolide, which serves as a powerful tool to explore the pharmacological mechanism of andrographolide.

  19. Poly(1,4-cyclohexanedimethylene 2,6-naphthalate polyester with high melting point: Effect of different synthesis methods on molecular weight and properties

    Directory of Open Access Journals (Sweden)

    N. Kasmi

    2018-03-01

    Full Text Available In the current manuscript, a new approach for the synthesis of poly(1,4- cyclohexanedimethylene 2,6-naphthalate (PCHDMN derived from dimethyl 2,6-naphthalenedicarboxylate (2,6-DMN and 1,4-Cyclohexanedimethanol (CHDM via melt polycondensation method is introduced. The effect of three different synthesis pathways, polycondensation time and temperature on polyesters molecular weight increase has been investigated. All of the prepared samples were characterized measuring their intrinsic viscosity (IV, thermal properties and morphology with differential scanning calorimetry (DSC and wide-angle X-ray diffraction (WAXD, respectively. The results demonstrated the effectiveness of the synthesis pathway proposed for the preparation of PCHDMN, resulting in high molecular weight (IV value around 0.5 dL/g and much shorter reaction time. Melt polycondensation temperatures above melting point of polyester should be avoided to be used due to the decomposition of polyester. This was proved by thermogravimetric analysis (TGA and Pyrolysis-gas chromatography–mass spectroscopy analysis (Py-GC/MS.

  20. New perspectives in the Fischer-Tropsch synthesis using cobalt supported on mesoporous molecular sieves; Novas perspectivas na sintese de Fischer-Tropsch usando cobalto suportado em peneiras moleculares mesoporosas

    Energy Technology Data Exchange (ETDEWEB)

    Souza, M.J.B.; Silva, A.O.S. [Universidade Federal do Rio Grande do Norte (UFRN), Natal, RN (Brazil). Dept. de Engenharia Quimica; Fernandes Junior, V.J.; Araujo, A.S. [Universidade Federal do Rio Grande do Norte (UFRN), Natal, RN (Brazil). Dept. de Quimica

    2004-07-01

    The conversion of synthesis gas to liquid products via Fischer-Tropsch synthesis (FTS) is an important process in the generation of clean fuels of sulfur and nitrogen compounds. Catalysts based on iron are very used in the conventional process due its cheap manufacture price. Recently the use of cobalt as promoter gave good results. MCM-41 mesoporous materials were discovered by Mobil scientists in the nineties and ever since they have great successes as support and catalyst in several processes of the oil industry as catalytic cracking, reformer and hydrotreating. In this work are presented new alternatives for FTS with the use of cobalt supported on molecular sieves of the type MCM-41. A comparative study with the usual catalysts based on silica was accomplished with different levels of cobalt. (author)

  1. Conception and synthesis of new molecular platforms based on cryptophanes. Application for the encapsulation of xenon and metallic cations in aqueous solution

    International Nuclear Information System (INIS)

    Chapellet, Laure-Lise

    2015-01-01

    Cryptophanes are molecular receptors known for their complexation properties of various substrates. Over the last fifteen years, cryptophanes were the subject of numerous studies for they can be used to obtain biosensors for xenon MRI. This field has experienced significant growth and advances to the point were in vivo applications are now envisioned, provided that large amounts of biosensors can be synthesized. More recently, polyphenolic cryptophanes have been studied for their ability to encapsulate monovalent metallic cations like Cs"+ and Tl"+ in aqueous solution. This could lead to applications for depollution of contaminated water sources but would require, once again, the synthesis of large amounts of cryptophanes.The work carried out during this thesis focus on the conception and the synthesis of new molecular platforms that could either be used to obtain new hyper-polarized xenon biosensors or to encapsulate monovalent metallic cations as Cs"+ and Tl"+. Synthetic routes have been developed to produce good amounts of a variety of new hydrosoluble molecular platforms designed for each application. The encapsulation properties of these new host molecules were studied through NMR of the encapsulated nucleus, circular dichroism or isothermal calorimetry. In each case, the new platforms meet the expected requirements thus opening the door for the envisioned applications. (author)

  2. Synthesis and characterization of Co (Ni or Cu)-MCM-41 mesoporous molecular sieves with different amount of metal obtained by using microwave irradiation method

    International Nuclear Information System (INIS)

    Jiang Tingshun; Zhao Qian; Chen Kangmin; Tang Yajing; Yu Longbao; Yin Hengbo

    2008-01-01

    Co (Ni or Cu)-MCM-41 mesoporous molecular sieves with different amount of metal were synthesized by using cetyltrimethyl ammonium bromide as a template and by a novel microwave irradiation method. These samples were characterized by powder X-ray diffraction (XRD), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR) and N 2 physical adsorption. The experimental results show that Co (Ni or Cu)-MCM-41 mesoporous molecular sieves were successfully synthesized. When the as-synthesized samples were calcined at 550 deg. C for 10 h, the template was effectively removed. Under microwave irradiation condition, Co-MCM-41 mesoporous molecular sieves have specific surface areas in a range of 745.7-1188.8 m 2 /g and average pore sizes in a range of 2.46-2.75 nm; Ni-MCM-41 mesoporous molecular sieves have specific surface areas in a range of 625.8-1161.3 m 2 /g and average pore sizes of ca. 2.7 nm; Cu-MCM-41 mesoporous molecular sieves have specific surface areas in a range of 601.6-1142.9 m 2 /g and average pore sizes in a range of 2.46-2.76 nm. On the other hand, with increasing the introduced metal amount, the specific surface area and pore volume of the synthesized Co (Ni or Cu)-MCM-41 mesoporous molecular sieves became small, and the mesoporous ordering of the samples became poor. Under the comparable synthesis conditions, the synthesized Co-MCM-41 mesoporous molecular sieve has a bigger specific surface area and a more uniform pore distribution as compared with the synthesized Ni-MCM-41and Cu-MCM-41 mesoporous molecular sieves

  3. Pharmacological therapy for amblyopia

    Directory of Open Access Journals (Sweden)

    Anupam Singh

    2017-01-01

    Full Text Available Amblyopia is the most common cause of preventable blindness in children and young adults. Most of the amblyopic visual loss is reversible if detected and treated at appropriate time. It affects 1.0 to 5.0% of the general population. Various treatment modalities have been tried like refractive correction, patching (both full time and part time, penalization and pharmacological therapy. Refractive correction alone improves visual acuity in one third of patients with anisometropic amblyopia. Various drugs have also been tried of which carbidopa & levodopa have been popular. Most of these agents are still in experimental stage, though levodopa-carbidopa combination therapy has been widely studied in human amblyopes with good outcomes. Levodopa therapy may be considered in cases with residual amblyopia, although occlusion therapy remains the initial treatment choice. Regression of effect after stoppage of therapy remains a concern. Further studies are therefore needed to evaluate the full efficacy and side effect profile of these agents.

  4. Pharmacological therapy for amblyopia

    Science.gov (United States)

    Singh, Anupam; Nagpal, Ritu; Mittal, Sanjeev Kumar; Bahuguna, Chirag; Kumar, Prashant

    2017-01-01

    Amblyopia is the most common cause of preventable blindness in children and young adults. Most of the amblyopic visual loss is reversible if detected and treated at appropriate time. It affects 1.0 to 5.0% of the general population. Various treatment modalities have been tried like refractive correction, patching (both full time and part time), penalization and pharmacological therapy. Refractive correction alone improves visual acuity in one third of patients with anisometropic amblyopia. Various drugs have also been tried of which carbidopa & levodopa have been popular. Most of these agents are still in experimental stage, though levodopa-carbidopa combination therapy has been widely studied in human amblyopes with good outcomes. Levodopa therapy may be considered in cases with residual amblyopia, although occlusion therapy remains the initial treatment choice. Regression of effect after stoppage of therapy remains a concern. Further studies are therefore needed to evaluate the full efficacy and side effect profile of these agents. PMID:29018759

  5. Molecular structure design and soft template synthesis of aza-, oxaaza- and thiaazamacrocyclic metal chelates in the gelatin matrix

    OpenAIRE

    Oleg V. Mikhailov

    2017-01-01

    The data about of soft template synthesis proceeding in gelatin matrices in [3d-element M(II) ion – (N,S)- or (N,O,S)-ambidentate ligson – mono- or dicarbonyl ligson] systems, have been considered and discussed. The chemical nature of the final products of template synthesis formed under these specific conditions, has been compared with the chemical nature of the final products formed by template synthesis in solutions. It has been noted that in many cases, the nature and chemical composition...

  6. A novel process for the synthesis of 'Designed Molecular Precursor' (DMP) of thorium useful for broad application spectrum

    International Nuclear Information System (INIS)

    Sarika Verma; Amritphalae, S.S.

    2016-01-01

    For the first time (Patent application filed in India vide N/F No-0018NF2015) a novel process for the synthesis of 'Designed Molecular Precursor' (DMP) of thorium has been developed, which involves the unique combination of two different (dual) capping agents, one is biomolecule: Cytosine and other is non biomolecule: cetyl trimethyl ammonium bromide. The DMP essentially consists of hybrid nanosized thorium oxalate and alkaline thorate whose application lies in the area of making thorium metal, densified thorium oxide, carbide and nitride, anhydrous thorium complexes and thorium boron silicates glasses. (author)

  7. Synthesis and pharmacological properties of new derivatives of 4-alkoxy-6-methyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones.

    Science.gov (United States)

    Sladowska, Helena; Sabiniarz, Aleksandra; Sapa, Jacek; Filipek, Barbara

    2009-01-01

    Synthesis of 2-(2-hydroxy-3-amino)propyl derivatives of 4-alkoxy-6-methyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones (24-35) is described. The chlorides used in the above synthesis exist mainly in the cyclic forms (18, 20-23). Only chloride with benzhydryl substituent at the nitrogen atom of piperazine has the chain structure (19). Among the studied imides the most active analgesics in the "writhing" syndrome test proved to be compounds 30 and 31 (with LD50 > 2000 mg/kg) containing 4-benzylpiperidino group. Furthermore, all imides suppressed significantly spontaneous locomotor activity of mice.

  8. Probing for improved potency and in vivo bioavailability of excitatory amino acid transporter subtype 1 inhibitors UCPH-101 and UCPH-102: Design, synthesis and pharmacological evaluation of substituted 7-biphenyl analogs

    DEFF Research Database (Denmark)

    Erichsen, Mette Norman; Hansen, J; Artacho Ruiz, Jose

    2014-01-01

    Uptake of the major excitatory neurotransmitter in the CNS, (S)-glutamate, is mediated by a family of excitatory amino acid transporters (EAAT). Previously we have explored the structure-activity relationship (SAR) of a series of EAAT1 selective inhibitors, leading to the development of the potent...... were designed, synthesized and characterized pharmacologically at EAAT1-3 in a [(3)H]-D-aspartate uptake assay. Most notably, the potent EAAT1 inhibition displayed of UCPH-101 and UCPH-102 was retained in analog 1d in which the napht-1-yl group in the 7-position of UCPH-102 has been replaced by an o...

  9. Role of Carboxylate ligands in the Synthesis of AuNPs: Size Control, Molecular Interaction and Catalytic Activity

    KAUST Repository

    Aljohani, Hind Abdullah

    2016-05-22

    then describe the effect of the concentrations and of various type of the stabilizer, and the post-synthesis treatment on gold nanoparticles size. In Chapter 4, we focus on determining the nature of the interactions at molecular level between citrate (and other carboxylate-containing ligands) and AuNP in terms of the mode of coordination at the surface, and the formal oxidation state of Au when interacting with these negatively charged carboxylate ligands (i.e., LX- in the Green formalism). We achieve this by combining very advanced 13C CP/MAS, 23Na MAS and low-temperature SSNMR, high-resolution transmission electron microscopy (HRTEM) and density functional theory (DFT) calculations. A particular emphasis will be based on SS-NMR. In Chapter 5, we study the influence of pretreatment of 1% Au/TiO2 catalysts on the resulting activity in the oxidation of carbon monoxide, the effect of the concentration and the type of the ligands on the catalytic activity. The catalysts were characterized by TPO, XRD, and TEM spectroscopy.

  10. Thermal synthesis of oxide molecular sieve and Mn (K-OMS-2) from K-birnessite obtained from Sol-gel method

    International Nuclear Information System (INIS)

    Rezende, D.S.; Figueira, B.A.M.; Moraes, M.C. de; Silva, L.N. da; Mercury, J.M.R.; Figueiredo, G.P. de

    2016-01-01

    This study presents the thermal synthesis of molecular sieve with K-OMS2 structure from K-birnessite tunneling process, one Mn oxide with structure in layer. According X-Ray diffraction data it was possible to monitoring the conversion of the layered structure around 550 deg C for (K-OMS-2) tunnel with tetragonal system and I2/m space group. The FTIR main spectrum bands of K-OMS-2 was observed in 700, 525 e 470 cm-1 region and are related to elongation Mn 3+ -O e Mn 4+ -O in the tunnel structure. The product morphology identified by Scanning Electron Microscopy it was verified as pseudo tetragonal, reflecting externally the crystallographic system of cryptomelane structure. The results reveal one simple route for the Mn oxide molecular sieve with K-OMS-2 structure

  11. Pharmacological Effects of Biotin in Animals.

    Science.gov (United States)

    Riveron-Negrete, Leticia; Fernandez-Mejia, Cristina

    2017-01-01

    In recent decades, it was found that vitamins affect biological functions in ways other than their long-known functions; niacin is the best example of a water-soluble vitamin known to possess multiple actions. Biotin, also known as vitamin B7 or vitamin H, is a water-soluble B-complex vitamin that serves as a covalently-bound coenzyme of carboxylases. It is now well documented that biotin has actions other than participating in classical enzyme catalysis reactions. Several lines of evidence have demonstrated that pharmacological concentrations of biotin affect glucose and lipid metabolism, hypertension, reproduction, development, and immunity. The effect of biotin on these functions is related to its actions at the transcriptional, translational, and post-translational levels. The bestsupported mechanism involved in the genetic effects of biotin is the soluble guanylate cyclase/protein kinase G (PKG) signaling cascade. Although there are commercially-available products containing pharmacological concentrations of biotin, the toxic effects of biotin have been poorly studied. This review summarizes the known actions and molecular mechanisms of pharmacological doses of biotin in animals and current information regarding biotin toxicity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  12. Influence of Multi-Valency, Electrostatics and Molecular Recognition on the Adsorption of Transition Metal Complexes on Metal Oxides: A Molecular Approach to Catalyst Synthesis

    Energy Technology Data Exchange (ETDEWEB)

    Rioux, Robert M. [Pennsylvania State Univ., University Park, PA (United States)

    2017-03-31

    In this work, we have primarily utilized isothermal titration calorimetry (ITC) and complimentary catalyst characterization techniques to study and assess the impact of solution conditions (i.e., solid-liquid) interface on the synthesis of heterogeneous and electro-catalysts. Isothermal titration calorimetry is well-known technique from biochemistry/physics, but has been applied to a far lesser extent to characterize buried solid-liquid interfaces in materials science. We demonstrate the utility and unique information provided by ITC for two distinct catalytic systems. We explored the thermodynamics associated catalyst synthesis for two systems: (i) ion-exchange or strong electrostatic adsorption for Pt and Pd salts on silica and alumina materials (ii) adsorption to provide covalent attachment of metal and metal-oxo clusters to Dion-Jacobsen perovskite materials.

  13. [Pharmacological treatment of obesity].

    Science.gov (United States)

    Gomis Barbará, R

    2004-01-01

    The pharmacological treatment of obesity should be considered when cannot be achieved a 10% weight loss with diet therapy and physical activity. The drugs effective in obesity treatment may act by different mechanisms such as reduction in food intake, inhibition of fat absorption, increase of thermogenesis and stimulation of adipocyte apoptosis. At present, we only have two marketed drugs for obesity treatment. Sibutramine is an inhibitor of norepinephrine, dopamine and serotonina reuptake which inhibits food intake and increases thermogenesis. Sibutramine administration for a year can induce a weight loss of 4-7%. Its main side effects are hypertension, headache, insomnia and constipation. Orlistat is an inhibitor of pancreatic lipase which is able to block the absorption of 30% of ingested fat. Its administration induces weight loss and reduction of ulterior weight regain. Also, this drug improves hypertension dyslipdaemia and helps to prevent diabetes in 52% of cases when administered over four years. The increase in frequency of stools and interference with vitamin absorption are its main side effects. Glucagon-like peptide 1, which increases insulin sensitivity and satiety, adiponectin and PPAR-gamma agonists which reduce insulin resistance and modulates adipocyte generation are the basis for future therapeutic approaches of obesity. Phosphatase inhibitors induce PPAR-gamma phosphorylation and UCP-1 expression leading to an increase in thermogenesis and reduction in appetite.

  14. Pharmacological therapy of spondyloarthritis.

    Science.gov (United States)

    Palazzi, Carlo; D'Angelo, Salvatore; Gilio, Michele; Leccese, Pietro; Padula, Angela; Olivieri, Ignazio

    2015-01-01

    The current pharmacological therapy of spondyloarthritis (SpA) includes several drugs: Non-steroidal anti-inflammatory drugs, corticosteroids, traditional disease-modifying antirheumatic drugs and biologic drugs. A systematic literature search was completed using the largest electronic databases (Medline, Embase and Cochrane), starting from 1995, with the aim to review data on traditional and biologic agents commercialised for SpA treatment. Randomised controlled trials and large observational studies were considered. In addition, studies performed in SpA patients treated with other, still unapproved, drugs (rituximab, anti-IL6 agents, apremilast, IL17 inhibitors and anakinra) were also taken into account. Biologic agents, especially anti-TNF drugs, have resulted in significant progress in improving clinical symptoms and signs, reducing inflammatory features in laboratory tests and imaging findings, and recovering all functional indexes. Anti-TNF drugs have radically changed the evolution of radiographic progression in peripheral joints; the first disappointing data concerning their efficacy on new bone formation of axial SpA has been recently challenged by studies enrolling patients who have been earlier diagnosed and treated. The opportunity to extend the interval of administration or to reduce the doses of anti-TNF agents can favourably influence the costs. Ustekinumab, the first non-anti-TNF biologic drug commercialised for psoriatic arthritis, offers new chances to patients that are unresponsive to anti-TNF.

  15. Pharmacology of midazolam.

    Science.gov (United States)

    Pieri, L; Schaffner, R; Scherschlicht, R; Polc, P; Sepinwall, J; Davidson, A; Möhler, H; Cumin, R; Da Prada, M; Burkard, W P; Keller, H H; Müller, R K; Gerold, M; Pieri, M; Cook, L; Haefely, W

    1981-01-01

    8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (midazolam, Ro 21-3981, Dormicum) is an imidazobenzodiazepine whose salts are soluble and stable in aqueous solution. It has a quick onset and, due to rapid metabolic inactivation, a rather short duration of action in all species studied. Midazolam has a similar pharmacologic potency and broad therapeutic range as diazepam. It produces all the characteristic effects of the benzodiazepine class, i.e., anticonvulsant, anxiolytic, sleep-inducing, muscle relaxant, and "sedative" effects. The magnitude of the anticonflict effect of midazolam is smaller than that of diazepam in rats and squirrel monkeys, probably because a more pronounced sedative component interferes with the increase of punished responses. In rodents, surgical anaesthesia is not attained with midazolam alone even in high i.v. doses, whereas this state is obtained in monkeys. The drug potentiates the effect of various central depressant agents. Midazolam is virtually free of effects on the cardiovascular system in conscious animals and produces only slight decreases in cardiac performance in dogs anaesthetized with barbiturates. No direct effects of the drugs on autonomic functions were found, however, stress-induced autonomic disturbances are prevented, probably by an effect on central regulatory systems. All animal data suggest the usefulness of midazolam as a sleep-inducer and i.v. anaesthetic of rapid onset and short duration.

  16. Pharmacology of pediatric resuscitation.

    Science.gov (United States)

    Ushay, H M; Notterman, D A

    1997-02-01

    The resuscitation of children from cardiac arrest and shock remains a challenging goal. The pharmacologic principles underlying current recommendations for intervention in pediatric cardiac arrest have been reviewed. Current research efforts, points of controversy, and accepted practices that may not be most efficacious have been described. Epinephrine remains the most effective resuscitation adjunct. High-dose epinephrine is tolerated better in children than in adults, but its efficacy has not received full analysis. The preponderance of data continues to point toward the ineffectiveness and possible deleterious effects of overzealous sodium bicarbonate use. Calcium chloride is useful in the treatment of ionized hypocalcemia but may harm cells that have experienced asphyxial damage. Atropine is an effective agent for alleviating bradycardia induced by increased vagal tone, but because most bradycardia in children is caused by hypoxia, improved oxygenation is the intervention of choice. Adenosine is an effective and generally well-tolerated agent for the treatment of supraventricular tachycardia. Lidocaine is the drug of choice for ventricular dysrhythmias, and bretylium, still relatively unexplored, is in reserve. Many pediatricians use dopamine for shock in the postresuscitative period, but epinephrine is superior. Most animal research on cardiac arrest is based on models with ventricular fibrillation that probably are not reflective of cardiac arrest situations most often seen in pediatrics.

  17. Catalytic NH3 Synthesis using N2 /H2 at Molecular Transition Metal Complexes: Concepts for Lead Structure Determination using Computational Chemistry.

    Science.gov (United States)

    Hölscher, Markus; Leitner, Walter

    2017-09-07

    While industrial NH 3 synthesis based on the Haber-Bosch-process was invented more than a century ago, there is still no molecular catalyst available which reduces N 2 in the reaction system N 2 /H 2 to NH 3 . As the many efforts of experimentally working research groups to develop a molecular catalyst for NH 3 synthesis from N 2 /H 2 have led to a variety of stoichiometric reductions it seems justified to undertake the attempt of systematizing the various approaches of how the N 2 molecule might be reduced to NH 3 with H 2 at a transition metal complex. In this contribution therefore a variety of intuition-based concepts are presented with the intention to show how the problem can be approached. While no claim for completeness is made, these concepts intend to generate a working plan for future research. Beyond this, it is suggested that these concepts should be evaluated with regard to experimental feasibility by checking barrier heights of single reaction steps and also by computation of whole catalytic cycles employing density functional theory (DFT) calculations. This serves as a tool which extends the empirically driven search process and expands it by computed insights which can be used to rationalize the various challenges which must be met. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Synthesis of molecularly imprinted silica nanospheres embedded mercaptosuccinic acid-coated CdTe quantum dots for selective recognition of λ-cyhalothrin

    Energy Technology Data Exchange (ETDEWEB)

    Wei, Xiao [School of Material Science and Engineering, Jiangsu University, Zhenjiang 212013 (China); School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang 212013 (China); Meng, Minjia; Song, Zhilong; Gao, Lin; Li, Hongji [School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang 212013 (China); Dai, Jiangdong; Zhou, Zhiping [School of Material Science and Engineering, Jiangsu University, Zhenjiang 212013 (China); Li, Chunxiang, E-mail: weixiaokeyan@163.com [School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang 212013 (China); Pan, Jianming; Yu, Ping; Yan, Yongsheng [School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang 212013 (China)

    2014-09-15

    In this study, a simple procedure for the determination of λ-cyhalothrin was reported. CdTe quantum dots (QDs) capped by molecularly imprinted polymers (MIPs) were prepared and characterized by spectrofluorometer, Fourier transform infrared spectroscopy (FTIR), transmission electron microscope (TEM) and scanning electron microscope (SEM). Mercaptosuccinic acid (MSA) was chosen as a stabilizer for CdTe QDs synthesis. The MSA stabilizer which comprises both thioglycolic acid (TGA)-like and 3-mercaptopropionic acid (MPA)-like moieties could accelerate the whole growth process of CdTe QDs comparing with TGA-like or MPA-like stabilizer. Meanwhile, the spectrofluorometer was used to evaluate the optical stability, effect of pH, and selective and sensitive determination of λ-cyhalothrin (LC). Moreover, LC could quench the fluorescence of the molecularly imprinted silica nanospheres (CdTe@SiO{sub 2}@MIPs) in a concentration-dependent manner, which was best described by a Stern–Volmer-type equation. - Highlights: • We choose Mercaptosuccinic acid (MSA) as the stabilizer for CdTe QDs synthesis. • The composite materials were prepared by the reverse microemulsion method. • The composite materials can be used for the direct analysis of relevant real samples.

  19. Mechanochemical Ring-Opening Polymerization of Lactide: Liquid-Assisted Grinding for the Green Synthesis of Poly(lactic acid) with High Molecular Weight.

    Science.gov (United States)

    Ohn, Nuri; Shin, Jihoon; Kim, Sung Sik; Kim, Jeung Gon

    2017-09-22

    Mechanochemical polymerization of lactide is carried out by using ball milling. Mechanical energy from collisions between the balls and the vessel efficiently promotes an organic-base-mediated metal- and solvent-free solid-state polymerization. Investigation of the parameters of the ball-milling synthesis revealed that the degree of lactide ring-opening polymerization could be modulated by the ball-milling time, vibration frequency, mass of the ball media, and liquid-assisted grinding. Liquid-assisted grinding was found to be an especially important factor for achieving a high degree of mechanochemical polymerization. Although polymer-chain scission from the strong collision energy prevented mechanical-force-driven high-molecular-weight polymer synthesis, the addition of only a small amount of liquid enabled sufficient energy dissipation and poly(lactic acid) was thereby obtained with a molecular weight of over 1×10 5  g mol -1 . © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Optimized Solid Phase-Assisted Synthesis of Dendrons Applicable as Scaffolds for Radiolabeled Bioactive Multivalent Compounds Intended for Molecular Imaging

    Directory of Open Access Journals (Sweden)

    Gabriel Fischer

    2014-05-01

    Full Text Available Dendritic structures, being highly homogeneous and symmetric, represent ideal scaffolds for the multimerization of bioactive molecules and thus enable the synthesis of compounds of high valency which are e.g., applicable in radiolabeled form as multivalent radiotracers for in vivo imaging. As the commonly applied solution phase synthesis of dendritic scaffolds is cumbersome and time-consuming, a synthesis strategy was developed that allows for the efficient assembly of acid amide bond-based highly modular dendrons on solid support via standard Fmoc solid phase peptide synthesis protocols. The obtained dendritic structures comprised up to 16 maleimide functionalities and were derivatized on solid support with the chelating agent DOTA. The functionalized dendrons furthermore could be efficiently reacted with structurally variable model thiol-bearing bioactive molecules via click chemistry and finally radiolabeled with 68Ga. Thus, this solid phase-assisted dendron synthesis approach enables the fast and straightforward assembly of bioactive multivalent constructs for example applicable as radiotracers for in vivo imaging with Positron Emission Tomography (PET.

  1. The pharmacology of regenerative medicine.

    Science.gov (United States)

    Christ, George J; Saul, Justin M; Furth, Mark E; Andersson, Karl-Erik

    2013-07-01

    Regenerative medicine is a rapidly evolving multidisciplinary, translational research enterprise whose explicit purpose is to advance technologies for the repair and replacement of damaged cells, tissues, and organs. Scientific progress in the field has been steady and expectations for its robust clinical application continue to rise. The major thesis of this review is that the pharmacological sciences will contribute critically to the accelerated translational progress and clinical utility of regenerative medicine technologies. In 2007, we coined the phrase "regenerative pharmacology" to describe the enormous possibilities that could occur at the interface between pharmacology, regenerative medicine, and tissue engineering. The operational definition of regenerative pharmacology is "the application of pharmacological sciences to accelerate, optimize, and characterize (either in vitro or in vivo) the development, maturation, and function of bioengineered and regenerating tissues." As such, regenerative pharmacology seeks to cure disease through restoration of tissue/organ function. This strategy is distinct from standard pharmacotherapy, which is often limited to the amelioration of symptoms. Our goal here is to get pharmacologists more involved in this field of research by exposing them to the tools, opportunities, challenges, and interdisciplinary expertise that will be required to ensure awareness and galvanize involvement. To this end, we illustrate ways in which the pharmacological sciences can drive future innovations in regenerative medicine and tissue engineering and thus help to revolutionize the discovery of curative therapeutics. Hopefully, the broad foundational knowledge provided herein will spark sustained conversations among experts in diverse fields of scientific research to the benefit of all.

  2. The role and molecular mechanism of D-aspartic acid in the release and synthesis of LH and testosterone in humans and rats

    Directory of Open Access Journals (Sweden)

    Ronsini Salvatore

    2009-10-01

    Full Text Available Abstract Background D-aspartic acid is an amino acid present in neuroendocrine tissues of invertebrates and vertebrates, including rats and humans. Here we investigated the effect of this amino acid on the release of LH and testosterone in the serum of humans and rats. Furthermore, we investigated the role of D-aspartate in the synthesis of LH and testosterone in the pituitary and testes of rats, and the molecular mechanisms by which this amino acid triggers its action. Methods For humans: A group of 23 men were given a daily dose of D-aspartate (DADAVIT® for 12 days, whereas another group of 20 men were given a placebo. For rats: A group of 10 rats drank a solution of either 20 mM D-aspartate or a placebo for 12 days. Then LH and testosterone accumulation was determined in the serum and D-aspartate accumulation in tissues. The effects of D-aspartate on the synthesis of LH and testosterone were gauged on isolated rat pituitary and Leydig cells. Tissues were incubated with D-aspartate, and then the concentration (synthesis of LH and cGMP in the pituitary and of testosterone and cAMP in the Leydig cells was determined. Results In humans and rats, sodium D-aspartate induces an enhancement of LH and testosterone release. In the rat pituitary, sodium D-aspartate increases the release and synthesis of LH through the involvement of cGMP as a second messenger, whereas in rat testis Leydig cells, it increases the synthesis and release of testosterone and cAMP is implicated as second messenger. In the pituitary and in testes D-Asp is synthesized by a D-aspartate racemase which convert L-Asp into D-Asp. The pituitary and testes possesses a high capacity to trapping circulating D-Asp from hexogen or endogen sources. Conclusion D-aspartic acid is a physiological amino acid occurring principally in the pituitary gland and testes and has a role in the regulation of the release and synthesis of LH and testosterone in humans and rats.

  3. Imaging of dopamine release induced by pharmacologic and nonpharmacologic stimulations

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Sang Soo; Kim, Sang Eun [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2007-04-15

    Technological advances in molecular imaging made it possible to image synaptic neurotransmitter concentration in living human brain. The dopaminergic system has been most intensively studied because of its importance in neurological as well as psychiatric disorders. This paper provides a brief overview of recent progress in imaging studies of dopamine release induced by pharmacologic and nonpharmacologic stimulations.

  4. PHARMAVIRTUA: Educational Software for Teaching and Learning Basic Pharmacology

    Science.gov (United States)

    Fidalgo-Neto, Antonio Augusto; Alberto, Anael Viana Pinto; Bonavita, André Gustavo Calvano; Bezerra, Rômulo José Soares; Berçot, Felipe Faria; Lopes, Renato Matos; Alves, Luiz Anastacio

    2014-01-01

    Information and communication technologies have become important tools for teaching scientific subjects such as anatomy and histology as well as other, nondescriptive subjects like physiology and pharmacology. Software has been used to facilitate the learning of specific concepts at the cellular and molecular levels in the biological and health…

  5. Precision pharmacology for Alzheimer's disease.

    Science.gov (United States)

    Hampel, Harald; Vergallo, Andrea; Aguilar, Lisi Flores; Benda, Norbert; Broich, Karl; Cuello, A Claudio; Cummings, Jeffrey; Dubois, Bruno; Federoff, Howard J; Fiandaca, Massimo; Genthon, Remy; Haberkamp, Marion; Karran, Eric; Mapstone, Mark; Perry, George; Schneider, Lon S; Welikovitch, Lindsay A; Woodcock, Janet; Baldacci, Filippo; Lista, Simone

    2018-04-01

    The complex multifactorial nature of polygenic Alzheimer's disease (AD) presents significant challenges for drug development. AD pathophysiology is progressing in a non-linear dynamic fashion across multiple systems levels - from molecules to organ systems - and through adaptation, to compensation, and decompensation to systems failure. Adaptation and compensation maintain homeostasis: a dynamic equilibrium resulting from the dynamic non-linear interaction between genome, epigenome, and environment. An individual vulnerability to stressors exists on the basis of individual triggers, drivers, and thresholds accounting for the initiation and failure of adaptive and compensatory responses. Consequently, the distinct pattern of AD pathophysiology in space and time must be investigated on the basis of the individual biological makeup. This requires the implementation of systems biology and neurophysiology to facilitate Precision Medicine (PM) and Precision Pharmacology (PP). The regulation of several processes at multiple levels of complexity from gene expression to cellular cycle to tissue repair and system-wide network activation has different time delays (temporal scale) according to the affected systems (spatial scale). The initial failure might originate and occur at every level potentially affecting the whole dynamic interrelated systems within an organism. Unraveling the spatial and temporal dynamics of non-linear pathophysiological mechanisms across the continuum of hierarchical self-organized systems levels and from systems homeostasis to systems failure is key to understand AD. Measuring and, possibly, controlling space- and time-scaled adaptive and compensatory responses occurring during AD will represent a crucial step to achieve the capacity to substantially modify the disease course and progression at the best suitable timepoints, thus counteracting disrupting critical pathophysiological inputs. This approach will provide the conceptual basis for effective

  6. Pharmacology Portal: An Open Database for Clinical Pharmacologic Laboratory Services.

    Science.gov (United States)

    Karlsen Bjånes, Tormod; Mjåset Hjertø, Espen; Lønne, Lars; Aronsen, Lena; Andsnes Berg, Jon; Bergan, Stein; Otto Berg-Hansen, Grim; Bernard, Jean-Paul; Larsen Burns, Margrete; Toralf Fosen, Jan; Frost, Joachim; Hilberg, Thor; Krabseth, Hege-Merete; Kvan, Elena; Narum, Sigrid; Austgulen Westin, Andreas

    2016-01-01

    More than 50 Norwegian public and private laboratories provide one or more analyses for therapeutic drug monitoring or testing for drugs of abuse. Practices differ among laboratories, and analytical repertoires can change rapidly as new substances become available for analysis. The Pharmacology Portal was developed to provide an overview of these activities and to standardize the practices and terminology among laboratories. The Pharmacology Portal is a modern dynamic web database comprising all available analyses within therapeutic drug monitoring and testing for drugs of abuse in Norway. Content can be retrieved by using the search engine or by scrolling through substance lists. The core content is a substance registry updated by a national editorial board of experts within the field of clinical pharmacology. This ensures quality and consistency regarding substance terminologies and classification. All laboratories publish their own repertoires in a user-friendly workflow, adding laboratory-specific details to the core information in the substance registry. The user management system ensures that laboratories are restricted from editing content in the database core or in repertoires within other laboratory subpages. The portal is for nonprofit use, and has been fully funded by the Norwegian Medical Association, the Norwegian Society of Clinical Pharmacology, and the 8 largest pharmacologic institutions in Norway. The database server runs an open-source content management system that ensures flexibility with respect to further development projects, including the potential expansion of the Pharmacology Portal to other countries. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

  7. Synthesis of cerium oxide catalysts supported on MCM-41 molecular sieve; Sintese de catalisadores de oxido de cerio suportados na peneira molecular MCM-41

    Energy Technology Data Exchange (ETDEWEB)

    Souza, E.L.S.; Barros, T.R.B.; Sousa, B.V. de, E-mail: emylle.souza@gmail.com [Universidade Federal de Campina Grande (UFCG), PB (Brazil). Unidade Academica de Engenharia Quimica

    2016-07-01

    Porous materials have been widely studied as catalysts and catalyst support. The MCM-41 structure is the one that has been most studied because of its application possibilities in chemical processes. This work aimed to obtain and characterize cerium oxide catalysts supported on MCM-41 molecular sieve. The molecular sieve was synthesized by the conventional method with the following molar composition: 1 SiO2: 0.30 CTABr: NH3 11: 144 H2O. Then, 25% w/w cerium was incorporated into the MCM-41 using the wet impregnation process and the material obtained was activated by calcination. From the XRD patterns was confirmed the structure of the molecular sieve, and were identified the cerium oxide phases in its structure. The textural catalysts characteristics were investigated by isotherms of N2 adsorption/desorption (BET method). (author)

  8. Synthesis, spectroscopic investigations, DFT studies, molecular docking and antimicrobial potential of certain new indole-isatin molecular hybrids: Experimental and theoretical approaches

    Science.gov (United States)

    Almutairi, Maha S.; Zakaria, Azza S.; Ignasius, P. Primsa; Al-Wabli, Reem I.; Joe, Isaac Hubert; Attia, Mohamed I.

    2018-02-01

    Indole-isatin molecular hybrids 5a-i have been synthesized and characterized by different spectroscopic methods to be evaluated as new antimicrobial agents against a panel of Gram positive bacteria, Gram negative bacteria, and moulds. Compound 5h was selected as a representative example of the prepared compounds 5a-i to perform computational investigations. Its vibrational properties have been studied using FT-IR and FT-Raman with the aid of density functional theory approach. The natural bond orbital analysis as well as HOMO and LUMO molecular orbitals investigations of compound 5h were carried out to explore its possible intermolecular delocalization or hyperconjugation and its possible interactions with the target protein. Molecular docking of compound 5h predicted its binding mode with the fungal target protein.

  9. DIVERSE POTENTIAL AND PHARMACOLOGICAL STUDIES OF ARGININE

    Directory of Open Access Journals (Sweden)

    Anju Meshram

    2015-09-01

    Full Text Available Arginine is metabolically flexible amino acid with major role in protein synthesis and detoxification of ammonia. It is involved in several metabolic pathways for the production of biologically active compounds such as creatine, nitric oxide, ornithine, glutamate, agmatine, citrulline and polyamines. Regarding this all, we review the crucial role of arginine in metabolism, diversified prospective uses and pharmacological applications. Arginine plays an important role in the treatment of tumorigenesis, asthama, gastric, erectile dysfunction, apoptosis, melanoma and congestive heart failure. Ability to produce nitric oxide offers various applications as in the prevention of age and hair loss. It serves as a precursor of creatine with ergogenic potential. The ability to increase endogenous growth hormone makes arginine a preferred supplement for the improvement of physical performance. In the present study details about the pharmacological applications of arginine based on modern scientific investigations have been discussed. There are immense properties hidden in arginine that need to be explored using the scientific investigations to make it beneficial for the medicine and human health. More research is needed to evaluate the role of arginine supplementation on exercise performance and training adaptations in healthy and diseased populations before taking any conclusions.

  10. Synthesis and Structural Characterization of a CHA-type AlPO4 Molecular Sieve with Penta-Coordinated Framework Aluminum Atoms.

    Science.gov (United States)

    Park, Gi Tae; Jo, Donghui; Ahn, Nak Ho; Cho, Jung; Hong, Suk Bong

    2017-07-17

    The structure-directing effects of a series of polymethylimidazolium cations with different numbers of methyl groups as organic structure-directing agents (OSDAs) in the synthesis of aluminophosphate (AlPO 4 )-based molecular sieves in both fluoride and hydroxide media are investigated. On the one hand, among the OSDAs studied here, the smallest 1,3-dimethylimidazolium and the largest 1,2,3,4,5-pentamethylimidazolium cations were found to direct the synthesis of a new variant of the triclinic chabazite (CHA)-type AlPO 4 material, designated AlPO 4 -34(t) V , and the one-dimensional small-pore silicoaluminophosphate (SAPO) molecular sieve STA-6 in hydroxide media, respectively. On the other hand, the intermediate-sized 1,2,3,4-tetramethylimidazolium cation gave SSZ-51, a two-dimensional large-pore SAPO material, in fluoride media. Synchrotron powder X-ray diffraction and Rietveld analyses reveal that as-made AlPO 4 -34(t) V contains penta-coordinated framework Al species connected by hydroxyl groups, as well as tetrahedral framework Al, which contrasts with the distortions arising from the two F - or OH - bridges between octahedral Al atoms in all already known AlPO 4 -34 materials. The presence of Al-OH-Al linkages in this triclinic AlPO 4 -34 molecular sieve has been further corroborated by thermal analysis, variable-temperature IR,27Al magic-angle spinning NMR, and dispersion-corrected density functional theory calculations.

  11. Deciphering a molecular mechanism of neonatal diabetes mellitus by the chemical synthesis of a protein diastereomer, [D-AlaB8]human proinsulin.

    Science.gov (United States)

    Avital-Shmilovici, Michal; Whittaker, Jonathan; Weiss, Michael A; Kent, Stephen B H

    2014-08-22

    Misfolding of proinsulin variants in the pancreatic β-cell, a monogenic cause of permanent neonatal-onset diabetes mellitus, provides a model for a disease of protein toxicity. A hot spot for such clinical mutations is found at position B8, conserved as glycine within the vertebrate insulin superfamily. We set out to investigate the molecular basis of the aberrant properties of a proinsulin clinical mutant in which residue Gly(B8) is replaced by Ser(B8). Modular total chemical synthesis was used to prepare the wild-type [Gly(B8)]proinsulin molecule and three analogs: [D-Ala(B8)]proinsulin, [L-Ala(B8)]proinsulin, and the clinical mutant [L-Ser(B8)]proinsulin. The protein diastereomer [D-Ala(B8)]proinsulin produced higher folding yields at all pH values compared with the wild-type proinsulin and the other two analogs, but showed only very weak binding to the insulin receptor. The clinical mutant [L-Ser(B8)]proinsulin impaired folding at pH 7.5 even in the presence of protein-disulfide isomerase. Surprisingly, although [L-Ser(B8)]proinsulin did not fold well under the physiological conditions investigated, once folded the [L-Ser(B8)]proinsulin protein molecule bound to the insulin receptor more effectively than wild-type proinsulin. Such paradoxical gain of function (not pertinent in vivo due to impaired secretion of the mutant insulin) presumably reflects induced fit in the native mechanism of hormone-receptor engagement. This work provides insight into the molecular mechanism of a clinical mutation in the insulin gene associated with diabetes mellitus. These results dramatically illustrate the power of total protein synthesis, as enabled by modern chemical ligation methods, for the investigation of protein folding and misfolding. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  12. Fuzzy pharmacology: theory and applications.

    Science.gov (United States)

    Sproule, Beth A; Naranjo, Claudio A; Türksen, I Burhan

    2002-09-01

    Fuzzy pharmacology is a term coined to represent the application of fuzzy logic and fuzzy set theory to pharmacological problems. Fuzzy logic is the science of reasoning, thinking and inference that recognizes and uses the real world phenomenon that everything is a matter of degree. It is an extension of binary logic that is able to deal with complex systems because it does not require crisp definitions and distinctions for the system components. In pharmacology, fuzzy modeling has been used for the mechanical control of drug delivery in surgical settings, and work has begun evaluating its use in other pharmacokinetic and pharmacodynamic applications. Fuzzy pharmacology is an emerging field that, based on these initial explorations, warrants further investigation.

  13. Altered Mitochondria, Protein Synthesis Machinery, and Purine Metabolism Are Molecular Contributors to the Pathogenesis of Creutzfeldt-Jakob Disease.

    Science.gov (United States)

    Ansoleaga, Belén; Garcia-Esparcia, Paula; Llorens, Franc; Hernández-Ortega, Karina; Carmona Tech, Margarita; Antonio Del Rio, José; Zerr, Inga; Ferrer, Isidro

    2016-06-12

    Neuron loss, synaptic decline, and spongiform change are the hallmarks of sporadic Creutzfeldt-Jakob disease (sCJD), and may be related to deficiencies in mitochondria, energy metabolism, and protein synthesis. To investigate these relationships, we determined the expression levels of genes encoding subunits of the 5 protein complexes of the electron transport chain, proteins involved in energy metabolism, nucleolar and ribosomal proteins, and enzymes of purine metabolism in frontal cortex samples from 15 cases of sCJD MM1 and age-matched controls. We also assessed the protein expression levels of subunits of the respiratory chain, initiation and elongation translation factors of protein synthesis, and localization of selected mitochondrial components. We identified marked, generalized alterations of mRNA and protein expression of most subunits of all 5 mitochondrial respiratory chain complexes in sCJD cases. Expression of molecules involved in protein synthesis and purine metabolism were also altered in sCJD. These findings point to altered mRNA and protein expression of components of mitochondria, protein synthesis machinery, and purine metabolism as components of the pathogenesis of CJD. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

  14. Synthesis of Sub-10 nm Two-Dimensional Covalent Organic Thin Film with Sharp Molecular Sieving Nanofiltration

    KAUST Repository

    Gadwal, Ikhlas; Sheng, Guan; Thankamony, Roshni Lilly; Liu, Yang; Li, Huifang; Lai, Zhiping

    2018-01-01

    We demonstrated here a novel and facile synthesis of two-dimensional (2D) covalent organic thin film with pore size around 1.5 nm using a planar, amphiphilic and substituted heptacyclic truxene based triamine and a simple dialdehyde as building

  15. The pharmacology of gynaecology.

    Science.gov (United States)

    Tothill, A

    1980-09-01

    Focus in this discussion of the pharmacology of gynecology is on the following: vaginal infections; genital herpes; genital warts; pelvic inflammatory disease; urinary infections; pruritus vulvae; menstrual problems; infertility; oral contraception; and hormone replacement therapy. Doctors in England working in Local Authority Family Planning Clinics are debarred from prescribing, and any patient with a vaginal infection has to be referred either to a special clinic or to her general practitioner which is often preferable as her medical history will be known. Vaginal discharge is a frequent complaint, and it is necessary to obtain full details. 1 of the most common infections is vaginal candidosis. Nystatin pessaries have always been a useful 1st-line treatment and are specific for this type of infection. Trichomonas infection also occurs frequently and responds well to metronidazole in a 200 mg dosage, 3 times daily for 7 days. It is necessary to treat the consort at the same time. Venereal diseases such as syphilis and gonorrhea always require vigorous treatment. Patients are now presenting with herpes genitalis far more often. The only treatment which is currently available, and is as good as any, is the application of warm saline to the vaginal area. Genital warts may be discovered on routine gynecological examination or may be reported to the doctor by the patient. 1 application of a 20% solution of podophyllum, applied carefully to each wart, usually effects a cure. Pelvic inflammatory disease seems to be on the increase. Provided any serious disease is ruled out a course of systemic antibiotics is often effective. Urinary infections are often seen in the gynecologic clinic, and many of these will respond well to 2 tablets of co-trimoxazole, 2 times daily for 14 days. In pruritus vulvae it is important to determine whether the cause is general or local. Menstrual problems regularly occur and have been increased by the IUD and the low-dose progesterone pill

  16. [Pharmacological therapy of obesity].

    Science.gov (United States)

    Pagotto, Uberto; Vanuzzo, Diego; Vicennati, Valentina; Pasquali, Renato

    2008-04-01

    Obesity is reaching epidemic proportions worldwide and it is correlated with various comorbidities, among which the most relevant are diabetes mellitus, arterial hypertension, and cardiovascular diseases. Obesity management is a modern challenge because of the rapid evolution of unfavorable lifestyles and unfortunately there are no effective treatments applicable to the large majority of obese/overweight people. The current medical attitude is to treat the complications of obesity (e.g. dyslipidemia, hypertension, diabetes, and cardiovascular diseases). However, the potential of treating obesity is enormous, bearing in mind that a volitional weight loss of 10 kg is associated with important risk factor improvement: blood pressure -10 mmHg, total cholesterol -10%, LDL cholesterol -15%, triglycerides -30%, fasting glucose -50%, HDL cholesterol +8%. Drug treatment for obesity is an evolving branch of pharmacology, burdened by severe side effects and consequences of the early drugs, withdrawn from the market, and challenged by the lack of long-term data on the effect of medications on obesity-related morbidity and mortality, first of all cardiovascular diseases. In Europe three antiobesity drugs are currently licensed: sibutramine, orlistat, and rimonabant; important trials with clinical endpoints are ongoing for sibutramine and rimonabant. While waiting for their results, it is convenient to evaluate these drugs for their effects on body weight and cardiometabolic risk factors. Sibutramine is a centrally acting serotonin/noradrenaline reuptake inhibitor that mainly increases satiety. At the level of brown adipose tissue, sibutramine can also facilitate energy expenditure by increasing thermogenesis. The long-term studies (five) documented a mean differential weight reduction of 4.45 kg for sibutramine vs placebo. Considering the principal studies, attrition rate was 43%. This drug not only reduces body weight and waist circumference, but it decreases triglycerides and

  17. Synthesis of core-shell molecularly imprinted polymer microspheres by precipitation polymerization for the inline molecularly imprinted solid-phase extraction of thiabendazole from citrus fruits and orange juice samples.

    Science.gov (United States)

    Barahona, Francisco; Turiel, Esther; Cormack, Peter A G; Martín-Esteban, Antonio

    2011-01-01

    In this work, the synthesis of molecularly imprinted polymer microspheres with narrow particle size distributions and core-shell morphology by a two-step precipitation polymerization procedure is described. Polydivinylbenzene (poly DVB-80) core particles were used as seed particles in the production of molecularly imprinted polymer shells by copolymerization of divinylbenzene-80 with methacrylic acid in the presence of thiabendazole (TBZ) and an appropriate porogen. Thereafter, polymer particles were packed into refillable stainless steel HPLC columns used in the development of an inline molecularly imprinted SPE method for the determination of TBZ in citrus fruits and orange juice samples. Under optimized chromatographic conditions, recoveries of TBZ within the range 81.1-106.4%, depending upon the sample, were obtained, with RSDs lower than 10%. This novel method permits the unequivocal determination of TBZ in the samples under study, according to the maximum residue levels allowed within Europe, in less than 20 min and without any need for a clean-up step in the analytical protocol. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. PHARMACOLOGY OF CANNABINOIDS

    Directory of Open Access Journals (Sweden)

    Ilonka Ferjan

    2015-06-01

    Full Text Available The discovery of cannabinoid receptors and endocannabinoid system has led to the potential therapeutic use of cannabis derivatives. Cannabinoids acting through the CB1 receptors modulate the release of other neurotransmitters in central nervous system, whereas the activation of peripheral CB2 receptors results in decreased inflammatory response and increased apoptosis of some tumor cells populations. The cannabinoids have been authorized for chemotherapy-induced nausea and vomiting; stimulation of appetite; to alleviate neuropathic pain and spasticity in multiple sclerosis, and to reduce pain in cancer patients. Efficacy in other diseases and clinical conditions should be proven in ongoing or future clinical trials. Isolation and identification of different cannabinoids from cannabis and synthesis of novel, more selective, derivatives widens their therapeutic potential. However, there are numerous adverse effects reported, especially when cannabinoids formulations with unknown quantitative and qualitative composition are used. Addiction, tolerance, withdrawal symptoms, increased risk of acute myocardial re-infarction, and increased risk of psychosis or worsening of psychosis are the most common adverse effects of cannabinoids. Acute adverse effects e. g. severe central nervous system depression, are more pronounced in children than in adults. Potential cannabinoid medicines should be subject to the same regulations as other potential drugs. Safety and efficacy of any potential drug candidate, regardless whether it is plant-derived or synthesized, should be proven in non-clinical studies and clinical trials, as well as the marketing authorization must be issued by the appropriate drug authority. Patients deserve a quality manufactured product, which always contains the specified amount of "Remedium cardinale."

  19. Design, Synthesis, and in Vitro Pharmacology of New Radiolabeled γ-Hydroxybutyric Acid Analogues Including Photolabile Analogues with Irreversible Binding to the High-Affinity γ-Hydroxybutyric Acid Binding Sites

    DEFF Research Database (Denmark)

    Sabbatini, Paola; Wellendorph, Petrine; Høg, Signe

    2010-01-01

    γ-Hydroxybutyric acid (GHB) is a psychotropic compound endogenous to the brain. Despite its potential physiological significance, the complete molecular mechanisms of action remain unexplained. To facilitate the isolation and identification of the high-affinity GHB binding site, we herein report ...

  20. Synthesis and pharmacological characterization of novel N-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)amides as potential multireceptor atypical antipsychotics.

    Science.gov (United States)

    Chen, Xiao-Wen; Sun, Yuan-Yuan; Fu, Lei; Li, Jian-Qi

    2016-11-10

    A series of novel benzisothiazolylpiperazine derivatives combining potent dopamine D2 and D3, and serotonin 5-HT1A and 5-HT2A receptor properties were synthesized and evaluated for their potential antipsychotic properties. The most-promising derivative was 9j. The unique pharmacological features of 9j were a high affinity for D2, D3, 5-HT1A, and 5-HT2A receptors, together with a 20-fold selectivity for the D3 versus D2 subtype, and a low affinity for muscarinic M1 (reducing the risk of anticholinergic side effects), and for hERG channels (reducing incidence of QT interval prolongation). In animal behavioral models, 9j inhibited the locomotor-stimulating effects of phencyclidine, blocked conditioned avoidance response, and improved the cognitive deficit in the novel object recognition tests in rats. 9j exhibited a low potential for catalepsy, consistent with results with risperidone. In addition, favorable brain penetration of 9j in rats was detected. These studies have demonstrated that 9j is a potential atypical antipsychotic candidate. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  1. Synthesis and Self-Assembly of Chiral Cylindrical Molecular Complexes: Functional Heterogeneous Liquid-Solid Materials Formed by Helicene Oligomers

    Directory of Open Access Journals (Sweden)

    Nozomi Saito

    2018-01-01

    Full Text Available Chiral cylindrical molecular complexes of homo- and hetero-double-helices derived from helicene oligomers self-assemble in solution, providing functional heterogeneous liquid-solid materials. Gels and liotropic liquid crystals are formed by fibril self-assembly in solution; molecular monolayers and fibril films are formed by self-assembly on solid surfaces; gels containing gold nanoparticles emit light; silica nanoparticles aggregate and adsorb double-helices. Notable dynamics appears during self-assembly, including multistep self-assembly, solid surface catalyzed double-helix formation, sigmoidal and stairwise kinetics, molecular recognition of nanoparticles, discontinuous self-assembly, materials clocking, chiral symmetry breaking and homogeneous-heterogeneous transitions. These phenomena are derived from strong intercomplex interactions of chiral cylindrical molecular complexes.

  2. Synthesis and characterization of molecular materials from N-trifluoromethanesulfonyl-1-azahexa-1,3,5-trieno derivates

    International Nuclear Information System (INIS)

    Rodriguez Gomez, A; Ortiz Rebollo, A; Sanchez Vergara, M.E

    2008-01-01

    Molecular materials have been developed recently for their diverse electrical properties, such as insulation, semiconductors, conductors and superconductors and they can also be used in diodes, transistors, solar cells and electronic switches among other things. The molecular materials are formed by condensation and organization of molecular units that can be organic, organometallic, or metal-organic and whose properties are individually characterized later. Because of their true nature, the properties of molecular materials can be derived from the characteristics of the molecular units that form them. For this study molecular materials were synthesized from electronic donors and acceptors: Cu (TAAB) +2 , Ni (TAAB) +2 and the NTrifluoromethanesulfonyl-1-azahexa-1,3,5-trieno derivatives that are especially attractive from the structural point of view, since in their neutral from they have an extensive electronic dislocation which gives them a very specific chemical behavior. The synthesized materials were chemically and structurally characterized by IR spectroscopy, scanning electron microscopy (SEM), energy-dispersive spectroscopy (EDS) and mass spectrometry. Thin films of the different materials were deposited and the optical activation energy was evaluated, using techniques like profilometry and UV-vis spectroscopy

  3. Quality management of pharmacology and safety pharmacology studies

    DEFF Research Database (Denmark)

    Spindler, Per; Seiler, Jürg P

    2002-01-01

    to safety pharmacology studies, and, when indicated, to secondary pharmacodynamic studies, does not influence the scientific standards of studies. However, applying formal GLP standards will ensure the quality, reliability and integrity of studies, which reflect sound study management. It is important...... to encourage a positive attitude among researchers and academics towards these lines, whenever possible. GLP principles applied to the management of non-clinical safety studies are appropriate quality standards when studies are used in the context of protecting public health, and these quality standards...... of pharmacology studies (ICH S7A): primary pharmacodynamic, secondary pharmacodynamic and safety pharmacology studies, and guidance on the quality standards (expectations for GLP conformity) for these study types have been provided. Primary pharmacodynamic studies are the only study types that are fully exempt...

  4. Actinide tris(hydrocarbyls). Synthesis, properties, structure, and molecular dynamics of thorium and uranium pentamethylcyclopentadienyl tris(eta/sup n/-benzyls)

    International Nuclear Information System (INIS)

    Mintz, E.A.; Moloy, K.G.; Marks, T.J.; Day, V.W.

    1982-01-01

    This report focuses on the synthesis, unusual molecular structure(s), and other interesting properties of ligands within a metal coordination sphere (cf. M(eta 5 -C 5 H 5 ) 3 R vs. M[eta 5 -(CH 3 ) 5 ] 2 R 2 chemistry, where M=Th or U). This report represents a continuing effort to ''tune'' the actinide ligation environment with respect to such factors as the chemical characteristics of actinide-to-carbon sigma bonds. These bonds are a sensitive function of the number and nature of the other ligands within the metal coordination sphere. Structural analysis is reported that examines the nature and arrangement of the bonds in Th[eta 5 -(CH 3 ) 5 C 5 ](CH 2 C 6 H 5 ) 3 and U[eta 5 -(CH 3 ) 5 C 5 ](CH 2 C 6 H 5 ) 3 complexes

  5. Synthesis, biological assessment and molecular modeling of new dihydroquinoline-3-carboxamides and dihydroquinoline-3-carbohydrazide derivatives as cholinesterase inhibitors, and Ca channel antagonists.

    Science.gov (United States)

    Tomassoli, Isabelle; Ismaili, Lhassane; Pudlo, Marc; de Los Ríos, Cristóbal; Soriano, Elena; Colmena, Inés; Gandía, Luis; Rivas, Luis; Samadi, Abdelouahid; Marco-Contelles, José; Refouvelet, Bernard

    2011-01-01

    The synthesis, biological evaluation, and molecular modeling of new 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides(4), 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbohydrazide (6), and some hexahydropyrimido[5,4-c]quinoline-2,5-diones (9) produced earlier by our laboratory, as AChE/BuChE inhibitors, is described. From these analyses compound 4c resulted equipotent regarding the inhibition of cholinesterases'; inhibitors 6k, 9a, 9b were selective for AChE, whereas product 4d proved selective for BuChE. Docking analysis has been carry out in order to identify the binding mode in the active site, and to explain the observed selectivities. Only compound 9a has been shown to decrease K(+)-induced calcium signals in bovine chromaffin cells. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

  6. Dimers of coumarin-1,2,3-triazole hybrids bearing alkyl spacer: Design, microwave-assisted synthesis, molecular docking and evaluation as antimycobacterial and antimicrobial agents

    Science.gov (United States)

    Ashok, Dongamanti; Gundu, Srinivas; Aamate, Vikas Kumar; Devulapally, Mohan Gandhi; Bathini, Raju; Manga, Vijjulatha

    2018-04-01

    The present study demonstrated the synthesis of new series of coumarin-1,2,3-triazole hybrids under microwave irradiation method. Several dimers of coumarin based 1,2,3-triazole derivatives were synthesized and their antimycobacterial and antimicrobial activities were investigated. The antimycobacterial activity screening results revealed that compounds 6i and 6j were the most active against Mycobacterium tuberculosis H37Rv strain. The active compounds were further evaluated for cytotoxicity with HEK cell lines and exhibited less % of inhibition. The same synthetic hybrids were evaluated for their antimicrobial activity against various bacterial strains and fungal strains and compounds 6e, 6h, 6i and 6j were found to be the most promising antimicrobial potent molecules. Furthermore, the active compounds against Mycobacterium tuberculosis were evaluated for their molecular docking studies against pantothenate synthetase (PS) enzyme of MTB and the docking results are in well agreement with the antitubercular evaluation results.

  7. The discovery of new potent non-peptide Angiotensin II AT1 receptor blockers: A concise synthesis, molecular docking studies and biological evaluation of N-substituted 5-butylimidazole derivatives

    Czech Academy of Sciences Publication Activity Database

    Agelis, G.; Resvani, A.; Durdagi, S.; Spyridaki, K.; Tůmová, Tereza; Slaninová, Jiřina; Giannopoulos, P.; Vlahakos, D.; Liapakis, G.; Mavromoustakos, T.; Matsoukas, J.

    2012-01-01

    Roč. 55, Sep (2012), s. 358-374 ISSN 0223-5234 Institutional research plan: CEZ:AV0Z40550506 Keywords : synthesis * angiotensin II receptor blockers * N-substituted 5-butylimidazole derivatives * antihypertensive activity * molecular docking Subject RIV: CC - Organic Chemistry Impact factor: 3.499, year: 2012

  8. Advantageous Microwave-Assisted Suzuki Polycondensation for the Synthesis of Aniline-Fluorene Alternate Copolymers as Molecular Model with Solvent Sensing Properties

    Directory of Open Access Journals (Sweden)

    Rebeca Vázquez-Guilló

    2018-02-01

    Full Text Available Polymerization via Suzuki coupling under microwave (µW irradiation has been studied for the synthesis of poly{1,4-(2/3-aminobenzene-alt-2,7-(9,9-dihexylfluorene} (PAF, chosen as molecular model. Briefly, µW-assisted procedures accelerated by two orders of magnitude the time required when using classical polymerization processes, and the production yield was increased (>95%. In contrast, although the sizes of the polymers that were obtained by non-conventional heating reactions were reproducible and adequate for most applications, with this methodology the molecular weight of final polymers were not increased with respect to conventional heating. Asymmetric orientation of the amine group within the monomer and the assignments of each dyad or regioregularity, whose values ranged from 38% to 95% with this molecule, were analysed using common NMR spectroscopic data. Additionally, the synthesis of a new cationic polyelectrolyte, poly{1,4-(2/3-aminobenzene-co-alt-2,7-[9,9´-bis(6’’-N,N,N-trimethylammonium-hexylfluorene]} dibromide (PAFAm, from poly{1,4-(2/3-aminobenzene-co-alt-2,7-[9,9´-bis(6’’-bromohexylfluorene]} (PAFBr by using previously optimized conditions for µW-assisted heating procedures was reported. Finally, the characterization of the final products from these batches showed unkown interesting solvatochromic properties of the PAF molecule. The study of the solvatochromism phenomena, which was investigated as a function of the polarity of the solvents, showed a well-defined Lippert correlation, indicating that the emission shift observed in PAF might be due to its interaction with surrounding environment. Proven high sensitivity to changes of its environment makes PAF a promising candidate of sensing applications.

  9. Synthesis, vibrational spectroscopic investigations, molecular docking, antibacterial studies and molecular dynamics study of 5-[(4-nitrophenyl)acetamido]-2-(4-tert-butylphenyl)benzoxazole

    Science.gov (United States)

    Sheena Mary, Y.; Al-Shehri, Mona M.; Jalaja, K.; Al-Omary, Fatmah A. M.; El-Emam, Ali A.; Yohannan Panicker, C.; Armaković, Stevan; Armaković, Sanja J.; Temiz-Arpaci, Ozlem; Van Alsenoy, C.

    2017-04-01

    Antimicrobial active 5-[(4-nitrophenyl)acetamido]-2-(4-tert-butylphenyl)benzoxazole (NATPB) was synthesized and observed IR, Raman bands are compared with the theoretically predicted wave numbers. In the IR spectrum the NH stretching wave number splits into a doublet with a noted difference and is red shifted from the computed value, which indicates the weakening of NH bond resulting in proton transfer to the neighbouring oxygen atom. The HOMO-LUMO plots reveal the charge transfer in the molecular system through the conjugated paths. The electrophilic and nucleophilic reactive sites are identified from the MEP plot. Mapping of average local ionization energy (ALIE) values to the electron density surface served us as a tool for prediction of molecule sites possibly prone to electrophilic attacks. Other important reactive centres of the title molecule were detected by calculations of Fukui functions. Calculations of bond dissociation energies (BDE) for hydrogen abstraction were used in order to assess whether the NATPB molecules is prone to autoxidation mechanism or not, while BDE of the remaining single acyclic bonds were used in order to determine the weakest bond. Interaction properties with water were investigated by molecular dynamics (MD) simulations and calculations of radial distribution functions (RDFs). The compound possessed broad spectrum activity against all of the tested Gram-positive and Gram-negative bacteria and yeasts, their minimum inhibitory concentrations (MICs) ranging between 32 and 128 μg/ml. The compound exhibited significant antibacterial activity (32 μg/ml) against an antibiotic resistant E. faecalis isolate, at same potency with the compared standard drugs vancomycin and gentamycin sulfate. The molecular docking studies show that the compound might exhibit inhibitory activity against CDK inhibitors.

  10. Synthesis, crystal structures, molecular docking, and in vitro biological activities evaluation of transition metal complexes with 4-(3,4-dichlorophenyl) piperazine-1-carboxylic acid

    Science.gov (United States)

    Chen, Zhi-Jian; Chen, Ya-Na; Xu, Chun-Na; Zhao, Shan-Shan; Cao, Qi-Yue; Qian, Shao-Song; Qin, Jie; Zhu, Hai-Liang

    2016-08-01

    Three novel mononuclear complexes, [MⅡ(L)2·2H2O], (M = Cu, Ni or Cd; HL = 4-(3,4-dichlorophenyl)piperazine-1-carboxylic acid)were synthesized and structurally determined by single-crystal X-ray diffraction. Molecular docking study preliminarily revealed that complex 1 had potential urease inhibitory activity. In accordance with the result of calculation, in vitro tests of the inhibitory activities of complexes 1-3 against jack bean urease showed complex 1 (IC50 = 8.17 ± 0.91 μM) had better inhibitory activities than the positive reference acetohydroxamic acid (AHA) (IC50 = 26.99 ± 1.43 μM), while complexes 2 and 3 showed no inhibitory activities., kinetics study was carried out to explore the mechanism of the inhibiting of the enzyme, and the result indicated that complex 1 was a competitive inhibitor of urease. Albumin binding experiment and in vitro toxicity evaluation of complex 1 were implemented to explore its Pharmacological properties.

  11. Synthesis and characterization of n-alkylamino derivatives of vitamin K3: Molecular structure of 2-propylamino-3-methyl-1,4-naphthoquinone and antibacterial activities

    Science.gov (United States)

    Chadar, Dattatray; Camilles, Maria; Patil, Rishikesh; Khan, Ayesha; Weyhermüller, Thomas; Salunke-Gawali, Sunita

    2015-04-01

    We would like to introduce eight analogues of n-alkylamino derivatives of vitamin K3 (2-methyl-1,4-naphthoquinone) viz, 2-(n-alkylamino)-3-methyl-1,4-naphthoquinone (where n-alkyl is methyl; LM-1, ethyl; LM-2, propyl; LM-3, butyl; LM-4, pentyl; LM-5, hexyl; LM-6, heptyl; LM-7, octyl; LM-8). All the above analogues have been successfully synthesized from vitamin K3 and characterized using different analytical techniques. Furthermore, in order to understand the mechanistic aspects of formation of LM-1 to LM-8 compounds, we could propose the mechanism. The FT-IR analysis of LM-1 to LM-8 indicate the presence of characteristic band of Nsbnd H group ∼3287-3364 cm-1, the variation was attributed to extensive intramolecular hydrogen bonding interaction. The molecular structure of LM-3 compound has been confirmed by single crystal X-ray diffraction analysis. LM-3 compound crystallises in triclinic space group P1. There were four independent molecules in asymmetric unit cell and their molecular interactions observed via Nsbnd H⋯O, Csbnd H⋯O and π-π stacking of quinonoid rings. Pharmacological potential of all compounds has been evaluated in terms of their antibacterial activities against Pseudomonas aeruginosa and Staphylococcus aureus. All the compounds were active against both the strains while LM-2 was found to be more effective with a minimum inhibition concentration of 0.3125 μg/mL and 0.156 μg/mL respectively.

  12. Identification of methionine aminopeptidase 2 as a molecular target of the organoselenium drug ebselen and its derivatives/analogues: Synthesis, inhibitory activity and molecular modeling study.

    Science.gov (United States)

    Węglarz-Tomczak, Ewelina; Burda-Grabowska, Małgorzata; Giurg, Mirosław; Mucha, Artur

    2016-11-01

    A collection of twenty-six organoselenium compounds, ebselen and its structural analogues, provided a novel approach for inhibiting the activity of human methionine aminopeptidase 2 (MetAP2). This metalloprotease, being responsible for the removal of the amino-terminal methionine from newly synthesized proteins, plays a key role in angiogenesis, which is essential for the progression of diseases, including solid tumor cancers. In this work, we discovered that ebselen, a synthetic organoselenium drug molecule with anti-inflammatory, anti-oxidant and cytoprotective activity, inhibits one of the main enzymes in the tumor progression pathway. Using three-step synthesis, we obtained twenty-five ebselen derivatives/analogues, ten of which are new, and tested their inhibitory activity toward three neutral aminopeptidases (MetAP2, alanine and leucine aminopeptidases). All of the tested compounds proved to be selective, slow-binding inhibitors of MetAP2. Similarly to ebselen, most of its analogues exhibited a moderate potency (IC 50 =1-12μM). Moreover, we identified three strong inhibitors that bind favorably to the enzyme with the half maximal inhibitory concentration in the submicromolar range. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Synthesis, binding affinity at glutamic acid receptors, neuroprotective effects, and molecular modeling investigation of novel dihydroisoxazole amino acids

    DEFF Research Database (Denmark)

    Conti, Paola; De Amici, Marco; Grazioso, Giovanni

    2005-01-01

    stereoisomers of the bicyclic analogue 5-amino-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-3,5-dicarboxylic acid (+)-2, (-)-2, (+)-3, and (-)-3 were tested at ionotropic and metabotropic glutamate receptor subtypes. The most potent NMDA receptor antagonists [(+)-2, (-)-4, and (+)-5] showed a significant......The four stereoisomers of 5-(2-amino-2-carboxyethyl)-4,5-dihydroisoxazole-3-carboxylic acid(+)-4, (-)-4, (+)-5, and (-)-5 were prepared by stereoselective synthesis of two pairs of enantiomers, which were subsequently resolved by enzymatic procedures. These four stereoisomers and the four...

  14. Synthesis of mesogenic phthalocyanine-C60 donor–acceptor dyads designed for molecular heterojunction photovoltaic devices

    Directory of Open Access Journals (Sweden)

    Yves Henri Geerts

    2009-10-01

    Full Text Available A series of phthalocyanine-C60 dyads 2a–d was synthesized. Key steps in their synthesis are preparation of the low symmetry phthalocyanine intermediate by the statistical condensation of two phthalonitriles, and the final esterification of the fullerene derivative bearing a free COOH group. Structural characterization of the molecules in solution was performed by NMR spectroscopy, UV–vis spectroscopy and cyclic voltammetry. Preliminary studies suggest formation of liquid crystalline (LC mesophases for some of the prepared dyads. To the best of our knowledge, this is the first example of LC phthalocyanine-C60 dyads.

  15. Molecular Medicine: Synthesis and In Vivo Detection of Agents for use in Boron Neutron Capture Therapy. Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Kabalka, G. W.

    2005-06-28

    The primary objective of the project was the development of in vivo methods for the detection and evaluation of tumors in humans. The project was focused on utilizing positron emission tomography (PET) to monitor the distribution and pharamacokinetics of a current boron neutron capture therapy (BNCT) agent, p-boronophenylalanine (BPA) by labeling it with a fluorine-18, a positron emitting isotope. The PET data was then used to develop enhanced treatment planning protocols. The study also involved the synthesis of new tumor selective BNCTagents that could be labeled with radioactive nuclides for the in vivo detection of boron.

  16. Molecular Medicine: Synthesis and In Vivo Detection of Agents for use in Boron Neutron Capture Therapy. Final Report

    International Nuclear Information System (INIS)

    Kabalka, G. W.

    2005-01-01

    The primary objective of the project was the development of in vivo methods for the detection and evaluation of tumors in humans. The project was focused on utilizing positron emission tomography (PET) to monitor the distribution and pharmacokinetics of a current boron neutron capture therapy (BNCT) agent, p-boronophenylalanine (BPA) by labeling it with a fluorine-18, a positron emitting isotope. The PET data was then used to develop enhanced treatment planning protocols. The study also involved the synthesis of new tumor selective BNCT agents that could be labeled with radioactive nuclides for the in vivo detection of boron

  17. The synthesis, structure and reactivity of iron-bismuth complexes : Potential Molecular Precursors for Multiferroic BiFeO3

    OpenAIRE

    Wójcik, Katarzyna

    2009-01-01

    The thesis presented here is focused on the synthesis of iron-bismuth alkoxides and siloxides as precursors for multiferroic BiFeO3 systems. Spectrum of novel cyclopentadienyl substituted iron-bismuth complexes of the general type [{Cpy(CO)2Fe}BiX2], as potential precursors for cyclopentadienyl iron-bismuth alkoxides or siloxides [{Cpy(CO)2Fe}Bi(OR)2] (R-OtBu, OSiMe2tBu), were obtained and characterised. The use of wide range of cyclopentadienyl rings in the iron carbonyl compounds allowed fo...

  18. Synthesis, molecular docking, DFT calculations and cytotoxicity activity of benzo[g]quinazoline derivatives in choline chloride-urea

    Science.gov (United States)

    Lakshmanan, Sivalingam; Govindaraj, Dharman; Ramalakshmi, Narayanan; Antony, S. Arul

    2017-12-01

    Green and highly efficient one-pot three component approach for the synthesis of benzo[g]quinazoline derivatives (6a-g) using Choline chloride-urea (DES). Synthesized compounds 6b and 6g showed the most potent biological activity against A549 lung cancer cell line. Docking simulation was performed to position compounds 6b and 6g showed the greater affinity for anaplastic lymphoma kinase (ALK) receptor. Quantum chemical studies were carried out on these compounds to understand the structural features essential for activity using DFT/6-31G level of theory.

  19. Pharmacological modulation of mitochondrial calcium homeostasis.

    Science.gov (United States)

    Arduino, Daniela M; Perocchi, Fabiana

    2018-01-10

    Mitochondria are pivotal organelles in calcium (Ca 2+ ) handling and signalling, constituting intracellular checkpoints for numerous processes that are vital for cell life. Alterations in mitochondrial Ca 2+ homeostasis have been linked to a variety of pathological conditions and are critical in the aetiology of several human diseases. Efforts have been taken to harness mitochondrial Ca 2+ transport mechanisms for therapeutic intervention, but pharmacological compounds that direct and selectively modulate mitochondrial Ca 2+ homeostasis are currently lacking. New avenues have, however, emerged with the breakthrough discoveries on the genetic identification of the main players involved in mitochondrial Ca 2+ influx and efflux pathways and with recent hints towards a deep understanding of the function of these molecular systems. Here, we review the current advances in the understanding of the mechanisms and regulation of mitochondrial Ca 2+ homeostasis and its contribution to physiology and human disease. We also introduce and comment on the recent progress towards a systems-level pharmacological targeting of mitochondrial Ca 2+ homeostasis. © 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.

  20. Harnessing Big Data for Systems Pharmacology.

    Science.gov (United States)

    Xie, Lei; Draizen, Eli J; Bourne, Philip E

    2017-01-06

    Systems pharmacology aims to holistically understand mechanisms of drug actions to support drug discovery and clinical practice. Systems pharmacology modeling (SPM) is data driven. It integrates an exponentially growing amount of data at multiple scales (genetic, molecular, cellular, organismal, and environmental). The goal of SPM is to develop mechanistic or predictive multiscale models that are interpretable and actionable. The current explosions in genomics and other omics data, as well as the tremendous advances in big data technologies, have already enabled biologists to generate novel hypotheses and gain new knowledge through computational models of genome-wide, heterogeneous, and dynamic data sets. More work is needed to interpret and predict a drug response phenotype, which is dependent on many known and unknown factors. To gain a comprehensive understanding of drug actions, SPM requires close collaborations between domain experts from diverse fields and integration of heterogeneous models from biophysics, mathematics, statistics, machine learning, and semantic webs. This creates challenges in model management, model integration, model translation, and knowledge integration. In this review, we discuss several emergent issues in SPM and potential solutions using big data technology and analytics. The concurrent development of high-throughput techniques, cloud computing, data science, and the semantic web will likely allow SPM to be findable, accessible, interoperable, reusable, reliable, interpretable, and actionable.

  1. Self-reduction and size controlled synthesis of silver nanoparticles on carbon nanospheres by grafting triazine-based molecular layer for conductivity improvement

    Science.gov (United States)

    Sang, Jing; Aisawa, Sumio; Hirahara, Hidetoshi; Kudo, Takahiro; Mori, Kunio

    2016-02-01

    A facile, self-reduction and size controlled synthesis method has been explored to fabricate silver nanoparticles (Ag NPs) on carbon nanosphere (CNs) under mild conditions. Without using predeposition of seed metals and reducing agent, a uniform and complete layer of Ag NPs was formed through grafting a molecular layer on CNs surfaces under UV irradiation. The size and thickness of Ag NPs were effectively tuned by adjusting the UV irradiation time. This direct formation of Ag NPs was attributed to self seed in aqueous Ag(NH3)2+ complex solution through a triazine-based silane coupling agent molecular layer, even at 25 °C. Scanning electron microscopy (SEM), Transmission electron microscope (TEM), and X-ray photoelectron spectroscopy (XPS) were employed to characterize the Ag NPs' properties. A substantial conductivity improvement of prepared Ag NPs on carbon nanosphere was demonstrated. The presented method is simple and environmentally friendly and thus should be of significant value for the industrial fabrication of Ag NPs on carbon nanosphere in conduct electricity paint and coating applications.

  2. A focus on polarity: Investigating the role of orientation cues in mediating student performance on mRNA synthesis tasks in an introductory cell and molecular biology course.

    Science.gov (United States)

    Olimpo, Jeffrey T; Quijas, Daniel A; Quintana, Anita M

    2017-11-01

    The central dogma has served as a foundational model for information flow, exchange, and storage in the biological sciences for several decades. Despite its continued importance, however, recent research suggests that novices in the domain possess several misconceptions regarding the aforementioned processes, including those pertaining specifically to the formation of messenger ribonucleic acid (mRNA) transcripts. In the present study, we sought to expand upon these observations through exploration of the influence of orientation cues on students' aptitude at synthesizing mRNAs from provided deoxyribonucleic acid (DNA) template strands. Data indicated that participants (n = 45) were proficient at solving tasks of this nature when the DNA template strand and the mRNA molecule were represented in an antiparallel orientation. In contrast, participants' performance decreased significantly on items in which the mRNA was depicted in a parallel orientation relative to the DNA template strand. Furthermore, participants' Grade Point Average, self-reported confidence in understanding the transcriptional process, and spatial ability were found to mediate their performance on the mRNA synthesis tasks. Collectively, these data reaffirm the need for future research and pedagogical interventions designed to enhance students' comprehension of the central dogma in a manner that makes transparent its relevance to real-world scientific phenomena. © 2017 by The International Union of Biochemistry and Molecular Biology, 45(6):501-508, 2017. © 2017 The International Union of Biochemistry and Molecular Biology.

  3. Microwave-assisted synthesis, molecular docking and antitubercular activity of 1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives

    Czech Academy of Sciences Publication Activity Database

    Mohan, S. B.; Kumar, B. V. V. R.; Dinda, S. C.; Naik, D.; Seenivasan, S. P.; Kumar, V.; Rana, D. N.; Brahmkshatriya, Pathik

    2012-01-01

    Roč. 22, č. 24 (2012), s. 7539-7542 ISSN 0960-894X Institutional research plan: CEZ:AV0Z40550506 Keywords : antitubercular * binding interactions * luciferase reporter phage (LRP) assay * microwave-assisted * molecular docking Subject RIV: CC - Organic Chemistry Impact factor: 2.338, year: 2012

  4. Molecular design of new hydrazone dyes for dye-sensitized solar cells: Synthesis, characterization and DFT study

    KAUST Repository

    Al-Sehemi, Abdullah G.

    2012-07-01

    Three new sensitizers 2-{4-[2-(4-Nitrobenzylidene)hydrazino)]phenyl} ethylene-1,1,2-tricarbonitrile (NBHPET), 2-{4-[2-p-Chlorobenzylidenehydrazino] phenyl}- ethylene-1,1,2-tri carbonitrile (CBHPET) and 2-{4-[2-p- Bromobenzylidenehydrazino] phenyl}ethylene-1,1,2-tricarbonitrile (BBHPET) have been synthesized. The dyes showed pronounced solvatochromic effects as the polarity of the solvents increased. The structures have been optimized at B3LYP/6-31G(d) level of theory. The torsion in E-isomer is smaller than Z-isomer and azo isomers. The highest occupied molecular orbitals are delocalized on whole molecule while lowest unoccupied molecular orbitals are distributed on the tricarbonitrile. The lowest unoccupied molecular orbital energies are above the conduction band of titanium dioxide, highest occupied molecular orbitals of the dyes are below the redox couple of new synthesized dyes and small energy gap revealed these dyes would be better sensitizers for dye-sensitized solar cells. © 2012 Elsevier B.V. All rights reserved.

  5. New inorganic-organic hybrid materials based on SBA-15 molecular sieves involved in the quinolines synthesis

    Czech Academy of Sciences Publication Activity Database

    López-Sanz, J.; Pérez-Mayoral, E.; Soriano, E.; Sturm, M.; Martín-Aranda, R. M.; López-Peinado, A. J.; Čejka, Jiří

    2012-01-01

    Roč. 187, č. 1 (2012), s. 97-103 ISSN 0920-5861 R&D Projects: GA AV ČR KAN100400701 Institutional support: RVO:61388955 Keywords : mesoporous molecular sieves * heterogeneous catalysis * quinolines Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 2.980, year: 2012

  6. Two-directional synthesis as a tool for diversity-oriented synthesis: Synthesis of alkaloid scaffolds

    Directory of Open Access Journals (Sweden)

    Kieron M. G. O’Connell

    2012-06-01

    Full Text Available Two-directional synthesis represents an ideal strategy for the rapid elaboration of simple starting materials and their subsequent transformation into complex molecular architectures. As such, it is becoming recognised as an enabling technology for diversity-oriented synthesis. Herein, we provide a thorough account of our work combining two-directional synthesis with diversity-oriented synthesis, with particular reference to the synthesis of polycyclic alkaloid scaffolds.

  7. Pharmacology Experiments on the Computer.

    Science.gov (United States)

    Keller, Daniel

    1990-01-01

    A computer program that replaces a set of pharmacology and physiology laboratory experiments on live animals or isolated organs is described and illustrated. Five experiments are simulated: dose-effect relationships on smooth muscle, blood pressure and catecholamines, neuromuscular signal transmission, acetylcholine and the circulation, and…

  8. Pharmacology of Marihuana (Cannabis sativa)

    Science.gov (United States)

    Maickel, Roger P.

    1973-01-01

    A detailed discussion of marihuana (Cannabis sativa) providing the modes of use, history, chemistry, and physiologic properties of the drug. Cites research results relating to the pharmacologic effects of marihuana. These effects are categorized into five areas: behavioral, cardiovascular-respiratory, central nervous system, toxicity-toxicology,…

  9. Chemotaxonomy and pharmacology of Gentianaceae

    DEFF Research Database (Denmark)

    Jensen, Søren Rosendal; Schripsema, Jan

    2002-01-01

    the remaining six are members of the Gentianeae. Based on the above results, a tentative list of chemical characteristics for the tribes of the Gentianaceae is presented. Finally, some pharmacologically interesting properties of plant extracts or compounds from taxa within Gentianaceae are listed....

  10. The Role of Pharmacology in Ureteral Physiology and Expulsive Therapy

    Science.gov (United States)

    Jerde, Travis J.; Nakada, Stephen Y.

    2007-04-01

    Research in the field of ureteral physiology and pharmacology has traditionally been directed toward relaxation of ureteral spasm as a mechanism of analgesia during painful ureteral obstruction, most often stone-induced episodes. However, interest in this field has expanded greatly in recent years with the expanded use of alpha-blocker therapy for inducing stone passage, a usage now termed "medical expulsive therapy". While most clinical reports involving expulsive therapy have focused on alpha receptor or calcium channel blockade, there are diverse studies investigating pharmacological ureteral relaxation with novel agents including cyclooxygenase inhibitors, small molecule beta receptor agonists, neurokinin antagonists, and phosphodiesterase inhibitors. In addition, cutting edge molecular biology research is revealing promising potential therapeutic targets aimed at specific molecular changes that occur during the acute obstruction that accompanies stone disease. The purpose of this report is to review the use of pharmacological agents as ureteral smooth muscle relaxants clinically, and to look into the future of expulsive therapy by reviewing the available literature of ureteral physiology and pharmacology research.

  11. Synthesis of surface molecular imprinting polymer on SiO{sub 2}-coated CdTe quantum dots as sensor for selective detection of sulfadimidine

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Zhiping; Ying, Haiqin; Liu, Yanyan [School of Materials Science and Engineering, Jiangsu University, Zhenjiang 212013 (China); Xu, Wanzhen, E-mail: xwz09@ujs.edu.cn [School of the Environment and Safety Engineering, Jiangsu University, Zhenjiang 212013 (China); Yang, Yanfei; Luan, Yu [Zhenjiang Institute for Drug Control of Jiangsu Province, Zhenjiang 212003 (China); Lu, Yi; Liu, Tianshu [Zhenjiang Entry-Exit Inspection Quarantine Bureau, Zhenjiang 212008 (China); Yu, Shui [School of Materials Science and Engineering, Jiangsu University, Zhenjiang 212013 (China); Yang, Wenming, E-mail: ywm@ujs.edu.cn [School of Materials Science and Engineering, Jiangsu University, Zhenjiang 212013 (China)

    2017-05-15

    Highlights: • Surface molecular imprinting technology and SiO{sub 2}-coated CdTe QDs were combined to prepare a novel fluorescent sensor for selective detection of sulfadimidine. • The relative fluorescent intensity weakened in a linear way with the increasing concentration of sulfadimidine in the range of 10–60 μmol L{sup −1}. • The practical application of the fluorescent MIP sensor was evaluated by means of analyzing sulfadimidine in the real milk samples. The recoveries were at the range of 90.3–99.6% and the relative standard deviation ranged from 1.9 to 3.1%. - Abstract: This paper demonstrates a facile method to synthesize surface molecular imprinting polymer (MIP) on SiO{sub 2}-coated CdTe QDs for selective detection of sulfadimidine (SM{sub 2}). The fluorescent MIP sensor was prepared using cadmium telluride quantum dots (CdTe QDs) as the material of fluorescent signal readout, sulfadimidine as template molecule, 3-aminopropyltriethoxysilane (APTES) as functional monomer and tetraethyloxysilane (TEOS) as cross-linking agent. The CdTe cores were embed in the silicon shells by a sol-gel reaction and then the molecular imprinting layers were immobilized on the surface of the SiO{sub 2}-coated CdTe QDs. Under the optimized conditions, the relative fluorescent intensity weakened in a linear way with the increasing concentration of sulfadimidine in the range of 10–60 μmol L{sup −1}. The practical application of the fluorescent MIP sensor was evaluated by means of analyzing sulfadimidine in the real milk samples. The recoveries were at the range of 90.3–99.6% and the relative standard deviation (RSD) ranged from 1.9 to 3.1%, which indicates the successful synthesis of the fluorescent MIP sensor. This sensor provides an alternative solution for selective determination of sulfadimidine from real milk samples.

  12. Molecular rheology of branched polymers: decoding and exploring the role of architectural dispersity through a synergy of anionic synthesis, interaction chromatography, rheometry and modeling.

    Science.gov (United States)

    van Ruymbeke, E; Lee, H; Chang, T; Nikopoulou, A; Hadjichristidis, N; Snijkers, F; Vlassopoulos, D

    2014-07-21

    An emerging challenge in polymer physics is the quantitative understanding of the influence of a macromolecular architecture (i.e., branching) on the rheological response of entangled complex polymers. Recent investigations of the rheology of well-defined architecturally complex polymers have determined the composition in the molecular structure and identified the role of side-products in the measured samples. The combination of different characterization techniques, experimental and/or theoretical, represents the current state-of-the-art. Here we review this interdisciplinary approach to molecular rheology of complex polymers, and show the importance of confronting these different tools for ensuring an accurate characterization of a given polymeric sample. We use statistical tools in order to relate the information available from the synthesis protocols of a sample and its experimental molar mass distribution (typically obtained from size exclusion chromatography), and hence obtain precise information about its structural composition, i.e. enhance the existing sensitivity limit. We critically discuss the use of linear rheology as a reliable quantitative characterization tool, along with the recently developed temperature gradient interaction chromatography. The latter, which has emerged as an indispensable characterization tool for branched architectures, offers unprecedented sensitivity in detecting the presence of different molecular structures in a sample. Combining these techniques is imperative in order to quantify the molecular composition of a polymer and its consequences on the macroscopic properties. We validate this approach by means of a new model asymmetric comb polymer which was synthesized anionically. It was thoroughly characterized and its rheology was carefully analyzed. The main result is that the rheological signal reveals fine molecular details, which must be taken into account to fully elucidate the viscoelastic response of entangled branched

  13. Molecular rheology of branched polymers: Decoding and exploring the role of architectural dispersity through a synergy of anionic synthesis, interaction chromatography, rheometry and modeling

    KAUST Repository

    Van Ruymbeke, Evelyne

    2014-01-01

    An emerging challenge in polymer physics is the quantitative understanding of the influence of a macromolecular architecture (i.e., branching) on the rheological response of entangled complex polymers. Recent investigations of the rheology of well-defined architecturally complex polymers have determined the composition in the molecular structure and identified the role of side-products in the measured samples. The combination of different characterization techniques, experimental and/or theoretical, represents the current state-of-the-art. Here we review this interdisciplinary approach to molecular rheology of complex polymers, and show the importance of confronting these different tools for ensuring an accurate characterization of a given polymeric sample. We use statistical tools in order to relate the information available from the synthesis protocols of a sample and its experimental molar mass distribution (typically obtained from size exclusion chromatography), and hence obtain precise information about its structural composition, i.e. enhance the existing sensitivity limit. We critically discuss the use of linear rheology as a reliable quantitative characterization tool, along with the recently developed temperature gradient interaction chromatography. The latter, which has emerged as an indispensable characterization tool for branched architectures, offers unprecedented sensitivity in detecting the presence of different molecular structures in a sample. Combining these techniques is imperative in order to quantify the molecular composition of a polymer and its consequences on the macroscopic properties. We validate this approach by means of a new model asymmetric comb polymer which was synthesized anionically. It was thoroughly characterized and its rheology was carefully analyzed. The main result is that the rheological signal reveals fine molecular details, which must be taken into account to fully elucidate the viscoelastic response of entangled branched

  14. Synthesis, in vitro pharmacologic characterization, and preclinical evaluation of N-[2-(1'-piperidinyl)ethyl]-3-[{sup 125}I]iodo-4-methoxybenzamide (P[{sup 125}I]MBA) for imaging breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    John, Christy S. E-mail: radcsj@gwumc.edu; Bowen, Wayne D.; Fisher, Susan J.; Lim, Benjamin B.; Geyer, Brian C.; Vilner, Bertold J.; Wahl, Richard L

    1999-05-01

    The goal of this study was to investigate the potential use of a radioiodinated benzamide, N-[2-(1'-piperidinyl)ethyl]-3-iodo[{sup 125}I]-4-methoxybenzamide (P[{sup 125}I]MBA), a sigma receptor binding radioligand for imaging breast cancer. The chemical and radiochemical syntheses of PIMBA are described. The pharmacological evaluation of PIMBA was carried out for sigma-1 and sigma-2 receptor sites. The in vivo pharmacokinetics of the radioiodinated benzamide were determined in rats and comparison of P[{sup 125}I]MBA with Tc-99m sestamibi were made in a rat mammary tumor model. Sigma-1 affinity (K{sub i}) for PIMBA in guinea pig brain membranes using [{sup 3}H](+)pentazocine was found to be 11.82{+-}0.68 nM, whereas sigma-2 affinity in rat liver using [{sup 3}H]DTG (1,3-o-di-tolylguanidine) was 206{+-}11 nM. Sites in guinea pig brain membranes labeled by P[{sup 125}I]MBA showed high affinity for haloperidol, (+)-pentazocine, BD1008, and PIMBA (K{sub i}=4.87{+-}1.49,8.81{+-}1.97,0.057{+-}0.005,46.9{+-}1.8 nM), respectively). Competition binding studies were carried out in human ductal breast carcinoma cells (T47D). A dose-dependent inhibition of specific binding was observed with several sigma ligands. K{sub i} values for the inhibition of P[{sup 125}I]MBA binding in T47D cells for haloperidol, N-[2-(1'-piperidinyl)]ethyl]4-iodobenzamide (IPAB), N-(N-benzylpiperidin-4-yl)-4-iodobenzamide (4-IBP), and PIMBA were found to be 1.30{+-}0.07, 13{+-}1.5, 5.19{+-}2.3, 1.06{+-}0.5 nM, respectively. The in vitro binding data in guinea pig brain membranes and breast cancer cells confirmed binding to sigma sites. The saturation binding of P[{sup 125}I]MBA in T47D cells as studied by Scatchard analysis showed saturable binding, with a K{sub d}=94{+-}7 nM and a B{sub max}=2035{+-}305 fmol/mg of proteins. Biodistribution studies in Sprague-Dawley rats showed a rapid clearance of P[{sup 125}I]MBA from the normal organs. The potential of PIMBA in imaging breast cancer was

  15. Synthesis, in vitro pharmacologic characterization, and preclinical evaluation of N-[2-(1'-piperidinyl)ethyl]-3-[125I]iodo-4-methoxybenzamide (P[125I]MBA) for imaging breast cancer

    International Nuclear Information System (INIS)

    John, Christy S.; Bowen, Wayne D.; Fisher, Susan J.; Lim, Benjamin B.; Geyer, Brian C.; Vilner, Bertold J.; Wahl, Richard L.

    1999-01-01

    The goal of this study was to investigate the potential use of a radioiodinated benzamide, N-[2-(1'-piperidinyl)ethyl]-3-iodo[ 125 I]-4-methoxybenzamide (P[ 125 I]MBA), a sigma receptor binding radioligand for imaging breast cancer. The chemical and radiochemical syntheses of PIMBA are described. The pharmacological evaluation of PIMBA was carried out for sigma-1 and sigma-2 receptor sites. The in vivo pharmacokinetics of the radioiodinated benzamide were determined in rats and comparison of P[ 125 I]MBA with Tc-99m sestamibi were made in a rat mammary tumor model. Sigma-1 affinity (K i ) for PIMBA in guinea pig brain membranes using [ 3 H](+)pentazocine was found to be 11.82±0.68 nM, whereas sigma-2 affinity in rat liver using [ 3 H]DTG (1,3-o-di-tolylguanidine) was 206±11 nM. Sites in guinea pig brain membranes labeled by P[ 125 I]MBA showed high affinity for haloperidol, (+)-pentazocine, BD1008, and PIMBA ( K i =4.87±1.49,8.81±1.97,0.057±0.005,46.9±1.8 nM, respectively). Competition binding studies were carried out in human ductal breast carcinoma cells (T47D). A dose-dependent inhibition of specific binding was observed with several sigma ligands. K i values for the inhibition of P[ 125 I]MBA binding in T47D cells for haloperidol, N-[2-(1'-piperidinyl)]ethyl]4-iodobenzamide (IPAB), N-(N-benzylpiperidin-4-yl)-4-iodobenzamide (4-IBP), and PIMBA were found to be 1.30±0.07, 13±1.5, 5.19±2.3, 1.06±0.5 nM, respectively. The in vitro binding data in guinea pig brain membranes and breast cancer cells confirmed binding to sigma sites. The saturation binding of P[ 125 I]MBA in T47D cells as studied by Scatchard analysis showed saturable binding, with a K d =94±7 nM and a B max =2035±305 fmol/mg of proteins. Biodistribution studies in Sprague-Dawley rats showed a rapid clearance of P[ 125 I]MBA from the normal organs. The potential of PIMBA in imaging breast cancer was evaluated in Lewis rats bearing syngeneic RMT breast cancers, a cancer that closely mimics

  16. Fatty acid synthesis in Xylella fastidiosa: correlations between genome studies, 13C NMR data, and molecular models

    International Nuclear Information System (INIS)

    Osiro, Denise; Muniz, Joao Renato C.; Coleta Filho, Helvecio Della; Alves de Sousa, Alessandra; Machado, Marcos Antonio; Garratt, Richard C.; Colnago, Luiz Alberto

    2004-01-01

    Xylella fastidiosa was the first plant pathogen to have its complete genome sequence elucidated. Routine database analyses suggested that two enzymes essential for fatty acid synthesis were missing, one of these is the holo-acyl-carrier-protein synthase. However, here we demonstrate, using 13 C NMR spectroscopy, that X. fastidiosa is indeed able to synthesize fatty acids from acetate via an apparently conventional metabolic pathway. We further identify a gene product HetI, an alternative phosphopantetheinyl transferase, which we propose to fill the missing link. Homology modeling of HetI shows conservation of the Coenzyme A binding site suggesting it to be an active enzyme and reveals several interesting structural features when compared with the surfactin synthase-activating enzyme, on which the model was built. These include a simplified topology due to N- and C-terminal deletions and the observation of a novel serine ladder

  17. Nitenpyram analogues with 1,4-dihydropyridine fixed cis-configuration:synthesis,insecticidal activities and molecular docking studies

    Directory of Open Access Journals (Sweden)

    XUE Sijia

    2013-08-01

    Full Text Available A novel series of Nitenpyram analogues(Ia-Ij with 1,4-dihydropyridine fixed cis-configuration were designed and synthesized.Preliminary bioassays showed that most of them exhibited good insecticidal activities against Aphis medicagini and Brown rice planthopper at 500 mg/L and 100 mg/L.The analogue Ij afforded the best activity in vitro,that had 100% mortality at 4 mg/L against Brown rice planthopper and Aphis medicagin.In addition,the molecular docking simulations revealed that the structural uniqueness of these analogues may lead to a unique molecular recognition and binding mode,and the results explained the SARs observed in vitro, which shed light on the novel insecticidal mechanism of these novel nitenpyam analogues.

  18. Synthesis of molecularly imprinted photocatalysts containing low TiO_2 loading: Evaluation for the degradation of pharmaceuticals

    International Nuclear Information System (INIS)

    Coelho de Escobar, Cícero; Lansarin, Marla Azário; Zimnoch dos Santos, João Henrique

    2016-01-01

    Highlights: • Molecularly imprinted photocatalyst (MIP) containing low TiO_2 loading were prepared by acid-catalyzed sol–gel process. • Seven pharmaceutical compounds were evaluated as a template. • Comparing to the P25, MIP has shown an increase of adsorption up to 752%. • Comparing to the P25, MIP has shown an increase of degradation up to 427%. • The presence of specific cavities on the silica domain could explain the better results for MIP. - Abstract: A molecularly imprinted (MI) photocatalyst containing a low TiO_2 loading (7.00–16.60 mg L"−"1 of TiO_2) was prepared via an acid-catalyzed sol–gel route using different classes of pharmaceutical compounds (i.e., Atorvastatin, Diclofenac, Ibuprofen, Tioconazole, Valsartan, Ketoconazole and Gentamicine) as the template. Herein, our main goal was to test the hypothesis that photocatalysts based on molecular imprinting may improve the degradation performance of pharmaceutical compounds compared to that of a commercial sample (Degussa P25) due to presence of specific cavities in the silica domain. To elucidate certain trends between the performance of photocatalysts and their structural and textural properties, as well the effect of the structure of the drugs on molecular imprinting, the data were analyzed in terms of pore diameter, pore volume, surface area, zeta potential and six-membered ring percentage of silica. In comparison to the commercial sample (P25), we have shown that adsorption and degradation were enhanced from 48 to 752% and from 5 to 427%, respectively. A comparison with the control system (non-imprinted) indicates that the increased performance of the MI systems was due to the presence of specific cavities on the silica domain, and the textural and structural aspects also support this conclusion. The MI photocatalyst was reusable for seven cycles of reuse in which approximately 60% of its photocatalytic efficiency was preserved for the system containing Diclofenac as the template.

  19. Synthesis, XRD single crystal structure analysis, vibrational spectral analysis, molecular dynamics and molecular docking studies of 2-(3-methoxy-4-hydroxyphenyl) benzothiazole

    Science.gov (United States)

    Sarau Devi, A.; Aswathy, V. V.; Sheena Mary, Y.; Yohannan Panicker, C.; Armaković, Stevan; Armaković, Sanja J.; Ravindran, Reena; Van Alsenoy, C.

    2017-11-01

    The vibrational spectra and corresponding vibrational assignments of 2-(3-methoxy-4-hydroxyphenyl)benzothiazole is reported. Single crystal XRD data of the title compound is reported and the orientation of methoxy group is cis to nitrogen atom of the thiazole ring. The phenyl ring breathing modes of the title compound are assigned at 1042 and 731 cm-1 theoretically. The charge transfer within the molecule is studied using frontier molecular orbital analysis. The chemical reactivity descriptors are calculated theoretically. The NMR spectral data predicted theoretically are in good agreement with the experimental data. The strong negative region spread over the phenyl rings, nitrogen atom and oxygen atom of the hydroxyl group in the MEP plot is due to the immense conjugative and hyper conjugative resonance charge delocalization of π-electrons. Molecule sites prone to electrophilic attacks have been determined by analysis of ALIE surfaces, while Fukui functions provided further insight into the local reactivity properties of title molecule. Autoxidation properties have been investigated by calculation of bond dissociation energies (BDEs) of hydrogen abstraction, while BDEs of the rest of the single acyclic bonds were valuable for the further investigation of degradation properties. Calculation of radial distribution functions was performed in order to determine which atoms of the title molecule have pronounced interactions with water molecules. The title compound forms a stable complex with aryl hydrocarbon receptor and can be a lead compound for developing new anti-tumor drug. Antimicrobial properties of the title compound was screened against one bacterial culture Escherchia coli and four fungal cultures viz., Aspergillus niger, Pencillum chrysogenum, Saccharomyces cerevisiae and Rhyzopus stolonifer.

  20. The investigation of Mitogen-Activated Protein kinase Phosphatase-1 as a potential pharmacological target in non-small cell lung carcinomas, assisted by non-invasive molecular imaging

    International Nuclear Information System (INIS)

    Tai, Cheng-Jeng; Lee, Horng-Mo; Deng, Win-Ping; Wu, Alexander TH; Chiou, Jeng-Feng; Jan, Hsun-Jin; Wei, Hon-Jian; Hsu, Chung-Huei; Lin, Che-Tong; Chiu, Wen-Ta; Wu, Cheng-Wen

    2010-01-01

    Invasiveness and metastasis are the most common characteristics of non small cell lung cancer (NSCLC) and causes of tumour-related morbidity and mortality. Mitogen-activated protein kinases (MAPKs) signalling pathways have been shown to play critical roles in tumorigenesis. However, the precise pathological role(s) of mitogen-activated protein kinase phosphatase-1 (MKP-1) in different cancers has been controversial such that the up-regulation of MKP-1 in different cancers does not always correlate to a better prognosis. In this study, we showed that the induction of MKP-1 lead to a significant retardation of proliferation and metastasis in NSCLC cells. We also established that rosiglitazone (a PPARγ agonist) elevated MKP-1 expression level in NSCLC cells and inhibited tumour metastasis. Both wildtype and dominant negative forms of MKP-1 were constitutively expressed in NSCLC cell line H441GL. The migration and invasion abilities of these cells were examined in vitro. MKP-1 modulating agents such as rosiglitazone and triptolide were used to demonstrate MKP-1's role in tumorigenesis. Bioluminescent imaging was utilized to study tumorigenesis of MKP-1 over-expressing H441GL cells and anti-metastatic effect of rosiglitazone. Over-expression of MKP-1 reduced NSCLC cell proliferation rate as well as cell invasive and migratory abilities, evident by the reduced expression levels of MMP-2 and CXCR4. Mice inoculated with MKP-1 over-expressing H441 cells did not develop NSCLC while their control wildtype H441 inoculated littermates developed NSCLC and bone metastasis. Pharmacologically, rosiglitazone, a peroxisome proliferator activated receptor-γ (PPARγ) agonist appeared to induce MKP-1 expression while reduce MMP-2 and CXCR4 expression. H441GL-inoculated mice receiving daily oral rosiglitazone treatment demonstrated a significant inhibition of bone metastasis when compared to mice receiving sham treatment. We found that rosiglitazone treatment impeded the ability

  1. Synthesis and pharmacological characterization of a new PET ligand for the serotonin transporter: [{sup 11}C]5-bromo-2-[2-(dimethylaminomethylphenylsulfanyl)]phenylamine ([{sup 11}C]DAPA)

    Energy Technology Data Exchange (ETDEWEB)

    Huang Yiyun E-mail: hh285@columbia.edu; Hwang, D.-R.; Zhu Zhihong; Bae, S.-A.; Guo Ningning; Sudo, Yasuhiko; Kegeles, Lawrence S.; Laruelle, Marc

    2002-10-01

    A new PET radioligand for the serotonin transporter (SERT), [{sup 11}C]-5-bromo-2-[2-(dimethylaminomethylphenylsulfanyl)]phenylamine ([{sup 11}C]DAPA (10), was synthesized and evaluated in vivo in rats and baboons. [{sup 11}C]DAPA (10) was prepared from its monomethylamino precursor 8 by reaction with high specific activity [{sup 11}C]methyl iodide. Radiochemical yield was 24{+-}5% based on [{sup 11}C]methyl iodide at end of bombardment (EOB, n=10) and specific activity was 1553{+-}939 Ci/mmol at end of synthesis (EOS, n=10). Binding assays indicated that [{sup 11}C]DAPA displays high affinity (Ki 1.49{+-}0.28 nM for hSERT) and good selectivity for the SERT in vitro. Biodistribution studies in rats indicated that [{sup 11}C]DAPA enters into the brain readily and localizes in brain regions known to contain high concentrations of SERT, such as the thalamus, hypothalamus, frontal cortex and striatum. Moreover, such binding in SERT-rich regions of the brain are blocked by pretreatment with either the selective serotonin reuptake inhibitor (SSRI) citalopram and by the cold compound itself, demonstrating that [{sup 11}C]DAPA binding in the rat brain is saturable and specific to SERT. Imaging experiments in baboons indicated that [{sup 11}C]DAPA binding is consistent with the known distribution of SERT in the baboon brain, with highest levels of radioactivity detected in the midbrain and thalamus, intermediate levels in the hippocampus and striatum, and lower levels in the cortical regions. Pretreatment of the baboon with citalopram 10 min before radioactivity injection blocked the binding of [{sup 11}C]DAPA in all brain regions that contain SERT. Kinetic analysis revealed that, in all brain regions examined, [{sup 11}C]DAPA specific to nonspecific distribution volume ratios (V{sub 3}'') are higher than [{sup 11}C](+)-McN 5652 and similar to [{sup 11}C]DASB. In summary, [{sup 11}C]DAPA appears to be a promising radioligand suitable for the visualization of SERT

  2. Synthesis, molecular structure, biological properties and molecular docking studies on Mn(II), Co(II) and Zn(II) complexes containing bipyridine-azide ligands.

    Science.gov (United States)

    Thamilarasan, Vijayan; Jayamani, Arumugam; Sengottuvelan, Nallathambi

    2015-01-07

    Metal complexes of the type Mn(bpy)2(N3)2 (1), Co(bpy)2(N3)2·3H2O (2) and Zn2(bpy)2(N3)4 (3) (Where bpy = 2,2-bipyridine) have been synthesized and characterized by elemental analysis and spectral (FT-IR, UV-vis) studies. The structure of complexes (1-3) have been determined by single crystal X-ray diffraction studies and the configuration of ligand-coordinated metal(II) ion was well described as distorted octahedral coordination geometry for Mn(II), Co(II) and distorted square pyramidal geometry for Zn(II) complexes. DNA binding interaction of these complexes (1-3) were investigated by UV-vis absorption, fluorescence circular dichroism spectral and molecular docking studies. The intrinsic binding constants Kb of complexes 1, 2 and 3 with CT-DNA obtained from UV-vis absorption studies were 8.37 × 10(4), 2.23 × 10(5) and 5.52 × 10(4) M(-1) respectively. The results indicated that the three complexes are able to bind to DNA with different binding affinity, in the order 2 > 1 > 3. Complexes (1-3) exhibit a good binding propensity to bovine serum albumin (BSA) proteins having relatively high binding constant values. Gel electrophoresis assay demonstrated the ability of the complexes 1-3 promote the cleavage ability of the pBR322 plasmid DNA in the presence of the reducing agent 3-mercaptopropionic acid (MPA) but with different cleavage mechanisms: the complex 3 cleaves DNA via hydrolytic pathway (T4 DNA ligase assay), while the DNA cleavage by complexes 1 and 2 follows oxidative pathway. The chemical nuclease activity follows the order: 2 > 1 > 3. The effects of various activators were also investigated and the nuclease activity efficacy followed the order MPA > GSH > H2O2 > Asc. The cytotoxicity studies of complexes 1-3 were tested in vitro on breast cancer cell line (MCF-7) and they found to be active. Copyright © 2014. Published by Elsevier Masson SAS.

  3. Synthesis of molecularly imprinted photocatalysts containing low TiO{sub 2} loading: Evaluation for the degradation of pharmaceuticals

    Energy Technology Data Exchange (ETDEWEB)

    Coelho de Escobar, Cícero; Lansarin, Marla Azário [Departamento de Engenharia Química—Universidade Federal do Rio Grande do Sul, Rua Eng. Luis Englert s/n, 90040-040 Porto Alegre, RS (Brazil); Zimnoch dos Santos, João Henrique, E-mail: jhzds@iq.ufrgs.br [Instituto de Química, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves, 9500, Porto Alegre CEP 91500-000 (Brazil)

    2016-04-05

    Highlights: • Molecularly imprinted photocatalyst (MIP) containing low TiO{sub 2} loading were prepared by acid-catalyzed sol–gel process. • Seven pharmaceutical compounds were evaluated as a template. • Comparing to the P25, MIP has shown an increase of adsorption up to 752%. • Comparing to the P25, MIP has shown an increase of degradation up to 427%. • The presence of specific cavities on the silica domain could explain the better results for MIP. - Abstract: A molecularly imprinted (MI) photocatalyst containing a low TiO{sub 2} loading (7.00–16.60 mg L{sup −1} of TiO{sub 2}) was prepared via an acid-catalyzed sol–gel route using different classes of pharmaceutical compounds (i.e., Atorvastatin, Diclofenac, Ibuprofen, Tioconazole, Valsartan, Ketoconazole and Gentamicine) as the template. Herein, our main goal was to test the hypothesis that photocatalysts based on molecular imprinting may improve the degradation performance of pharmaceutical compounds compared to that of a commercial sample (Degussa P25) due to presence of specific cavities in the silica domain. To elucidate certain trends between the performance of photocatalysts and their structural and textural properties, as well the effect of the structure of the drugs on molecular imprinting, the data were analyzed in terms of pore diameter, pore volume, surface area, zeta potential and six-membered ring percentage of silica. In comparison to the commercial sample (P25), we have shown that adsorption and degradation were enhanced from 48 to 752% and from 5 to 427%, respectively. A comparison with the control system (non-imprinted) indicates that the increased performance of the MI systems was due to the presence of specific cavities on the silica domain, and the textural and structural aspects also support this conclusion. The MI photocatalyst was reusable for seven cycles of reuse in which approximately 60% of its photocatalytic efficiency was preserved for the system containing

  4. Design and synthesis of a fluorescent molecular imprinted polymer for use in an optical fibre-based cocaine sensor

    Science.gov (United States)

    Wren, Stephen P.; Piletsky, Sergey A.; Karim, Kal; Gascoine, Paul; Lacey, Richard; Sun, Tong; Grattan, Kenneth T. V.

    2014-05-01

    Previously, we have developed chemical sensors using fibre optic-based techniques for the detection of Cocaine, utilising molecularly imprinted polymers (MIPs) containing fluorescein moieties as the signalling groups. Here, we report the computational design of a fluorophore which was incorporated into a MIP for the generation of a novel sensor that offers improved sensitivity for Cocaine with a detection range of 1-100μM. High selectivity for Cocaine over a suite of known Cocaine interferants (25μM) was also demonstrated by measuring changes in the intensity of fluorescence signals received from the sensor.

  5. Potent new small-molecule inhibitor of botulinum neurotoxin serotype A endopeptidase developed by synthesis-based computer-aided molecular design.

    Directory of Open Access Journals (Sweden)

    Yuan-Ping Pang

    2009-11-01

    Full Text Available Botulinum neurotoxin serotype A (BoNTA causes a life-threatening neuroparalytic disease known as botulism. Current treatment for post exposure of BoNTA uses antibodies that are effective in neutralizing the extracellular toxin to prevent further intoxication but generally cannot rescue already intoxicated neurons. Effective small-molecule inhibitors of BoNTA endopeptidase (BoNTAe are desirable because such inhibitors potentially can neutralize the intracellular BoNTA and offer complementary treatment for botulism. Previously we reported a serotype-selective, small-molecule BoNTAe inhibitor with a K(i (app value of 3.8+/-0.8 microM. This inhibitor was developed by lead identification using virtual screening followed by computer-aided optimization of a lead with an IC(50 value of 100 microM. However, it was difficult to further improve the lead from micromolar to even high nanomolar potency due to the unusually large enzyme-substrate interface of BoNTAe. The enzyme-substrate interface area of 4,840 A(2 for BoNTAe is about four times larger than the typical protein-protein interface area of 750-1,500 A(2. Inhibitors must carry several functional groups to block the unusually large interface of BoNTAe, and syntheses of such inhibitors are therefore time-consuming and expensive. Herein we report the development of a serotype-selective, small-molecule, and competitive inhibitor of BoNTAe with a K(i value of 760+/-170 nM using synthesis-based computer-aided molecular design (SBCAMD. This new approach accounts the practicality and efficiency of inhibitor synthesis in addition to binding affinity and selectivity. We also report a three-dimensional model of BoNTAe in complex with the new inhibitor and the dynamics of the complex predicted by multiple molecular dynamics simulations, and discuss further structural optimization to achieve better in vivo efficacy in neutralizing BoNTA than those of our early micromolar leads. This work provides new insight

  6. Three millimeter molecular line observations in Sagittarius B2. 1: Full synthesis mapping study of HNO, CCS, and HC(13)CCN

    Science.gov (United States)

    Kuan, Yi-Jehng; Snyder, Lewis E.

    1994-01-01

    We present the first full synthesis maps of the small molecules HNO, CCS, and HC(13)CCN in Sgr B2. We have observed the 3.8 mm continuum, the HNO J(sub K(sub -1)K(sub 1)) = 1(sub O1)-0(sub OO), the CCS J(sub N) = 7(sub 6)-6(sub 5), and the HC(13)CCN J = 9-8 transitions in the core of the Sgr B2 molecular cloud, using the Berkeley Illinois Maryland Association (BIMA) millimeter array and the NRAO 12 m telescope. We have found that HNO exists in five major gas clumps in the Sgr B2 region, which we have labeled HNO(N), HNO(NW), HNO(E), HNO(M), and HNO(S). Of particular interest is HNO(M), a major molecular gas concentration approximately 15 sec west of Sgr B2(M) in a region of young star formation. HNO is found to be closely associated with the ionized gas and might be depleted around bright H II complexes. In general, the peak intensity of the HNO emission is found to be offset from the peak of the continuum emission. We found evidence for some chemical differentiation among the three species, HNO, CCS, and HC(13)CCN, but the abundance ratios are in fair agreement with theoretical models. Two unidentified lines, U81420 and U81518, were observed, and a previously unknown compact dust source was detected. Our HNO data indicate the presence of a rotating approximately (2.2-4.4) x 10(exp 3)solar mass gas envelope surrounding Sgr B2(N), a possible bipolar gas outflow in HNO(M), and possibly a large (approximately 4.2 x 10(exp 4)solar mass) extended rotating disk associated with HNO(S). In addition, the CCS and HC(13)CCN data approximately outline the extended component of Sgr B2 and clearly show that the southern continuum source Sgr B2(S) is actually a major molecular source as well. Consequently, the kinematics of the Sgr B2 molecular cloud is quite complex, but in moving from the northwest to south, the LSR velocity generally changes from 79 to 46 km/s.

  7. Bacterial Peptide Deformylase Inhibition of Tetrazole-Substituted Biaryl Acid Analogs: Synthesis, Biological Evaluations, and Molecular Docking Study.

    Science.gov (United States)

    Khan, Firoz A Kalam; Patil, Rajendra H; Patil, Manjiri; Arote, Rohidas; Shinde, Devanand B; Sangshetti, Jaiprakash N

    2016-12-01

    The synthesis and screening of tetrazole-substituted biaryl acid analogs 7a-l as bacterial peptide deformylase (PDF) enzyme inhibitors is reported. The compounds 7e (IC 50 value = 5.50 μM) and 7g (IC 50 value = 7.25 μM) showed good PDF inhibition activity. The compounds 7e (MIC range = 10.75-11.66 μg/mL) and 7g (MIC range = 8.91-12.83 μg/mL) also showed potent antibacterial activity when compared with the standard ciprofloxacin (MIC range = 25-50 μg/mL). Thus, the active derivatives were not only potent PDF enzyme inhibitors but also efficient antibacterial agents. In order to gain more insight into the binding mode of the compounds with the PDF enzyme, the most active compounds 7e and 7g, the moderately active compound 7k, and the least active compound 7h were docked against the PDF enzyme of Escherichia coli. The docking study of the most active compounds 7e and 7g against the PDF enzyme exhibited good binding properties. Hence, we believe our synthesized compounds 7a-l could serve as reservoir for bacterial PDF inhibitor development. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Toward a Molecular Lego Approach for the Diversity-Oriented Synthesis of Cyclodextrin Analogues Designed as Scaffolds for Multivalent Systems.

    Science.gov (United States)

    Lepage, Mathieu L; Schneider, Jérémy P; Bodlenner, Anne; Compain, Philippe

    2015-11-06

    A modular strategy has been developed to access a diversity of cyclic and acyclic oligosaccharide analogues designed as prefunctionalized scaffolds for the synthesis of multivalent ligands. This convergent approach is based on bifunctional sugar building blocks with two temporarily masked functionalities that can be orthogonally activated to perform Cu(I)-catalyzed azide-alkyne cycloaddition reactions (CuAAC). The reducing end is activated as a glycosyl azide and masked as a 1,6-anhydro sugar, while the nonreducing end is activated as a free alkyne and masked as a triethylsilyl-alkyne. Following a cyclooligomerization approach, the first examples of close analogues of cyclodextrins composed of d-glucose residues and triazole units bound together through α-(1,4) linkages were obtained. The cycloglucopyranoside analogue containing four sugar units was used as a template to prepare multivalent systems displaying a protected d-mannose derivative or an iminosugar by way of CuAAC. On the other hand, the modular approach led to acyclic alkyne-functionalized scaffolds of a controlled size that were used to synthesize multivalent iminosugars.

  9. 1-ethyl gallate-2-substituted phenoxymethyl benzimidazoles: synthesis, molecular structure, antimicrobial activities and complex with cr(iii)

    International Nuclear Information System (INIS)

    Zhao, L.; Wu, J.; Wu, J.; Wang, Z.; Gu, H.

    2017-01-01

    The design of gallate and benzimidazole containing derivatives is expected to produce new bioactive molecules with multiple applications. Here the synthesis of eight novel benzimidazole compounds containing ethyl gallate and substituted phenoxymethyl units are reported. Firstly, the ring closure reaction between o-phenylendiamine and substituted phenoxyacetic acids resulted in 2-substituted phenoxymethyl benzimidazoles that were then modified by the N-hydroxyethylation with 2-chloroethyl alcohol under a phase transfer catalysis condition. The obtained 1-hydroxyethyl-2-substituted phenoxymethyl benzimidazoles were finally translated into the target title compounds 8a-h by an indirect esterification method in which three O-H groups of gallic acid were first protected by acetyls and deprotected after the esterification reaction by adding hydrazine hydrate. The structures of the title products 8a-h were fully characterized and confirmed by elemental analysis, MS, IR, 1H-NMR, 13C-NMR and single crystal X-ray diffraction techniques. Antimicrobial tests by inhibition zones indicated that these compounds exhibited diverse inhibitory effects against the test bacteria and fungi, and the type and position of the substituent groups in the phenoxymethyl moieties had obvious influence on their antimicrobial activities. Furthermore, the Cr(III) complex of 8h was synthesized, and various spectral, elemental and thermal analysis results confirmed that the central Cr(III) atom coordinated with adjacent hydroxyl groups of two 8h ligands, nitrate and H2O, respectively. (author)

  10. Synthesis of a molecularly defined single-active site heterogeneous catalyst for selective oxidation of N-heterocycles.

    Science.gov (United States)

    Zhang, Yujing; Pang, Shaofeng; Wei, Zhihong; Jiao, Haijun; Dai, Xingchao; Wang, Hongli; Shi, Feng

    2018-04-13

    Generally, a homogeneous catalyst exhibits good activity and defined active sites but it is difficult to recycle. Meanwhile, a heterogeneous catalyst can easily be reused but its active site is difficult to reveal. It is interesting to bridge the gap between homogeneous and heterogeneous catalysis via controllable construction of a heterogeneous catalyst containing defined active sites. Here, we report that a molecularly defined, single-active site heterogeneous catalyst has been designed and prepared via the oxidative polymerization of maleimide derivatives. These polymaleimide derivatives can be active catalysts for the selective oxidation of heterocyclic compounds to quinoline and indole via the recycling of -C=O and -C-OH groups, which was confirmed by tracing the reaction with GC-MS using maleimide as the catalyst and by FT-IR analysis with polymaleimide as the catalyst. These results might promote the development of heterogeneous catalysts with molecularly defined single active sites exhibiting a comparable activity to homogeneous catalysts.

  11. Synthesis of core-shell magnetic molecularly imprinted polymers and detection of sildenafil and vardenafil in herbal dietary supplements

    International Nuclear Information System (INIS)

    Ding Meijuan; Wu Xiaoli; Yuan Lihua; Wang Shu; Li Yun; Wang Ruoyu; Wen Tingting; Du Shuhu; Zhou, Xuemin

    2011-01-01

    An analytical procedure for selective extraction of sildenafil and vardenafil in herbal dietary supplements (HDSs) has been set up by using the magnetic molecularly imprinted polymers (MMIPs) as the extraction and clean-up materials, followed by high performance liquid chromatography-ultraviolet (HPLC-UV). The MMIPs were prepared by a surface molecular imprinting technique, using Fe 3 O 4 magnetite as a magnetically susceptible component, sildenafil as template molecule, 2-(trifluoromethyl) acrylic acid (TFMAA) as functional monomer, ethylene glycol dimethacrylate (EGDMA) as polymeric matrix components. The MMIPs were characterized by transmission electron microscope (TEM), Fourier transform infrared spectrometer (FT-IR), X-ray diffraction (XRD) and vibrating sample magnetometer (VSM), respectively. The heterogeneity of the MMIPs was modeled with the Freundlich isotherm equation. The resulting MMIPs had high recognition ability and fast binding kinetics for sildenafil. The MMIPs were used as dispersive solid-phase extraction (DSPE) materials to selectively extract sildenafil and vardenafil from HDSs, the contents of sildenafil and vardenafil were found to be 8.05 and 3.86 μg g -1 , respectively, and the average recoveries in spiked HDSs were 70.91-91.75% with a relative standard deviation (R.S.D.) below 7%. The MMIPs were successfully used to selectively enrich and determine sildenafil and vardenafil from HDSs.

  12. Synthesis of a Neutral Mixed-Valence Diferrocenyl Carborane for Molecular Quantum-Dot Cellular Automata Applications.

    Science.gov (United States)

    Christie, John A; Forrest, Ryan P; Corcelli, Steven A; Wasio, Natalie A; Quardokus, Rebecca C; Brown, Ryan; Kandel, S Alex; Lu, Yuhui; Lent, Craig S; Henderson, Kenneth W

    2015-12-14

    The preparation of 7-Fc(+) -8-Fc-7,8-nido-[C2 B9 H10 ](-) (Fc(+) FcC2 B9 (-) ) demonstrates the successful incorporation of a carborane cage as an internal counteranion bridging between ferrocene and ferrocenium units. This neutral mixed-valence Fe(II) /Fe(III) complex overcomes the proximal electronic bias imposed by external counterions, a practical limitation in the use of molecular switches. A combination of UV/Vis-NIR spectroscopic and TD-DFT computational studies indicate that electron transfer within Fc(+) FcC2 B9 (-) is achieved through a bridge-mediated mechanism. This electronic framework therefore provides the possibility of an all-neutral null state, a key requirement for the implementation of quantum-dot cellular automata (QCA) molecular computing. The adhesion, ordering, and characterization of Fc(+) FcC2 B9 (-) on Au(111) has been observed by scanning tunneling microscopy. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. A Molecular Precursor to Phosphaethyne and Its Application in Synthesis of the Aromatic 1,2,3,4-Phosphatriazolate Anion

    Energy Technology Data Exchange (ETDEWEB)

    Transue, Wesley J.; Velian, Alexandra; Nava, Matthew; Martin-Drumel, Marie-Aline; Womack, Caroline C.; Jiang, Jun; Hou, Gao-Lei; Wang, Xue-Bin; McCarthy, Michael C.; Field, Robert W.; Cummins, Christopher C.

    2016-06-01

    Dibenzo-7-phosphanorbornadiene Ph3PC(H)PA (1, A = C14H10, anthracene) is reported as a molecular precursor to phosphaethyne (HC≡P), produced together with anthracene and triphenylphosphine. HCP generated by thermolysis of 1 has been characterized by molecular beam mass spectrometry (MBMS), laser-induced fluorescence (LIF), microwave spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy. In toluene, fragmentation of 1 has been found to proceed with activation parameters of ΔH = 25.5 kcal/mol and ΔS = ₋2.43 e.u., and is accompanied by formation of an orange insoluble precipitate. Results from computational studies of the mechanism of HCP generation are in good agreement with experimental data. This high temperature method of HCP generation has pointed to new reaction chemistry with azide anion to produce the 1,2,3,4-phosphatriazolate anion, HCPN3- , for which structural data have been obtained in a single-crystal Xray diffraction study. Negative ion photoelectron spectroscopy has shown the adiabatic detachment energy for this anion to be 3.555(10) eV. The aromaticity of HCPN3- has been assessed using nucleus-independent chemical shift (NICS), quantum theory of atoms in molecules (QTAIM), and natural bond orbital (NBO) methods.

  14. Pharmacological Treatment for Atrial Fibrillation

    Directory of Open Access Journals (Sweden)

    Kaoru Sugi, MD PhD

    2005-01-01

    Full Text Available Pharmacological treatment for atrial fibrillation has a variety of purposes, such as pharmacological defibrillation, maintenance of sinus rhythm, heart rate control to prevent congestive heart failure and prevention of both cerebral infarction and atrial remodeling. Sodium channel blockers are superior to potassium channel blockers for atrial defibrillation, while both sodium and potassium channel blockers are effective in the maintenance of sinus rhythm. In general, digitalis or Ca antagonists are used to control heart rate during atrial fibrillation to prevent congestive heart failure, while amiodarone or bepridil also reduce heart rates during atrial fibrillation. Anticoagulant therapy with warfarin is recommended to prevent cerebral infarction and angiotensin converting enzyme antagonists or angiotensin II receptor blockers are also used to prevent atrial remodeling. One should select appropriate drugs for treatment of atrial fibrillation according to the patient's condition.

  15. Pharmacological challenges in chronic pancreatitis

    OpenAIRE

    Olesen, Anne Estrup; Brokjaer, Anne; Fisher, Iben Wendelboe; Larsen, Isabelle Myriam

    2013-01-01

    Drug absorption in patients with chronic pancreatitis might be affected by the pathophysiology of the disease. The exocrine pancreatic insufficiency is associated with changes in gastrointestinal intraluminal pH, motility disorder, bacterial overgrowth and changed pancreatic gland secretion. Together these factors can result in malabsorption and may also affect the efficacy of pharmacological intervention. The lifestyle of chronic pancreatitis patients may also contribute to gastrointestinal ...

  16. Applications of stable isotopes in clinical pharmacology

    NARCIS (Netherlands)

    Schellekens, Reinout C A; Stellaard, Frans; Woerdenbag, Herman J; Frijlink, Henderik W; Kosterink, Jos G W

    2011-01-01

    This review aims to present an overview of the application of stable isotope technology in clinical pharmacology. Three main categories of stable isotope technology can be distinguished in clinical pharmacology. Firstly, it is applied in the assessment of drug pharmacology to determine the

  17. One-pot synthesis of Zn{sub x}Cd{sub 1-x}S nanocrystals with tunable optical properties from molecular precursors

    Energy Technology Data Exchange (ETDEWEB)

    Chen Zhigang, E-mail: zgchen@dhu.edu.c [State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620 (China); Tian Qiwei; Song Yuelin [State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620 (China); Yang Jianmao [Research Center for Analysis and Measurement, Donghua University, Shanghai 201620 (China); Hu Junqing, E-mail: hu.junqing@dhu.edu.c [State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620 (China)

    2010-09-17

    We have reported a non-injection one-pot synthesis of the alloyed Zn{sub x}Cd{sub 1-x}S semiconductor nanocrystals (SNCs) with controlled shapes and compositions. This non-injection approach involves heating two molecular precursors (cadmium ethylxanthate and zinc ethylxanthate) as metal and S sources in organic solvents at 320 {sup o}C for 30 min, which results in the thermal decompositions of the molecular precursors to produce Zn{sub x}Cd{sub 1-x}S. The effects of solvents and compositions on the shapes and structures of Zn{sub x}Cd{sub 1-x}S SNCs have been investigated. The mixture solvent containing oleic acid, paraffin oil and oleylamine (such as a volume ratio: 1/2/1) results in the preparation of uniform Zn{sub x}Cd{sub 1-x}S nanoparticles with diameters of 7-13 nm, while pure oleylamine or the mixture of oleylamine and paraffin oil as the solvent leads to the formation of uniform Zn{sub x}Cd{sub 1-x}S nanorods. Monodisperse wurtzite Zn{sub x}Cd{sub 1-x}S nanorods with different compositions have been prepared in pure oleylamine, and no obvious effects of the compositions on their shapes are found. Their alloying nature is consistently confirmed by the results of high-resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD) and optical measurements. These alloyed Zn{sub x}Cd{sub 1-x}S nanorods exhibit composition-dependent absorption and emission properties, and therefore they can be promising candidates as emitting materials.

  18. Design, synthesis, molecular docking, anti-Proteus mirabilis and urease inhibition of new fluoroquinolone carboxylic acid derivatives.

    Science.gov (United States)

    Abdullah, Mohammed A A; Abuo-Rahma, Gamal El-Din A A; Abdelhafez, El-Shimaa M N; Hassan, Heba A; Abd El-Baky, Rehab M

    2017-02-01

    New hydroxamic acid, hydrazide and amide derivatives of ciprofloxacin in addition to their analogues of levofloxacin were prepared and identified by different spectroscopic techniques. Some of the prepared compounds revealed good activity against the urease splitting bacteria, Proteus mirabilis. The urease inhibitory activity was investigated using indophenol method. Most of the tested compounds showed better activity than the reference acetohydroxamic acid (AHA). The ciprofloxacin hydrazide derivative 3a and levofloxacin hydroxamic acid 7 experienced the highest activity (IC 50 =1.22μM and 2.20μM, respectively). Molecular docking study revealed high spontaneous binding ability of the tested compounds to the active site of urease. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Dansyl-labeled anionic amphiphile with a hexadecanoic carbon chain: Synthesis and detection for shape transitions in organized molecular assemblies

    Science.gov (United States)

    Gao, Lining; Xia, Huiyun; Wang, Xiaoman; Li, Li; Chen, Huaxin

    2015-03-01

    The probing properties of a new fluorophore-labeled anionic surfactant, sodium 16-(N-dansyl)aminocetylate (16-DAN-ACA) were investigated systematically in molecular assemblies, especially in the transitions between micelles and vesicles. 16-DAN-ACA can efficiently differentiate the two different aggregate types in mixed cationic and anionic surfactant systems. The fluorescence anisotropy of 16-DAN-ACA was found to be sensitive for directly detecting the micellar growth in micelles containing oppositely charged surfactants; both cationic cetyltrimethylammonium bromide (CTAB) systems and anionic sodium dodecyl sulfate (SDS) systems were studied. The results indicated that the 16-DAN-ACA is a good fluorescent probe for differentiating the different aggregates, and even more can be used to detect the micellar growth.

  20. Radiation synthesis of carboxymethyl cellulose hydrogel imprinted with β-estradiol for molecular recognition of endocrine disruptive chemicals

    International Nuclear Information System (INIS)

    Dela Cruz, Rafael Miguel M.; Estorque, Kit Joshua J.

    2015-03-01

    This study demonstrates the possibility of synthesizing molecularly imprinted polymers (MIP) using carboxymethyl cellulose in low concentration and pH, and intiated by γ-irradiation. The capability of the synthesized MIPs to absorb specific molecules was demonstrated using an NIP which adsorbing capability was successfully done. The selectivity of molecules is beyond the scope of this study. Right amount of monomer and solvents affects the capability of the imprinted polymer to be formed. It was also found out that it is important to acidify the CMC mixture to enable the cross-linking of CMC chains without using a cross-linker. It was confirmed that β-estradiol is soluble in acentonitrile by subjecting the mixture to UV-Vis spectrophotometry. The Incorporation of β-estradiol to CMC after γ-irradiation was also confirmed using FTIR-ATR. (author)

  1. Synthesis, antimalarial activity, heme binding and docking studies of N-substituted 4-aminoquinoline-pyrimidine molecular hybrids.

    Science.gov (United States)

    Maurya, Shiv Shyam; Khan, Shabana I; Bahuguna, Aparna; Kumar, Deepak; Rawat, Diwan S

    2017-03-31

    A series of novel N-substituted 4-aminoquinoline-pyrimidine hybrids have been synthesized via simple and economic route and evaluated for their antimalarial activity. Most compounds showed potent antimalarial activity against both CQ-sensitive and CQ-resistant strains with high selectivity index. All the compounds were found to be non-toxic to the mammalian cell lines. The most active compound 7b was analysed for heme binding activity using UV-spectrophotometer. Compound was found to interact with heme and a complex formation between compound and heme in a 1:1 stoichiometry ratio was determined using job plots. The interaction of these hybrids was also investigated by the molecular docking studies in the binding site of wild type Pf-DHFR-TS and quadruple mutant Pf-DHFR-TS. The pharmacokinetic property analysis of best active compounds was also studied by ADMET prediction. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  2. Rational design and synthesis of water-compatible molecularly imprinted polymers for selective solid phase extraction of amiodarone.

    Science.gov (United States)

    Muhammad, Turghun; Cui, Liu; Jide, Wang; Piletska, Elena V; Guerreiro, Antonio R; Piletsky, Sergey A

    2012-01-04

    Novel water-compatible molecularly imprinted polymers (MIPs) selective for amiodarone (AD) were designed via a new methodology which relies on screening library of non-imprinted polymers (NIPs). The NIP library consisted of eighteen cross-linked co-polymers synthesized from monomers commonly used in molecular imprinting. The binding capacity of each polymer in the library was analyzed in two different solvents. Binding in water was used to assess non-specific (hydrophobic) interactions and binding in an appropriate organic solvent was used to assess specific interactions. A good correlation was found between the screening tests and modeling of monomer-template interactions performed using computational approach. Additionally, analysis of template-monomer interactions was performed using UV-vis spectroscopy. As the result, 4-vinylpyridine (4-VP) was selected as the best monomer for developing MIP for AD. The 4-VP-based polymers demonstrated imprinting factor equal 3.9. The polymers performance in SPE was evaluated using AD and its structural analogues. The recovery of AD was as high as 96% when extracted from spiked phosphate buffer (pH 4.5) solution and 82.1% from spiked serum samples. The developed MIP shown as a material with specific binding to AD, comparing to its structural analogues, 1-(2-diethylaminoethoxy)-2,6-diiodo-4-nitrobenzene and lidocaine, which shown 9.9% and 25.4% of recovery from the buffer solution, correspondingly. We believe that the screening of NIP library could be proposed as an alternative to commonly used computational and combinatorial approaches. Copyright © 2011 Elsevier B.V. All rights reserved.

  3. Synthesis, anticancer activity and molecular docking studies on a series of heterocyclic trans-cyanocombretastatin analogues as antitubulin agents.

    Science.gov (United States)

    Penthala, Narsimha Reddy; Zong, Hongliang; Ketkar, Amit; Madadi, Nikhil Reddy; Janganati, Venumadav; Eoff, Robert L; Guzman, Monica L; Crooks, Peter A

    2015-03-06

    A series of heterocyclic combretastatin analogues have been synthesized and evaluated for their anticancer activity against a panel of 60 human cancer cell lines. The most potent compounds were two 3,4,5-trimethoxy phenyl analogues containing either an (Z)-indol-2-yl (8) or (Z)-benzo[b]furan-2-yl (12) moiety; these compounds exhibited GI50 values of Compounds 8, and 12 and two previously reported compounds in the same structural class, i.e. 29 and 31, also showed potent anti-leukemic activity against leukemia MV4-11 cell lines with LD50 values = 44 nM, 47 nM, 18 nM, and 180 nM, respectively. From the NCI anti-cancer screening results and the data from the in vitro toxicity screening on cultured AML cells, seven compounds: 8, 12, 21, 23, 25, 29 and 31 were screened for their in vitro inhibitory activity on tubulin polymerization in MV4-11 AML cells; at 50 nM, 8 and 29 inhibited polymerization of tubulin by >50%. The binding modes of the three most active compounds (8, 12 and 29) to tubulin were also investigated utilizing molecular docking studies. All three molecules were observed to bind in the same hydrophobic pocket at the interface of α- and β-tubulin that is occupied by colchicine, and were stabilized by van der Waals' interactions with surrounding tubulin residues. The results from the tubulin polymerization and molecular docking studies indicate that compounds 8 and 29 are the most potent anti-leukemic compounds in this structural class, and are considered lead compounds for further development as anti-leukemic drugs. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  4. d-Amino acids in molecular evolution in space - Absolute asymmetric photolysis and synthesis of amino acids by circularly polarized light.

    Science.gov (United States)

    Sugahara, Haruna; Meinert, Cornelia; Nahon, Laurent; Jones, Nykola C; Hoffmann, Søren V; Hamase, Kenji; Takano, Yoshinori; Meierhenrich, Uwe J

    2018-07-01

    Living organisms on the Earth almost exclusively use l-amino acids for the molecular architecture of proteins. The biological occurrence of d-amino acids is rare, although their functions in various organisms are being gradually understood. A possible explanation for the origin of biomolecular homochirality is the delivery of enantioenriched molecules via extraterrestrial bodies, such as asteroids and comets on early Earth. For the asymmetric formation of amino acids and their precursor molecules in interstellar environments, the interaction with circularly polarized photons is considered to have played a potential role in causing chiral asymmetry. In this review, we summarize recent progress in the investigation of chirality transfer from chiral photons to amino acids involving the two major processes of asymmetric photolysis and asymmetric synthesis. We will discuss analytical data on cometary and meteoritic amino acids and their potential impact delivery to the early Earth. The ongoing and future ambitious space missions, Hayabusa2, OSIRIS-REx, ExoMars 2020, and MMX, are scheduled to provide new insights into the chirality of extraterrestrial organic molecules and their potential relation to the terrestrial homochirality. This article is part of a Special Issue entitled: d-Amino acids: biology in the mirror, edited by Dr. Loredano Pollegioni, Dr. Jean-Pierre Mothet and Dr. Molla Gianluca. Copyright © 2018 Elsevier B.V. All rights reserved.

  5. Influence of ionizing radiation on synthesis and molecular heterogeneity of catalase in tissue culture of Rauwolfia serpentina; Vliyanie ioniziruyushchego izlucheniya na biosintez i molekulyarnuyu geterogennost' katalazy v kul'ture tkani Rauwolfia serpentina

    Energy Technology Data Exchange (ETDEWEB)

    Komov, V P; Bespalova, E V; Strelkova, M A [Sankt-Peterburgskaya Khimiko-Farmatsevticheskaya Akademiya, Kafedra Biologii, S.-Peterburg (Russian Federation)

    1998-12-01

    Changes in activity and molecular heterogeneity of catalase in tissue culture of Rauwolfia serpentina following irradiation in early growth period at the doses of 8 and 50 Gy has been studied. Ionizing radiation accelerate the synthesis and degradation rates of catalase and total protein. A comparative study of changes in enzyme and protein turnover during growth on irradiated and non-irradiated medium has been made.

  6. Synthesis of caffeic acid molecularly imprinted polymer microspheres and high-performance liquid chromatography evaluation of their sorption properties.

    Science.gov (United States)

    Valero-Navarro, Angel; Gómez-Romero, María; Fernández-Sánchez, Jorge F; Cormack, Peter A G; Segura-Carretero, Antonio; Fernández-Gutiérrez, Alberto

    2011-10-14

    In the current work, a molecularly imprinted polymer (MIP) has been synthesised and used to enable the extraction of a naturally-occurring antioxidant from complex media. More specifically, we describe the first example of a caffeic acid (CA) MIP which has been synthesised in the form of well-defined polymer microspheres, and its use for the extraction of CA from fruit juice sample. The CA MIP was synthesised by precipitation polymerisation using 4-vinylpyridine as functional monomer, divinylbenzene-80 as crosslinker and acetonitrile:toluene (75/25, v/v) as porogen. The particle sizing and morphological characterisation of the polymers was carried out by means of scanning electron microscopy (narrow particle size distribution; ∼5 and 1.5 μm particle diameters for the MIP and NIP [non-imprinted polymer], respectively) and nitrogen sorption porosimetry (specific surface areas of 340 and 350 m(2)g(-1), and specific pore volumes of 0.17 and 0.19 cm(3)g(-1) for the MIP and NIP, respectively). The polymers were evaluated further by batch rebinding experiments, and from the derived isotherms their binding capacity and binding strength were determined (number of binding sites (N(K))=0.6 and 0.3 mmol g(-1) for the MIP and NIP, respectively, and apparent average adsorption constant (K(N))=10.0 and 1.6L mmol(-1) for the MIP and NIP, respectively). To evaluate the molecular recognition character of the MIP it was packed into a stainless steel column (50 mm × 4.6 mm i.d.) and evaluated as an HPLC-stationary phase. The mobile phase composition, flow rate, and the elution profile were then optimised in order to improve the peak shape without negatively affecting the imprinting factor (IF). Very interesting, promising properties were revealed. The imprinting factor (IF) under the optimised conditions was 11.9. Finally, when the imprinted LC column was used for the selective recognition of CA over eight related compounds, very good selectivity was obtained. This outcome enabled

  7. Design, synthesis and molecular modeling of new 4-phenylcoumarin derivatives as tubulin polymerization inhibitors targeting MCF-7 breast cancer cells.

    Science.gov (United States)

    Batran, Rasha Z; Kassem, Asmaa F; Abbas, Eman M H; Elseginy, Samia A; Mounier, Marwa M

    2018-07-23

    A new set of 4-phenylcoumarin derivatives was designed and synthesized aiming to introduce new tubulin polymerization inhibitors as anti-breast cancer candidates. All the target compounds were evaluated for their cytotoxic effects against MCF-7 cell line, where compounds 2f, 3a, 3b, 3f, 7a and 7b, showed higher cytotoxic effect (IC 50  = 4.3-21.2 μg/mL) than the reference drug doxorubicin (IC 50  = 26.1 μg/mL), additionally, compounds 1 and 6b exhibited the same potency as doxorubicin (IC 50  = 25.2 and 28.0 μg/mL, respectively). The thiazolidinone derivatives 3a, 3b and 3f with potent and selective anticancer effects towards MCF-7 cells (IC 50  = 11.1, 16.7 and 21.2 μg/mL) were further assessed for tubulin polymerization inhibition effects which showed that the three compounds were potent tubulin polymerization suppressors with IC 50 values of 9.37, 2.89 and 6.13 μM, respectively, compared to the reference drug colchicine (IC 50  = 6.93 μM). The mechanistic effects on cell cycle progression and induction of apoptosis in MCF-7 cells were determined for compound 3a due to its potent and selective cytotoxic effects in addition to its promising tubulin polymerization inhibition potency. The results revealed that compound 3a induced cell cycle cessation at G2/M phase and accumulation of cells in pre-G1 phase and prevented its mitotic cycle, in addition to its activation of caspase-7 mediating apoptosis of MCF-7 cells. Molecular modeling studies for compounds 3a, 3b and 3f were carried out on tubulin crystallography, the results indicated that the compounds showed binding mode similar to the co-crystalized ligand; colchicine. Moreover, pharmacophore constructed models and docking studies revealed that thiazolidinone, acetamide and coumarin moieties are crucial for the activity. Molecular dynamics (MD) studies were carried out for the three compounds over 100 ps. MD results of compound 3a showed that it reached the stable state

  8. Pharmacological Activity and Clinical Use of PDRN

    Directory of Open Access Journals (Sweden)

    Francesco Squadrito

    2017-04-01

    Full Text Available PDRN is a proprietary and registered drug that possesses several activities: tissue repairing, anti-ischemic, and anti-inflammatory. These therapeutic properties suggest its use in regenerative medicine and in diabetic foot ulcers. PDRN holds a mixture of deoxyribonucleotides with molecular weights ranging between 50 and 1,500 KDa, it is derived from a controlled purification and sterilization process of Oncorhynchus mykiss (Salmon Trout or Oncorhynchus keta (Chum Salmon sperm DNA. The procedure guarantees the absence of active protein and peptides that may cause immune reactions. In vitro and in vivo experiments have suggested that PDRN most relevant mechanism of action is the engagement of adenosine A2A receptors. Besides engaging the A2A receptor, PDRN offers nucleosides and nucleotides for the so called “salvage pathway.” The binding to adenosine A2A receptors is a unique property of PDRN and seems to be linked to DNA origin, molecular weight and manufacturing process. In this context, PDRN represents a new advancement in the pharmacotherapy. In fact adenosine and dipyridamole are non-selective activators of adenosine receptors and they may cause unwanted side effects; while regadenoson, the only other A2A receptor agonist available, has been approved by the FDA as a pharmacological stress agent in myocardial perfusion imaging. Finally, defibrotide, another drug composed by a mixture of oligonucleotides, has different molecular weight, a DNA of different origin and does not share the same wound healing stimulating effects of PDRN. The present review analyses the more relevant experimental and clinical evidences carried out to characterize PDRN therapeutic effects.

  9. Pharmacological Activity and Clinical Use of PDRN

    Science.gov (United States)

    Squadrito, Francesco; Bitto, Alessandra; Irrera, Natasha; Pizzino, Gabriele; Pallio, Giovanni; Minutoli, Letteria; Altavilla, Domenica

    2017-01-01

    PDRN is a proprietary and registered drug that possesses several activities: tissue repairing, anti-ischemic, and anti-inflammatory. These therapeutic properties suggest its use in regenerative medicine and in diabetic foot ulcers. PDRN holds a mixture of deoxyribonucleotides with molecular weights ranging between 50 and 1,500 KDa, it is derived from a controlled purification and sterilization process of Oncorhynchus mykiss (Salmon Trout) or Oncorhynchus keta (Chum Salmon) sperm DNA. The procedure guarantees the absence of active protein and peptides that may cause immune reactions. In vitro and in vivo experiments have suggested that PDRN most relevant mechanism of action is the engagement of adenosine A2A receptors. Besides engaging the A2A receptor, PDRN offers nucleosides and nucleotides for the so called “salvage pathway.” The binding to adenosine A2A receptors is a unique property of PDRN and seems to be linked to DNA origin, molecular weight and manufacturing process. In this context, PDRN represents a new advancement in the pharmacotherapy. In fact adenosine and dipyridamole are non-selective activators of adenosine receptors and they may cause unwanted side effects; while regadenoson, the only other A2A receptor agonist available, has been approved by the FDA as a pharmacological stress agent in myocardial perfusion imaging. Finally, defibrotide, another drug composed by a mixture of oligonucleotides, has different molecular weight, a DNA of different origin and does not share the same wound healing stimulating effects of PDRN. The present review analyses the more relevant experimental and clinical evidences carried out to characterize PDRN therapeutic effects. PMID:28491036

  10. Effective synthesis of magnetic porous molecularly imprinted polymers for efficient and selective extraction of cinnamic acid from apple juices.

    Science.gov (United States)

    Shi, Shuyun; Fan, Dengxin; Xiang, Haiyan; Li, Huan

    2017-12-15

    An effective strategy was proposed to prepare novel magnetic porous molecularly imprinted polymers (MPMIPs) for highly selective extraction of cinnamic acid (CMA) from complex matrices. Characterization and various parameters affecting adsorption and desorption behaviors were investigated. Results revealed adsorption behavior between CMA and MPMIPs followed Freundlich equation adsorption isotherm with a maximum adsorption capacity at 4.35mg/g and pseudo-second-order reaction kinetics with equilibrium time at 60min. Subsequently, MPMIPs were successfully used to selectively extract CMA from apple juice with a relatively satisfactory recovery (92.7-101.4%). Coupling with high-performance liquid chromatography and ultraviolet detection (HPLC-UV), the limit of detection (LOD) for CMA was 0.006µg/mL, and the linear range (0.02-10μg/mL) was wide with correlation coefficient at 0.9995. Finally, the contents of CMA in two kinds of apple juices were determined as 0.132 and 0.120μg/mL. Results indicated the superiority of MPMIPs in the selective extraction field. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Molecular mechanisms of flavonoids in melanin synthesis and the potential for the prevention and treatment of melanoma.

    Science.gov (United States)

    Liu-Smith, Feng; Meyskens, Frank L

    2016-06-01

    Flavonoids are becoming popular nutraceuticals. Different flavonoids show similar or distinct biological effects on different tissues or cell types, which may limit or define their usefulness in cancer prevention and/or treatment application. This review focuses on a few selected flavonoids and discusses their functions in normal and transformed pigment cells, including cyanidin, apigenin, genistein, fisetin, EGCG, luteolin, baicalein, quercetin and kaempferol. Flavonoids exhibit melanogenic or anti-melanogenic effects mainly via transcriptional factor MiTF and/or the melanogenesis enzymes tyrosinase, DCT or TYRP-1. To identify a direct target has been a challenge as most studies were not able to discriminate whether the effect(s) of the flavonoid were from direct targeting or represented indirect effects. Flavonoids exhibit an anti-melanoma effect via inhibiting cell proliferation and invasion and inducing apoptosis. The mechanisms are also multi-fold, via ROS-scavenging, immune-modulation, cell cycle regulation and epigenetic modification including DNA methylation and histone deacetylation. In summary, although many flavonoid compounds are extremely promising nutraceuticals, their detailed molecular mechanism and their multi-target (simultaneously targeting multiple molecules) nature warrant further investigation before advancement to translational studies or clinical trials. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Fluorescent silver nanoclusters capped by polyethyleneimine with different molecular weights: Universal synthesis and application as a temperature sensor

    Energy Technology Data Exchange (ETDEWEB)

    Qu, Fei, E-mail: qufei3323@163.com [The Key Laboratory of Life-Organic Analysis, Qufu Normal University, Qufu 273165, Shandong (China); Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Qufu Normal University, Qufu 273165, Shandong (China); Li, Qingjin [The Key Laboratory of Life-Organic Analysis, Qufu Normal University, Qufu 273165, Shandong (China); Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Qufu Normal University, Qufu 273165, Shandong (China); You, Jinmao, E-mail: jmyou6304@163.com [The Key Laboratory of Life-Organic Analysis, Qufu Normal University, Qufu 273165, Shandong (China); Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Qufu Normal University, Qufu 273165, Shandong (China); Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810001 (China)

    2016-09-15

    In this paper, we developed a universal, applicable and simple synthetic method of Ag nanoclusters capped by polyethyleneimine (PEI) with different molecular weights (AgNC-PEIs), including Mw 600, 1300, 1800, 2000, 10,000, 25,000, 70,000, and 750,000. Using formaldehyde as the sole reducing agent, silver nanoclusters could be successfully prepared by using these templates. Subsequently, several characterization techniques were employed to investigate the properties of AgNC-PEIs, and the results suggested that these AgNC-PEIs had similar sizes, structures, and optical features. However, besides the common characteristics, different temperature sensitivities were found for these nanoclusters, in which AgNC-PEI 25000 was proper to be applied as a temperature sensor. With increasing temperature, the fluorescence quenched dramatically, and this change could be readily observed by naked eyes under UV light. Injection of these temperature sensitive nanoclusters into a glass tube, a simple thermometer could be fabricated easily, thus AgNC-PEI 25000 would be a promising candidate for temperature sensing as a visible indicator.

  13. Design, synthesis, biological assessment and molecular docking studies of new 2-aminoimidazole-quinoxaline hybrids as potential anticancer agents

    Science.gov (United States)

    Ghanbarimasir, Zahra; Bekhradnia, Ahmadreza; Morteza-Semnani, Katayoun; Rafiei, Alireza; Razzaghi-Asl, Nima; Kardan, Mostafa

    2018-04-01

    In a search for novel antiproliferative agents, a series of quinoxaline derivatives containing 2-aminoimidazole (8a-8x) were designed and synthesized. The structures of synthesized compounds were confirmed by IR, 1H NMR, 13C NMR, Mass Spectroscopy and analyzed using HSQC, COSY, ROESY, HMBC techniques. The anticancer activity of all derivatives were evaluated for colon cancer and breast cancer cell lines by the MTT assay and acridine orange/ethidium bromide double staining method. The anti-cancer effect in human colon cancer (HCT-116) and breast cancer (MCF-7) cell lines exhibited that compounds 8a, 8s, 8t, 8w, 8x appeared as potent antiproliferative agents and especially inhibited the human colon cancer cell proliferation with percentage of inhibition by over 50%. The most active compound was (E)-4-phenyl-1-((quinoxalin-2-ylmethylene)amino)-1H-imidazol-2-amine (8a) with the highest inhibition for MCF-7 (83.3%) and HCT-116 (70%) cell lines after 48 and 24 h, respectively. Molecular docking studies of these derivatives within c-kit active site as a validated target might be suggested them as appropriate candidates for further efforts toward more potent anticancer compounds.

  14. Synthesis of Cu and Ce co-doped ZnO nanoparticles: crystallographic, optical, molecular, morphological and magnetic studies

    Directory of Open Access Journals (Sweden)

    Rawat Mohit

    2017-07-01

    Full Text Available In the present research work, crystallographic, optical, molecular, morphological and magnetic properties of Zn1-xCuxO (ZnCu and Zn1-x-yCeyCuxO (ZnCeCu nanoparticles have been investigated. Polyvinyl alcohol (PVA coated ZnCu and ZnCeCu nanoparticles have been synthesized by chemical sol-gel method and thoroughly studied using various characterization techniques. X-ray diffraction pattern indicates the wurtzite structure of the synthesized ZnCu and ZnCeCu particles. Transmission electron microscopy analysis shows that the synthesized ZnCu and ZnCeCu particles are of spherical shape, having average sizes of 27 nm and 23 nm, respectively. The incorporation of Cu and Ce in the ZnO lattice has been confirmed through Fourier transform infrared spectroscopy. Room temperature photoluminescence spectra of the ZnO doped with Cu and co-doped Ce display two emission bands, predominant ultra-violet near-band edge emission at 409.9 nm (3 eV and a weak green-yellow emission at 432.65 nm (2.27 eV. Room temperature magnetic study confirms the diamagnetic behavior of ZnCu and ferromagnetic behavior of ZnCeCu.

  15. Structure-Based Design, Synthesis, Biological Evaluation, and Molecular Docking of Novel PDE10 Inhibitors with Antioxidant Activities

    Science.gov (United States)

    Li, Jinxuan; Chen, Jing-Yi; Deng, Ya-Lin; Zhou, Qian; Wu, Yinuo; Wu, Deyan; Luo, Hai-Bin

    2018-05-01

    Phosphodiesterase 10 is a promising target for the treatment of a series of central nervous system (CNS) diseases. Imbalance between oxidative stress and antioxidant defense systems as a universal condition in neurodegenerative disorders is widely studied as a potential therapy for CNS diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). To discover multifunctional pharmaceuticals as a treatment for neurodegenerative diseases, a series of quinazoline-based derivatives with PDE10 inhibitory activities and antioxidant activities were designed and synthesized. Nine out of thirteen designed compounds showed good PDE10 inhibition at the concentration of 1.0 μM. Among these compounds, eight exhibited moderate to excellent antioxidant activity with ORAC (oxygen radical absorbance capacity) value above 1.0. Molecular docking was performed for better understanding of the binding patterns of these compounds with PDE10. Compound 11e, which showed remarkable inhibitory activity against PDE10 and antioxidant activity may serve as a lead for the further modification.

  16. Molecular structure, chemical synthesis, and antibacterial activity of ABP-dHC-cecropin A from drury (Hyphantria cunea).

    Science.gov (United States)

    Zhang, Jiaxin; Movahedi, Ali; Wang, Xiaoli; Wu, Xiaolong; Yin, Tongming; Zhuge, Qiang

    2015-06-01

    The increasing resistance of bacteria and fungi to currently available antibiotics is a major concern worldwide, leading to enormous efforts to develop new antibiotics with new modes of actions. In this paper, cDNA encoding cecropin A was amplified from drury (Hyphantria cunea) (dHC) pupa fatbody total RNA using RT-PCR. The full-length dHC-cecropin A cDNA encoded a protein of 63 amino acids with a predicted 26-amino acid signal peptide and a 37-amino acid functional domain. We synthesized the antibacterial peptide (ABP) from the 37-amino acid functional domain (ABP-dHC-cecropin A), and amidated it via the C-terminus. Time-of-flight mass spectrometry showed its molecular weight to be 4058.94. The ABP-dHC-cecropin A was assessed in terms of its protein structure using bioinformatics and CD spectroscopy. The protein's secondary structure was predicted to be α-helical. In an antibacterial activity analysis, the ABP-dHC-cecropin A exhibited strong antibacterial activity against E. coli K12D31 and Agrobacterium EHA105. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. Synthesis of bis-indolylmethanes as new potential inhibitors of β-glucuronidase and their molecular docking studies.

    Science.gov (United States)

    Taha, Muhammad; Ullah, Hayat; Al Muqarrabun, Laode Muhammad Ramadhan; Khan, Muhammad Naseem; Rahim, Fazal; Ahmat, Norizan; Ali, Muhammad; Perveen, Shahnaz

    2018-01-01

    Thirty-two (32) bis-indolylmethane-hydrazone hybrids 1-32 were synthesized and characterized by 1 HNMR, 13 CNNMR and HREI-MS. All compounds were evaluated in vitro for β-glucuronidase inhibitory potential. All analogs showed varying degree of β-glucuronidase inhibitory potential ranging from 0.10 ± 0.01 to 48.50 ± 1.10 μM when compared with the standard drug d-saccharic acid-1,4-lactone (IC 50 value 48.30 ± 1.20 μM). Derivatives 1-32 showed the highest β-glucuronidase inhibitory potentials which is many folds better than the standard drug d-saccharic acid-1,4-lactone. Further molecular docking study validated the experimental results. It was proposed that bis-indolylmethane may interact with some amino acid residues located within the active site of β-glucuronidase enzyme. This study has culminated in the identification of a new class of potent β-glucuronidase inhibitors. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  18. Synthesis and Molecular Structures of (E-non-2-enoic Acid and (E-dec-2-enoic Acid

    Directory of Open Access Journals (Sweden)

    Marcel Sonneck

    2015-10-01

    Full Text Available The molecular structures of (E-non-2-enoic acid (C9 and (E-dec-2-enoic acid (C10 are reported. The title compounds were crystallized by slow evaporation of ethanolic solutions at −30 °C. C9 crystallizes in the monoclinic space group P21/c and C10 in the triclinic space group P-1, each with 4 molecules in the unit cell. The unit cell parameters for C9 are: a = 10.6473(4 Å, b = 5.2855(2 Å, c = 17.0313(7 Å; β = 106.0985(10° and V = 920.87(6 Å3. The unit cell parameters for C10 are: a = 4.1405(2 Å, b = 15.2839(6 Å, c = 17.7089(7 Å; α = 68.3291(11°, β = 83.3850(13°, γ = 85.0779(12° and V = 1033.39(8 Å3.

  19. Synthesis, spectroscopy, X-ray crystallography, DFT calculations, DNA binding and molecular docking of a propargyl arms containing Schiff base.

    Science.gov (United States)

    Balakrishnan, C; Subha, L; Neelakantan, M A; Mariappan, S S

    2015-11-05

    A propargyl arms containing Schiff base (L) was synthesized by the condensation of 1-[2-hydroxy-4-(prop-2-yn-1-yloxy)phenyl]ethanone with trans-1,2-diaminocyclohexane. The structure of L was characterized by IR, (1)H NMR, (13)C NMR and UV-Vis spectroscopy and by single crystal X-ray diffraction analysis. The UV-Visible spectral behavior of L in different solvents exhibits positive solvatochromism. Density functional calculation of the L in gas phase was performed by using DFT (B3LYP) method with 6-31G basis set. The computed vibrational frequencies and NMR signals of L were compared with the experimental data. Tautomeric stability study inferred that the enolimine is more stable than the ketoamine form. The charge delocalization has been analyzed using natural bond orbital (NBO) analysis. Electronic absorption and emission spectral studies were used to study the binding of L with CT-DNA. The molecular docking was done to identify the interaction of L with A-DNA and B-DNA. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Synthesis, crystal structure and magnetic characterization of a cyanide-bridged Mo-Ni nanosized molecular wheel

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Daopeng; Zhang, Hongyan; Wang, Ping [Shandong Univ. of Technology, College of Chemical Engineering, Zibo (China); Kong, Lingqian [Liaocheng Univ. (China). Dongchang College

    2015-11-01

    By using K{sub 4}[Mo(CN){sub 8}] and [Ni(L)(H{sub 2}O){sub 2}][ClO{sub 4}]{sub 2} as reagents (L = 2,12-dimethyl-3,7,11,17-tetraazabicyclo [11.3.1]heptadeca-1(17),13,15-triene), a new cyanide-bridged Mo-Ni complex containing the building blocks [Ni(H{sub 2}O)(L)]{sup 2+} and [Ni(L)]{sup 2+} bridged by [Mo(CN){sub 8}]{sup 4-} units has been obtained. The complex with the formula {[Ni(H_2O)(L)][Ni(L)][Mo(CN)_8]}{sub 6} . 36H{sub 2}O . 2CH{sub 3}OH (1) was characterized by elemental analysis, IR spectroscopy and single-crystal X-ray diffraction. The structure determination reveals an octadecanuclear cluster in the form of a 36-membered macrocycle, in which the largest intramolecular W..W and Ni..Ni distances are 16.5 and 14.4 Aa, respectively, indicating that complex 1 is a nanosized molecular wheel. Investigation of its magnetic properties has shown weak antiferromagnetic coupling between the adjacent Ni(II) ions bridged by the diamagnetic [Mo(CN){sub 8}]{sup 4-} ions.

  1. Synthesis, molecular structure, spectroscopic properties and stability of (Z)-N-methyl-C-2,4,6-trimethylphenylnitrone

    Science.gov (United States)

    Lasri, Jamal; Ismail, Ali I.; Haukka, Matti; Soliman, Saied M.

    2015-02-01

    New N-methyl-C-2,4,6-trimethylphenylnitrone 1 has been synthesized starting from N-methylhydroxylamine and mesitaldehyde. The product was fully characterized using different spectroscopic techniques; FTIR, NMR, UV-Vis, high resolution mass spectrometry and X-ray diffraction. The relative stability and percent of population of its two possible isomers (E and Z) were calculated using the B3LYP/6-311++G(d,p) method in gas phase and in solution. In agreement with the X-ray results, it was found that Z-isomer is the most stable one in both gas phase and solution. The molecular geometry, vibrational frequencies, gauge-including atomic orbital (GIAO), and chemical shift values were also calculated using the same level of theory. The TD-DFT results of the studied nitrone predicted a π-π∗ transition band at 285.1 nm (fosc = 0.3543) in the gas phase. The rest of the spectral bands undergo either hyperchromic or hypsochromic shifts in the presence of solvent. Polarizability and HOMO-LUMO gap values were used to predict the nonlinear optical properties (NLO) of the studied compound. NBO analysis has been used to determine the most accurate Lewis structure of the studied molecule.

  2. Iomazenil: pharmacological and animal data

    International Nuclear Information System (INIS)

    Beer, H.F.; Blaeuenstein, P.A.; Hasler, P.H.; Schubiger, P.A.; Hunkeler, W.; Bibettu, E.P.; Pieri, L.; Grayson Richards, J.

    1990-01-01

    The flumazenil analogue Ro 16-0154 (Iomazenil), a benzodiazepine partial inverse agonist, has been labelled by halogen exchange to enable SPECT investigations of central benzodiazepine receptors in human brain. The purified 123 I-Ro 16-0154 was found to be stable in rat brain preparations and to be metabolized in rat liver preparations. Its pharmacological properties were comparable to those of flumazenil with the exception of the antagonism of diazepam versus pentylenetetrazol. Biodistribution in rats (1 h p.i.) resulted in a high brain to blood ratio of 16. Clinical studies revealed images of the bezodiazepine receptor density in the brain. (author) 9 figs., 3 tabs., 27 refs

  3. Pharmacological approach to acute pancreatitis

    DEFF Research Database (Denmark)

    Bang, U.C.; Semb, S.; Nøjgaard, Camilla

    2008-01-01

    The aim of the present review is to summarize the current knowledge regarding pharmacological prevention and treatment of acute pancreatitis (AP) based on experimental animal models and clinical trials. Somatostatin (SS) and octreotide inhibit the exocrine production of pancreatic enzymes and may...... be useful as prophylaxis against post endoscopic retrograde cholangiopancreatography pancreatitis (PEP). The protease inhibitor gabexate mesilate (GM) is used routinely as treatment to AP in some countries, but randomized clinical trials and a meta-analysis do not support this practice. Nitroglycerin (NGL...

  4. Pharmacological approach to acute pancreatitis

    DEFF Research Database (Denmark)

    Bang, Ulrich-Christian; Semb, Synne; Nojgaard, Camilla

    2008-01-01

    -steroidal anti-inflammatory drugs (NSAID) indomethacin and diclofenac have in randomized studies showed potential as prophylaxis against PEP. Interleukin 10 (IL-10) is a cytokine with anti-inflammatory properties but two trials testing IL-10 as prophylaxis to PEP have returned conflicting results. Antibodies...... pharmacological treatment of AP is limited and studies on the effect of potent anti-inflammatory drugs are warranted....... against tumor necrosis factor-alpha (TNF-alpha) have a potential as rescue therapy but no clinical trials are currently being conducted. The antibiotics beta-lactams and quinolones reduce mortality when necrosis is present in pancreas and may also reduce incidence of infected necrosis. Evidence based...

  5. Gaultheria: Phytochemical and Pharmacological Characteristics

    Directory of Open Access Journals (Sweden)

    Ren-Bing Shi

    2013-09-01

    Full Text Available The genus Gaultheria, comprised of approximately 134 species, is mostly used in ethnic drugs to cure rheumatism and relieve pain. Phytochemical investigations of the genus Gaultheria have revealed the presence of methyl salicylate derivatives, C6-C3 constituents, organic acids, terpenoids, steroids, and other compounds. Methyl salicylate glycoside is considered as a characteristic ingredient in this genus, whose anti-rheumatic effects may have a new mechanism of action. In this review, comprehensive information on the phytochemistry, volatile components and the pharmacology of the genus Gaultheria is provided to explore its potential and advance research.

  6. Molecular imaging of σ receptors: synthesis and evaluation of the potent σ1 selective radioligand [18F]fluspidine

    International Nuclear Information System (INIS)

    Fischer, Steffen; Hiller, Achim; Deuther-Conrad, Winnie; Scheunemann, Matthias; Steinbach, Joerg; Brust, Peter; Wiese, Christian; Grosse Maestrup, Eva; Schepmann, Dirk; Wuensch, Bernhard

    2011-01-01

    Neuroimaging of σ 1 receptors in the human brain has been proposed for the investigation of the pathophysiology of neurodegenerative and psychiatric diseases. However, there is a lack of suitable 18 F-labelled PET radioligands for that purpose. The selective σ 1 receptor ligand [ 18 F]fluspidine (1'-benzyl-3-(2-[ 18 F]fluoroethyl)-3H-spiro[[2]benzofuran-1,4'-piperidine]) was synthesized by nucleophilic 18 F - substitution of the tosyl precursor. In vitro receptor binding affinity and selectivity were assessed by radioligand competition in tissue homogenate and autoradiographic approaches. In female CD-1 mice, in vivo properties of [ 18 F]fluspidine were evaluated by ex vivo brain section imaging and organ distribution of intravenously administered radiotracer. Target specificity was validated by organ distribution of [ 18 F]fluspidine after treatment with 1 mg/kg i.p. of the σ receptor antagonist haloperidol or the emopamil binding protein (EBP) inhibitor tamoxifen. In vitro metabolic stability and in vivo metabolism were investigated by LC-MS n and radio-HPLC analysis. [ 18 F]Fluspidine was obtained with a radiochemical yield of 35-45%, a radiochemical purity of ≥ 99.6% and a specific activity of 150-350 GBq/μmol (n = 6) within a total synthesis time of 90-120 min. In vitro, fluspidine bound specifically and with high affinity to σ 1 receptors (K i = 0.59 nM). In mice, [ 18 F]fluspidine rapidly accumulated in brain with uptake values of 3.9 and 4.7%ID/g and brain to blood ratios of 7 and 13 at 5 and 30 min after intravenous application of the radiotracer, respectively. By ex vivo autoradiography of brain slices, resemblance between binding site occupancy of [ 18 F]fluspidine and the expression of σ 1 receptors was shown. The radiotracer uptake in the brain as well as in peripheral σ 1 receptor expressing organs was significantly inhibited by haloperidol but not by tamoxifen. Incubation with rat liver microsomes led to a fast biotransformation of

  7. Molecular Electronics

    DEFF Research Database (Denmark)

    Jennum, Karsten Stein

    This thesis includes the synthesis and characterisation of organic compounds designed for molecular electronics. The synthesised organic molecules are mainly based on two motifs, the obigo(phenyleneethynylenes) (OPE)s and tetrathiafulvalene (TTF) as shown below. These two scaffolds (OPE and TTF......) are chemically merged together to form cruciform-like structures that are an essential part of the thesis. The cruciform molecules were subjected to molecular conductance measurements to explore their capability towards single-crystal field-effect transistors (Part 1), molecular wires, and single electron......, however, was obtained by a study of a single molecular transistor. The investigated OPE5-TTF compound was captured in a three-terminal experiment, whereby manipulation of the molecule’s electronic spin was possible in different charge states. Thus, we demonstrated how the cruciform molecules could...

  8. Synthesis route and three different core-shell impacts on magnetic characterization of gadolinium oxide-based nanoparticles as new contrast agents for molecular magnetic resonance imaging

    Science.gov (United States)

    Azizian, Gholamreza; Riyahi-Alam, Nader; Haghgoo, Soheila; Moghimi, Hamid Reza; Zohdiaghdam, Reza; Rafiei, Behrooz; Gorji, Ensieh

    2012-10-01

    Despite its good resolution, magnetic resonance imaging intrinsically has low sensitivity. Recently, contrast agent nanoparticles have been used as sensitivity and contrast enhancer. The aim of this study was to investigate a new controlled synthesis method for gadolinium oxide-based nanoparticle preparation. For this purpose, diethyleneglycol coating of gadolinium oxide (Gd2O3-DEG) was performed using new supervised polyol route, and small particulate gadolinium oxide (SPGO) PEGylation was obtained with methoxy-polyethylene-glycol-silane (550 and 2,000 Da) coatings as SPGO-mPEG-silane550 and 2,000, respectively. Physicochemical characterization and magnetic properties of these three contrast agents in comparison with conventional Gd-DTPA were verified by dynamic light scattering transmission electron microscopy, Fourier transform infrared spectroscopy, inductively coupled plasma, X-ray diffraction, vibrating sample magnetometer, and the signal intensity and relaxivity measurements were performed using 1.5-T MRI scanner. As a result, the nanoparticle sizes of Gd2O3-DEG, SPGO-mPEG-silane550, and SPGO-mPEG-silane2000 could be reached to 5.9, 51.3, 194.2 nm, respectively. The image signal intensity and longitudinal ( r 1) and transverse relaxivity ( r 2) measurements in different concentrations (0.3 to approximately 2.5 mM), revealed the r 2/ r 1 ratios of 1.13, 0.89, 33.34, and 33.72 for Gd-DTPA, Gd2O3-DEG, SPGO-mPEG-silane550, and SPGO-mPEG-silane2000, respectively. The achievement of new synthesis route of Gd2O3-DEG resulted in lower r 2/ r 1 ratio for Gd2O3-DEG than Gd-DTPA and other previous synthesized methods by this and other groups. The smaller r 2/ r 1 ratios of two PEGylated-SPGO contrast agents in our study in comparison with r 2/ r 1 ratio of previous PEGylation ( r 2/ r 1 = 81.9 for mPEG-silane 6,000 MW) showed that these new three introduced contrast agents could potentially be proper contrast enhancers for cellular and molecular MR imaging.

  9. Geometrically and conformationally restrained cinnamoyl compounds as inhibitors of HIV-1 integrase: synthesis, biological evaluation, and molecular modeling.

    Science.gov (United States)

    Artico, M; Di Santo, R; Costi, R; Novellino, E; Greco, G; Massa, S; Tramontano, E; Marongiu, M E; De Montis, A; La Colla, P

    1998-10-08

    Various cinnammoyl-based structures were synthesized and tested in enzyme assays as inhibitors of the HIV-1 integrase (IN). The majority of compounds were designed as geometrically or conformationally constrained analogues of caffeic acid phenethyl ester (CAPE) and were characterized by a syn disposition of the carbonyl group with respect to the vinylic double bond. Since the cinnamoyl moiety present in flavones such as quercetin (inactive on HIV-1-infected cells) is frozen in an anti arrangement, it was hoped that fixing our compounds in a syn disposition could favor anti-HIV-1 activity in cell-based assays. Geometrical and conformational properties of the designed compounds were taken into account through analysis of X-ray structures available from the Cambridge Structural Database. The polyhydroxylated analogues were prepared by reacting 3,4-bis(tetrahydropyran-2-yloxy)benzaldehyde with various compounds having active methylene groups such as 2-propanone, cyclopentanone, cyclohexanone, 1,3-diacetylbenzene, 2, 4-dihydroxyacetophenone, 2,3-dihydro-1-indanone, 2,3-dihydro-1, 3-indandione, and others. While active against both 3'-processing and strand-transfer reactions, the new compounds, curcumin included, failed to inhibit the HIV-1 multiplication in acutely infected MT-4 cells. Nevertheless, they specifically inhibited the enzymatic reactions associated with IN, being totally inactive against other viral (HIV-1 reverse transcriptase) and cellular (RNA polymerase II) nucleic acid-processing enzymes. On the other hand, title compounds were endowed with remarkable antiproliferative activity, whose potency correlated neither with the presence of catechols (possible source of reactive quinones) nor with inhibition of topoisomerases. The SARs developed for our compounds led to novel findings concerning the molecular determinants of IN inhibitory activity within the class of cinnamoyl-based structures. We hypothesize that these compounds bind to IN featuring the

  10. Selective kainate receptor (GluK1) ligands structurally based upon1H-Cyclopentapyrimidin-2,4(1H,3H)-dione: synthesis, molecular modeling, and pharmacological and biostructural characterization

    DEFF Research Database (Denmark)

    Venskutonyte, Raminta; Butini, Stefania; Coccone, Salvatore Sanna

    2011-01-01

    The physiological function of kainate receptors (GluK1- GluK5) in the central nervous system is not fully understood yet. With the aim of developing potent and selective GluK1 ligands, we have synthesized a series of new thiophene-based GluK1 agonists (6a-c) and antagonists (7a-d). Pharmacologica...

  11. Selective agonists at group II metabotropic glutamate receptors: synthesis, stereochemistry, and molecular pharmacology of (S)- and (R)-2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid

    DEFF Research Database (Denmark)

    Clausen, Rasmus P; Bräuner-Osborne, Hans; Greenwood, Jeremy R

    2002-01-01

    Homologation of analogues of the central excitatory neurotransmitter glutamic acid (Glu), in which the distal carboxy group has been bioisosterically replaced by acidic heterocyclic units, has previously provided subtype selective ligands for metabotropic Glu receptors (mGluRs). The (S......)-form of the 1,2,5-thiadiazol-3-ol Glu analogue, 2-amino-3-(4-hydroxy[1,2,5]thiadiazol-3-yl)propionic acid (TDPA, 6), is an 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor agonist, which in addition stereospecifically activates group I mGluRs. We have now synthesized the (S)- and (R......)-forms of 2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid (homo-TDPA, 7) and shown that whereas neither enantiomer interacts with AMPA receptors, (S)- and (R)-7 appear to be selective and equipotent agonists at group II mGluRs as represented by the mGluR2 subtype. The activities of (S)- and (R)-7...

  12. Pharmacologic therapy for acute pancreatitis

    Science.gov (United States)

    Kambhampati, Swetha; Park, Walter; Habtezion, Aida

    2014-01-01

    While conservative management such as fluid, bowel rest, and antibiotics is the mainstay of current acute pancreatitis management, there is a lot of promise in pharmacologic therapies that target various aspects of the pathogenesis of pancreatitis. Extensive review of preclinical studies, which include assessment of therapies such as anti-secretory agents, protease inhibitors, anti-inflammatory agents, and anti-oxidants are discussed. Many of these studies have shown therapeutic benefit and improved survival in experimental models. Based on available preclinical studies, we discuss potential novel targeted pharmacologic approaches that may offer promise in the treatment of acute pancreatitis. To date a variety of clinical studies have assessed the translational potential of animal model effective experimental therapies and have shown either failure or mixed results in human studies. Despite these discouraging clinical studies, there is a great clinical need and there exist several preclinical effective therapies that await investigation in patients. Better understanding of acute pancreatitis pathophysiology and lessons learned from past clinical studies are likely to offer a great foundation upon which to expand future therapies in acute pancreatitis. PMID:25493000

  13. Pharmacological management of panic disorder

    Directory of Open Access Journals (Sweden)

    Carlo Marchesi

    2008-03-01

    Full Text Available Carlo MarchesiPsychiatric Section, Department of Neuroscience, University of Parma, Parma, ItalyAbstract: Panic disorder (PD is a disabling condition which appears in late adolescence or early adulthood and affects more frequently women than men. PD is frequently characterized by recurrences and sometimes by a chronic course and, therefore, most patients require longterm treatments to achieve remission, to prevent relapse and to reduce the risks associated with comorbidity. Pharmacotherapy is one of the most effective treatments of PD. In this paper, the pharmacological management of PD is reviewed. Many questions about this effective treatment need to be answered by the clinician and discussed with the patients to improve her/his collaboration to the treatment plan: which is the drug of choice; when does the drug become active; which is the effective dose; how to manage the side effects; how to manage nonresponse; and how long does the treatment last. Moreover, the clinical use of medication in women during pregnancy and breastfeeding or in children and adolescents was reviewed and its risk-benefit balance discussed.Keywords: panic disorder, pharmacological treatment, treatment guidelines

  14. Portulaca oleracea L.: a review of phytochemistry and pharmacological effects.

    Science.gov (United States)

    Zhou, Yan-Xi; Xin, Hai-Liang; Rahman, Khalid; Wang, Su-Juan; Peng, Cheng; Zhang, Hong

    2015-01-01

    Portulaca oleracea L., belonging to the Portulacaceae family, is commonly known as purslane in English and Ma-Chi-Xian in Chinese. It is a warm-climate, herbaceous succulent annual plant with a cosmopolitan distribution. It is eaten extensively as a potherb and added in soups and salads around the Mediterranean and tropical Asian countries and has been used as a folk medicine in many countries. Diverse compounds have been isolated from Portulaca oleracea, such as flavonoids, alkaloids, polysaccharides, fatty acids, terpenoids, sterols, proteins vitamins and minerals. Portulaca oleracea possesses a wide spectrum of pharmacological properties such as neuroprotective, antimicrobial, antidiabetic, antioxidant, anti-inflammatory, antiulcerogenic, and anticancer activities. However, few molecular mechanisms of action are known. This review provides a summary of phytochemistry and pharmacological effects of this plant.

  15. Pharmacological and non- pharmacological treatment of hypertension: A review article

    Directory of Open Access Journals (Sweden)

    Marjan Seyedmazhari

    2013-01-01

    Full Text Available BACKGROUND: Hypertension is a worldwide epidemic disease. It is more common and more severe in elderly persons. Various studies however have estimated 41.9 million men and 27.8 million women to have prehypertension. Diagnosis and early treatment of prehypertension are of utmost importance. Although hypertension is usually divided into 2 general categories of essential (primary and secondary hypertension, the initial treatment for hypertension often depends on its stage which is determined by systolic and diastolic blood pressure. Lifestyle modification is the first step in treating stage one hypertension. Pharmaceutical treatments including diuretics, angiotensin converting enzyme (ACE inhibitors, calcium blockers, beta blockers, and angiotensin receptor blockers will be recommended if lifestyle modification fails to control blood pressure.    METHODS: The PubMed database was searched by a number of keywords including hypertension, pharmaceutical treatment, and non-pharmaceutical treatment. The results were limited by determining a date range of 2008-11.    RESULTS: High blood pressure causes major health problems for many people around the world. It should be controlled because of its high mortality and morbidity. However, in order to select an appropriate treatment modality, it is initially important to diagnose the kinds and stages of hypertension. Pharmaceutical or non-pharmaceutical treatments can then be employed to control this serious disease.    CONCLUSION: Treating hypertension depends on the kinds and stages of this disease. Several tips should be considered when selecting a method of treatment.       Keywords: Hypertension, Pharmacological treatment, Non-pharmacological treatment

  16. Synthesis of new PET radiotracer 18F-Fluoro Ethyl Losartan for molecular imaging of AT1R in tumor model

    International Nuclear Information System (INIS)

    Ortega Pijeira, Martha Sahylí; Rodríguez Riera, Zalua; Pérez Nario, Arian; Soares Bernardes, Emerson; Gonçalves Nunes, Paulo; Sérgio Ivone Carvalho; Chammas, Roger; Elsinga, Philip

    2016-01-01

    Losartan is an antagonist of type 1 angiotensin II receptor (AT1R) and a drug widely used for the treatment of hypertension. Several studies have shown that losartan derivatives radiolabelled beta and gamma detect and quantify the expression of AT1R in some organs such as the heart and kidneys through the use of molecular imaging techniques. Furthermore, an expression of the AT1 receptor has been described in various types of tumors and correlates with an increased proliferation index and angiogenesis. Several groups have confirmed the antitumor effect of losartan potential, for example, in reducing tumor growth of a subtype of breast cancer. In this paper the synthesis of new radiotracer 18 F-fluoroethyl Losartan, and its standard compound is described. The standard compound was synthesized via fluoroethyl losartan reaction between losartan and fluoroethyl tosylate potassium in dimethylformamide at 80 ° C for 2 hours under argon. The base used in the reaction was sodium hydride. a complex mixture of products including the desired product fluoroethyl losartan with 14% yield was obtained. This compound was analyzed by HPLC and characterized by widely different spectroscopic techniques: 1H NMR, 13C NMR, 19F NMR, HSQC, HMBC and mass spectroscopy. 18 F synthesis losartan-fluoroethyl by indirect labeling of losartan potassium with 18 F-fluoroethyl prosthetic group tosylate to 80°C for 20 min under nitrogen is achieved manually, using hydrate of sodium as base. The compound was purified by preparative HPLC semi-(Acetonitrile (A) / agua 0 ,1% TFA (B), 60-80% A for 30 min, 4 mL / min, tR 8.9 min) and was obtained in 8 -21% (n = 5) and higher yield 99% radiochemical purity. The product identity was confirmed by comparison of residence times of the labeled product and the standard compound, HPLC analysis obtained under the same conditions: Acetonitrile (A) / agua 0 ,1% TFA (B), 55:45 A / B , 1 mL / min, tR 9.6 min. The 18 F-labeled prosthetic group fluoroethyl tosylate was

  17. Microwave synthesis of gibberellin acid 3 magnetic molecularly imprinted polymer beads for the trace analysis of gibberellin acids in plant samples by liquid chromatography-mass spectrometry detection.

    Science.gov (United States)

    Zhang, Zhuomin; Tan, Wei; Hu, Yuling; Li, Gongke; Zan, Song

    2012-02-21

    In this study, novel GA3 magnetic molecularly imprinted polymer (mag-MIP) beads were synthesized by a microwave irradiation method, and the beads were applied for the trace analysis of gibberellin acids (GAs) in plant samples including rice and cucumber coupled with high performance liquid chromatography-mass spectrometry (HPLC-MS). The microwave synthetic procedure was optimized in detail. In particular, the interaction between GA3 and functional monomers was further studied for the selection of the optimal functional monomers during synthesis. It can be seen that the interaction between GA3 and acrylamide (AM) finally selected was stronger than that between GA3 and other functional monomers. GA3 mag-MIP beads were characterized by a series of physical tests. GA3 mag-MIP beads had a porous and homogeneous surface morphology with stable chemical, thermal and magnetic properties. Moreover, GA3 mag-MIP beads demonstrated selective and specific absorption behavior for the target compounds during unsaturated extraction, which resulted in a higher extraction capacity (∼708.4 pmol for GA3) and selectivity than GA3 mag-non-imprinted polymer beads. Finally, an analytical method of GA3 mag-AM-MIP bead extraction coupled with HPLC-MS detection was established and applied for the determination of trace GA1, GA3, GA4 and GA7 in rice and cucumber samples. It was satisfactory that GA4 could be actually found to be 121.5 ± 1.4 μg kg(-1) in real rice samples by this novel analytical method. The recoveries of spiked rice and cucumber samples were found to be 76.0-109.1% and 79.9-93.6% with RSDs of 2.8-8.8% and 3.1-7.7% (n = 3), respectively. The proposed method is efficient and applicable for the trace analysis of GAs in complicated plant samples.

  18. Laser synthesis of a copper–single-walled carbon nanotube nanocomposite via molecular-level mixing and non-equilibrium solidification

    International Nuclear Information System (INIS)

    Tu, Jay F; Rajule, Nilesh; Molian, Pal; Liu, Yi

    2016-01-01

    A copper–single-walled carbon nanotube (Cu–SWCNT) metal nanocomposite could be an ideal material if it can substantially improve the strength of copper while preserving the metal’s excellent thermal and electrical properties. However, synthesis of such a nanocomposite is highly challenging, because copper and SWCNTs do not form intermetallic compounds and are insoluble; as a result, there are serious issues regarding wettability and fine dispersion of SWCNTs within the copper matrix. In this paper we present a novel wet process, called the laser surface implantation process (LSI), to synthesize Cu–SWCNT nanocomposites by mixing SWCNTs into molten copper. The LSI process includes drilling several microholes on a copper substrate, filling the microholes with SWCNTs suspended in solution, and melting the copper substrate to create a micro-well of molten copper. The molten copper advances radially outward to engulf the microholes with pre-deposited SWCNTs to form the Cu–SWCNT implant upon solidification. Rapid and non-equilibrium solidification is achieved due to copper’s excellent heat conductivity, so that SWCNTs are locked in position within the copper matrix without agglomerating into large clusters. This wet process is very different from the typical dry processes used in powder metallurgy. Very high hardness improvement, up to 527% over pure copper, was achieved, confirmed by micro-indentation tests, with only a 0.23% SWCNT volume fraction. The nanostructure of the nanocomposite was characterized by TEM imaging, energy-dispersive x-ray spectroscopy mapping and spectroscopy measurements. The SWCNTs were found to be finely dispersed within the copper matrix with cluster sizes in the range of nanometers, achieving the goal of molecular-level mixing. (paper)

  19. Synthesis, spectroscopic properties, molecular docking, anti-colon cancer and anti-microbial studies of some novel metal complexes for 2-amino-4-phenylthiazole derivative

    Science.gov (United States)

    Al-Harbi, Sami A.; Bashandy, Mahmoud S.; Al-Saidi, Hammed M.; Emara, Adel A. A.; Mousa, Tarek A. A.

    2015-06-01

    This article describes the synthesis of novel bidentate Schiff base (H2L) from condensation of 2-amino-4-phenylthiazole (APT) with 4,6-diacetylresorcinol (DAR) in the molar ratio 2:1. We studied interaction of ligand (H2L) with transition metal ions such as Cr(III), Fe(III), Cu(II), Zn(II) and Cd(II). The ligand (H2L) has two bidentate sets of (N-O) units which can coordinate with two metal ions to afford novel binuclear metal complexes. The directions of coordinate bonds are from nitrogen atoms of azomethine groups and oxygen atoms of the phenolic groups. Structures of the newly synthesized complexes were confirmed by elemental analysis, IR, UV, 1H NMR, ESR, TGA and mass spectral data. All of the newly synthesized complexes were evaluated for their antibacterial and anti-fungal activities. They were also evaluated for their in vitro anticancer activity against human colon carcinoma cells (HCT-116) and mammalian cells of African green monkey kidney (VERO). The Cu(II) complex with selectivity index (S.I.) = 21.26 exhibited better activity than methotrexate (MTX) as a reference drug with S.I. value = 13.30, while Zn(II) complex with S.I. value = 10.24 was found to be nearly as active as MTX. Molecular docking studies further helped in understanding the mode of action of the compounds through their various interactions with active sites of dihydrofolate reductase (DHFR) enzyme. The observed activity of Fe(III) and Cu(II) complexes gave rise to the conclusion that they might exert their action through inhibition of the DHFR enzyme.

  20. Pharmacological Treatment of Binge Eating Disorder: Update Review and Synthesis

    Science.gov (United States)

    Reas, Deborah L.; Grilo, Carlos M.

    2015-01-01

    Introduction Binge-eating disorder (BED), a formal eating-disorder diagnosis in the DSM-5, is characterized by recurrent binge-eating, marked distress about binge-eating, and the absence of extreme weight compensatory behaviors. BED is more prevalent than other eating-disorders, with broader distribution across age, sex, and ethnic/racial groups, and is associated strongly with obesity and heightened risk for psychiatric/medical comorbidities. Areas Covered This article provides an overview of pharmacotherapy for BED with a focus on III randomized controlled trials (RCTs). The search with minimal methodological inclusion requirements yielded 22 RCTs investigating several different medication classes; most were pharmacotherapy-only trials with eight trials testing combination approaches with psychological-behavioral methods. Expert Opinion The evidence base regarding pharmacotherapy for BED remains limited, although this year the FDA approved the first medication (i.e., lisdexamfetamine dimesylate; LDX) specifically for moderate-to-severe BED. Data from RCTs suggests certain medications are superior to placebo for reducing binge-eating over the short-term; almost no data exist regarding longer-term effects of pharmacotherapy for BED. Except for topiramate, which significantly reduces both binge-eating and weight, tested medications yield minimal weight loss and LDX is not indicated for weight loss. Psychological-behavioral and combination approaches with certain medications yield superior outcomes to pharmacotherapy-only acutely and over longer-term follow-up. PMID:26044518

  1. Oxaprozin: Synthesis, SAR study, physico-chemical characteristics and pharmacology

    Directory of Open Access Journals (Sweden)

    Božić Bojan Đ.

    2011-01-01

    Full Text Available Oxaprozin (3-(4,5-difeniloksazol-2-ylpropanoic acid is a nonsteroidal anti-inflammatory drug (NSAID used in the treatment of numerous inflammatory musculoskeletal diseases, including rheumatoid arthritis, osteoarthritis, tendonitis, ankylosing spondylitis and bursitis. It is the first representative member of the diaryl-substituted heterocyclic compounds, which have found clinical use as selective cyclooxygenase-2 (COX-2 inhibitors. U.S. Food and Drug Administration (FDA approved its official use in 1992. Both anti-inflammatory and analgesic properties of oxaprozin are mainly due to the potent inhibition of COX. However, oxaprozin-induced benefits might be also regulated by other COX-independent pathways. It has been shown that oxaprozin induced direct proapoptotic effects in CD40L-treated human monocytes independently of COX inhibition. It also has several advantages in the treatment of inflammatory diseases in comparison to other NSAIDs such as aspirin, naproxen, indomethacin and phenylbutazone, which enabled oxaprozin to become one of the most used NSAIDs in America. Oxaprozin, as other members of the group of NSAIDs, can cause gastrointestinal complications, but significantly lower due to relatively high pKa value. In this paper, importance of oxaprozin in the treatment of arthritis and its pharmacokinetic properties were described, therewith its activity and side effects were compared with other commercially available anti-inflammatory drugs.

  2. Synthesis and pharmacological evaluation of neurosteroid photoaffinity ligands

    Energy Technology Data Exchange (ETDEWEB)

    Savechenkov, Pavel Y.; Chiara, David C.; Desai, Rooma; Stern, Alexander T.; Zhou, Xiaojuan; Ziemba, Alexis M.; Szabo, Andrea L.; Zhang, Yinghui; Cohen, Jonathan B.; Forman, Stuart A.; Miller, Keith W.; Bruzik, Karol S.

    2017-08-01

    Neuroactive steroids are potent positive allosteric modulators of GABAA receptors (GABAAR), but the locations of their GABAAR binding sites remain poorly defined. To discover these sites, we synthesized two photoreactive analogs of alphaxalone, an anesthetic neurosteroid targeting GABAAR, 11β-(4-azido-2,3,5,6-tetrafluorobenzoyloxy)allopregnanolone, (F4N3Bzoxy-AP) and 11-aziallopregnanolone (11-AziAP). Both photoprobes acted with equal or higher potency than alphaxalone as general anesthetics and potentiators of GABAAR responses, left-shifting the GABA concentration – response curve for human α1β3γ2 GABAARs expressed in Xenopus oocytes, and enhancing [3H]muscimol binding to α1β3γ2 GABAARs expressed in HEK293 cells. With EC50 of 110 nM, 11-AziAP is one the most potent general anesthetics reported. [3H]F4N3Bzoxy-AP and [3H]11-AziAP, at anesthetic concentrations, photoincorporated into α- and β-subunits of purified α1β3γ2 GABAARs, but labeling at the subunit level was not inhibited by alphaxalone (30 μM). The enhancement of photolabeling by 3H-azietomidate and 3H-mTFD-MPAB in the presence of either of the two steroid photoprobes indicates the neurosteroid binding site is different from, but allosterically related to, the etomidate and barbiturate sites. Our observations are consistent with two hypotheses. First, F4N3Bzoxy-AP and 11-aziAP bind to a high affinity site in such a pose that the 11-photoactivatable moiety, that is rigidly attached to the steroid backbone, points away from the protein. Second, F4N3Bzoxy-AP, 11-aziAP and other steroid anesthetics, which are present at very high concentration at the lipid-protein interface due to their high lipophilicity, act via low affinity sites, as proposed by Akk et al. (Psychoneuroendocrinology 2009, 34S1, S59-S66).

  3. Synthesis and Antibiotic Activity of Mebendazole Derivatives of Pharmacological Interest

    Directory of Open Access Journals (Sweden)

    Kavita Rathore

    2007-01-01

    Full Text Available Mebendazole is a well known anti-helimintic and belongs to the benzimidazole group of medicines. In order to achieve better medicinal results, i.e. enhanced activity and low toxicity, structural modifications are made in the existing drugs. Some 5-benzoyl-N-[1-(alkoxyphthalimido benzimidazol-2-yl] carbamic acid methyl ester (3a-c and 5-benzoyl-N-[1-(2,3-bis oxyphthalimido∕oxysuccinimido propyl benzimidazol-2-yl carbamic acid methyl ester (7a-b have been synthesized from two different routes. Structures of the compounds have been established on the basis of elemental analysis and spectral studies. All the synthesized compounds (3a-c and (7a-b were assayed in vitro for antimicrobial activity against mebendazole (itself and standard [ciprofloxacin (antibacterial and fluconazole (antifungal].

  4. Studies on Synthesis of Pyrimidine Derivatives and their Pharmacological Evaluation

    Directory of Open Access Journals (Sweden)

    T. A. Naik

    2007-01-01

    Full Text Available 1,3,4-Oxadiazoles were associated with broad spectrum of biological activities including antituberculosis, anticonvulsant, anti-inflammatory, insecticidal, antifungal, analgesic and antitumor properties. Morpholine derivatives find their wide spectrum of antimicrobial activity and exhibit anthelmintic, bactericidal and insecticidal activity. Pyrimidine derivatives are also reported to possess antibacterial, antimicrobial, antifungal, anticancer and anticonvulsant activities. Encouraged by this observations we decided to synthesised novel pyrimidine derivatives.

  5. Synthesis, spectroscopic characterization and pharmacological evaluation of oxazolone derivatives

    Directory of Open Access Journals (Sweden)

    Fareed Ghulam

    2013-01-01

    Full Text Available A series of 4-aryl methylidene-2-phenyl/methyl-5-(4H-oxazolone derivatives (2-7 have been synthesized using the reported method by condensation of aldehydes with N-benzoyl / N-acetyl glycine in the presence of zinc oxide as a catalyst and acetic anhydride at room temperature in ethanol. The compounds (2-6 are new derivatives. The structures of compounds were evaluated on the basis of 1H-NMR, 13C-NMR, EIMS, FT-IR and elemental analysis. All the compounds were screened for their antibacterial and urease inhibition activity. Antibacterial activity was tested by agar well diffusion method using Mueller Hinton Agar medium. Compound (2 showed excellent activity against S. aureus which has 16 mm (80% inhibition and above 24 mm (70% against S. typhi. The most active compound against E. coli was compound (6 having 20 mm (80% inhibition followed by compound (5 having above 18 mm (70% inhibition. Urease inhibition activity of all the compounds was determined by indophenol method. Compounds (3, 6 and (7 showed significant inhibition against Jacks bean urease.

  6. Synthesis, characterization and pharmacological evaluation of substituted phenoxy acetamide derivatives

    Directory of Open Access Journals (Sweden)

    Rani Priyanka

    2015-01-01

    Full Text Available A novel series of 2-(substituted phenoxy-N-(1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylacetamide and N-(2-bromocyclohexyl-2-(substituted phenoxyacetamide derivatives having cyclohexyl nucleus as common in both types were synthesized and assessed for their anti-inflammatory activity by a carrageenan induced rat paw oedema method, analgesic activity by Eddy’s hot plate method and antipyretic activity by brewer’s yeast induced pyrexia method. All the novel derivatives have been synthesized by the reaction of camphor and similar ketone having cyclohexane nucleus (e.g. 2-bromocyclohexanone with ammonium carbonate and formic acid resulting in the formation of aromatic amines (1a-b. These amines on further chloroacetylation with chloroacetylchloride give compounds (2a-b. Compounds (2a-b are converted to 2-(substituted phenoxy-N-(1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetamide and N-(2-bromocyclohexyl-2-(substituted phenoxyacetamide derivatives on treatment with substituted phenol. Among the series 3a-f, 3i, 3k, 3l compounds showed significant anti-inflammatory activity as compared to the standard drug diclofenac sodium and also compound 3a-f, 3h, 3j, 3k exhibit significant analgesic activity as compared to the standard drug. Compounds 3a-f and 3k showed antipyretic activity nearly to the standard drug indomethacin. Compounds 3a-f and 3k possess anti-inflammatory, analgesic and antipyretic activities near to the standard.

  7. Synthesis and pharmacological evaluation of several N-(2-nitrophenylpiperazine derivatives

    Directory of Open Access Journals (Sweden)

    DEANA ANDRIC

    2007-05-01

    Full Text Available Six newly synthesized heterocyclic (2-nitrophenylpiperazines, with a specific structure of the heteroaryl group, whichmimics the catechol moiety of dopamine (benzimidazoles and substituted benzimidazoles, were evaluated for their binding affinity to rat dopamine (DA, serotonin (5-HT and α1 receptors. All compounds with a benzimidazole group had a 5-HT2A/D2 receptors binding ratio characteristic for atypical neuroleptics (>1, pKi values. Compound 7c, 4-bromo-6-{2-[4-(2-nitrophenylpiperazin-1-yl]ethyl}-1H-benzimidazole, expressed higher affinities for all receptor classes than clozapine. Also, it exhibited the best characteristic for atypical neuroleptics and presents a compound with the best profile for further in vivo investigations.

  8. Pharmacological challenges in chronic pancreatitis

    DEFF Research Database (Denmark)

    Olesen, Anne Estrup; Brokjaer, Anne; Fischer, Iben Wendelboe Deleuran

    2014-01-01

    food intake is more or less substituted with alcohol, tobacco and coffee. Alcohol and drug interaction are known to influence the pharmacokinetics by altering either drug absorption or by affecting liver metabolism. Since patients suffering from chronic pancreatitis experience severe pain, opioids......Drug absorption in patients with chronic pancreatitis might be affected by the pathophysiology of the disease. The exocrine pancreatic insufficiency is associated with changes in gastrointestinal intraluminal pH, motility disorder, bacterial overgrowth and changed pancreatic gland secretion....... Together these factors can result in malabsorption and may also affect the efficacy of pharmacological intervention. The lifestyle of chronic pancreatitis patients may also contribute to gastrointestinal changes. Many patients limit their food intake because of the pain caused by eating and in some cases...

  9. Pharmacological challenges in chronic pancreatitis

    DEFF Research Database (Denmark)

    Olesen, Anne Estrup; Brokjaer, Anne; Fischer, Iben Wendelboe Deleuran

    2014-01-01

    food intake is more or less substituted with alcohol, tobacco and coffee. Alcohol and drug interaction are known to influence the pharmacokinetics by altering either drug absorption or by affecting liver metabolism. Since patients suffering from chronic pancreatitis experience severe pain, opioids....... Together these factors can result in malabsorption and may also affect the efficacy of pharmacological intervention. The lifestyle of chronic pancreatitis patients may also contribute to gastrointestinal changes. Many patients limit their food intake because of the pain caused by eating and in some cases......Drug absorption in patients with chronic pancreatitis might be affected by the pathophysiology of the disease. The exocrine pancreatic insufficiency is associated with changes in gastrointestinal intraluminal pH, motility disorder, bacterial overgrowth and changed pancreatic gland secretion...

  10. Pharmacology of human experimental anxiety

    Directory of Open Access Journals (Sweden)

    F.G. Graeff

    2003-04-01

    Full Text Available This review covers the effect of drugs affecting anxiety using four psychological procedures for inducing experimental anxiety applied to healthy volunteers and patients with anxiety disorders. The first is aversive conditioning of the skin conductance responses to tones. The second is simulated public speaking, which consists of speaking in front of a video camera, with anxiety being measured with psychometric scales. The third is the Stroop Color-Word test, in which words naming colors are painted in the same or in a different shade, the incongruence generating a cognitive conflict. The last test is a human version of a thoroughly studied animal model of anxiety, fear-potentiated startle, in which the eye-blink reflex to a loud noise is recorded. The evidence reviewed led to the conclusion that the aversive conditioning and potentiated startle tests are based on classical conditioning of anticipatory anxiety. Their sensitivity to benzodiazepine anxiolytics suggests that these models generate an emotional state related to generalized anxiety disorder. On the other hand, the increase in anxiety determined by simulated public speaking is resistant to benzodiazepines and sensitive to drugs affecting serotonergic neurotransmission. This pharmacological profile, together with epidemiological evidence indicating its widespread prevalence, suggests that the emotional state generated by public speaking represents a species-specific response that may be related to social phobia and panic disorder. Because of scant pharmacological data, the status of the Stroop Color-Word test remains uncertain. In spite of ethical and economic constraints, human experimental anxiety constitutes a valuable tool for the study of the pathophysiology of anxiety disorders.

  11. Carotenoids: biochemistry, pharmacology and treatment.

    Science.gov (United States)

    Milani, Alireza; Basirnejad, Marzieh; Shahbazi, Sepideh; Bolhassani, Azam

    2017-06-01

    Carotenoids and retinoids have several similar biological activities such as antioxidant properties, the inhibition of malignant tumour growth and the induction of apoptosis. Supplementation with carotenoids can affect cell growth and modulate gene expression and immune responses. Epidemiological studies have shown a correlation between a high carotenoid intake in the diet with a reduced risk of breast, cervical, ovarian, colorectal cancers, and cardiovascular and eye diseases. Cancer chemoprevention by dietary carotenoids involves several mechanisms, including effects on gap junctional intercellular communication, growth factor signalling, cell cycle progression, differentiation-related proteins, retinoid-like receptors, antioxidant response element, nuclear receptors, AP-1 transcriptional complex, the Wnt/β-catenin pathway and inflammatory cytokines. Moreover, carotenoids can stimulate the proliferation of B- and T-lymphocytes, the activity of macrophages and cytotoxic T-cells, effector T-cell function and the production of cytokines. Recently, the beneficial effects of carotenoid-rich vegetables and fruits in health and in decreasing the risk of certain diseases has been attributed to the major carotenoids, β-carotene, lycopene, lutein, zeaxanthin, crocin (/crocetin) and curcumin, due to their antioxidant effects. It is thought that carotenoids act in a time- and dose-dependent manner. In this review, we briefly describe the biological and immunological activities of the main carotenoids used for the treatment of various diseases and their possible mechanisms of action. This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc. © 2016 The British Pharmacological Society.

  12. A metal-catalyzed enyne-cyclization step for the synthesis of bi- and tricyclic scaffolds amenable to molecular library production

    DEFF Research Database (Denmark)

    Wu, Peng; Cohrt, Anders Emil O'Hanlon; Petersen, Rico

    2016-01-01

    A facile metal-catalyzed diversification step for the synthesis of novel bi- and tricyclic scaffolds from enyne substrates is reported in this study. From a single starting material, topologically diverse scaffolds for library synthesis can be generated and decorated in a few steps. The methodology...

  13. Magnetismo Molecular (Molecular Magentism)

    Energy Technology Data Exchange (ETDEWEB)

    Reis, Mario S [Universidade Federal Fluminense, Brasil; Moreira Dos Santos, Antonio F [ORNL

    2010-07-01

    The new synthesis processes in chemistry open a new world of research, new and surprising materials never before found in nature can now be synthesized and, as a wonderful result, observed a series of physical phenomena never before imagined. Among these are many new materials the molecular magnets, the subject of this book and magnetic properties that are often reflections of the quantum behavior of these materials. Aside from the wonderful experience of exploring something new, the theoretical models that describe the behavior these magnetic materials are, in most cases, soluble analytically, which allows us to know in detail the physical mechanisms governing these materials. Still, the academic interest in parallel this subject, these materials have a number of properties that are promising to be used in technological devices, such as in computers quantum magnetic recording, magnetocaloric effect, spintronics and many other devices. This volume will journey through the world of molecular magnets, from the structural description of these materials to state of the art research.

  14. Molecular Iodine: A Versatile Catalyst for the Synthesis of 4-Aryl-3-methyl-1-phenyl-1H-benzo[h]pyrazolo[3,4-b]quinoline-5,10-diones in Water

    International Nuclear Information System (INIS)

    Wu, Liqiang; Yang, Limin; Yan, Fulin; Yang, Chunguang; Fang, Lizhen

    2010-01-01

    An efficient methodology for the synthesis of 4-aryl-3-methyl-1-phenyl-1H-benzo[h]pyrazolo[3,4-b]quinoline-5,10-diones has been developed. To our best knowledge, this is the first report for the synthesis of these compounds by multicomponent condensation of 3-methyl-1-phenyl-1H-pyrazol-5-amine, aldehydes and 2-hydroxynaphthalene-1,4-dione in the presence of molecular iodine as a catalyst in water. The simple experimental procedure, utilization of an inexpensive and readily available catalyst, and excellent yields are the advantages of the present method. Multicomponent reactions (MCRs) have attracted considerable attention since they are performed without need to isolate any intermediate during their processes; may reduce time and save both energy and raw materials. They have merits over two-component reactions in several aspects including the simplicity of a one-pot procedure, possible structural variations and building up complex molecules

  15. Parameter trajectory analysis to identify treatment effects of pharmacological interventions.

    Directory of Open Access Journals (Sweden)

    Christian A Tiemann

    Full Text Available The field of medical systems biology aims to advance understanding of molecular mechanisms that drive disease progression and to translate this knowledge into therapies to effectively treat diseases. A challenging task is the investigation of long-term effects of a (pharmacological treatment, to establish its applicability and to identify potential side effects. We present a new modeling approach, called Analysis of Dynamic Adaptations in Parameter Trajectories (ADAPT, to analyze the long-term effects of a pharmacological intervention. A concept of time-dependent evolution of model parameters is introduced to study the dynamics of molecular adaptations. The progression of these adaptations is predicted by identifying necessary dynamic changes in the model parameters to describe the transition between experimental data obtained during different stages of the treatment. The trajectories provide insight in the affected underlying biological systems and identify the molecular events that should be studied in more detail to unravel the mechanistic basis of treatment outcome. Modulating effects caused by interactions with the proteome and transcriptome levels, which are often less well understood, can be captured by the time-dependent descriptions of the parameters. ADAPT was employed to identify metabolic adaptations induced upon pharmacological activation of the liver X receptor (LXR, a potential drug target to treat or prevent atherosclerosis. The trajectories were investigated to study the cascade of adaptations. This provided a counter-intuitive insight concerning the function of scavenger receptor class B1 (SR-B1, a receptor that facilitates the hepatic uptake of cholesterol. Although activation of LXR promotes cholesterol efflux and -excretion, our computational analysis showed that the hepatic capacity to clear cholesterol was reduced upon prolonged treatment. This prediction was confirmed experimentally by immunoblotting measurements of SR-B1

  16. 多级孔分子筛的合成及催化应用研究进展%Research progress of synthesis and catalytic applications of hierarchical molecular sieves

    Institute of Scientific and Technical Information of China (English)

    宋菁; 张君涛; 申志兵; 梁生荣

    2017-01-01

    综述了近几年国内外多级孔分子筛的研究进展,重点介绍了“自上而下”和“自下而上”两大类合成方法,并进一步阐述了脱硅法、重结晶法、硬模板法、软模板法、无模板自组装等具体合成方法的优势及局限性,同时介绍了不同方法制得的多级孔分子筛的催化应用,最后对多级孔分子筛的发展前景进行了展望.%The synthesis methods and catalytic applications of hierarchical molecular sieves in recent years have been reviewed.Various synthesis approaches of hierarchical molecular sieves are introduced,including Top-down approach and Bottom-up approach.Advantages and limitations of the different methods such as demetalization,recrystallization,hard template,soft template,template-free,and so on,will also be addressed.Meanwhile,the catalytic applications of the as-synthesized zeolites are discussed.The prospect of hierarchical molecular sieves is outlined in the end.

  17. Pharmacologic treatment of depression in multiple sclerosis

    NARCIS (Netherlands)

    Koch, Marcus W.; Glazenborg, Arjon; Uyttenboogaart, Maarten; Mostert, Jop; De Keyser, Jacques

    2011-01-01

    Background Depression is a common problem in patients with multiple sclerosis (MS). It is unclear which pharmacologic treatment is the most effective and the least harmful. Objectives To investigate the efficacy and tolerability of pharmacologic treatments for depression in patients with MS. Search

  18. Complex Pharmacology of Free Fatty Acid Receptors

    DEFF Research Database (Denmark)

    Milligan, Graeme; Shimpukade, Bharat; Ulven, Trond

    2017-01-01

    pharmacology have shaped understanding of the complex pharmacology of receptors that recognize and are activated by nonesterified or "free" fatty acids (FFAs). The FFA family of receptors is a recently deorphanized set of GPCRs, the members of which are now receiving substantial interest as novel targets...

  19. The Dutch vision of clinical pharmacology

    NARCIS (Netherlands)

    Schellens, J H M; Grouls, R; Guchelaar, H J; Touw, D J; Rongen, G A; de Boer, A; Van Bortel, L M

    Recent position papers addressing the profession of clinical pharmacology have expressed concerns about the decline of interest in the field among clinicians and medical educators in the United Kingdom and other Western countries, whether clinical pharmacology is actually therapeutics, and whether

  20. α-Mangostin from Garcinia mangostana Linn: An updated review of its pharmacological properties

    Directory of Open Access Journals (Sweden)

    Mohamed Yousif Ibrahim

    2016-05-01

    Full Text Available Over the past decades, various studies have highlighted the pure natural compound, α-mangostin as their main topic. The compound’s pre-clinical and pharmacological properties have been recognized and defined in these studies. α-Mangostin shows strong pharmacological effects in in vitro and in vivo model systems by targeting a number of vital cellular factors through various mechanisms of action. Despite its important molecular versatility, the α-mangostin still has limited clinical application. In order to optimize the conditions of this compound as a chemotherapeutic and chemopreventive agent, for instance in diseases such as cancer, obesity, diabetes as well as inflammatory disorders, the recent tendency is to limit the range of its pharmacological properties. The present work reviews recent studies on the central and potential pharmacological principles as well as the preclinical applications of the α-mangostin.