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Sample records for benzamides

  1. Benzamides used in medicine

    International Nuclear Information System (INIS)

    The synthesis and the characterization of [125I]N-(2-diethylaminoethyl)-4-iodobenzamide, [131I]N-(2-diethylaminoethyl)-4-iodobenzamide, [125I]N-2-piperindinylaminoethyl)-4-iodobenzamide and [131I]N-(2-piperidinylaminoethyl)-4-iodobenzamide are described as well as the purification and separation of the molecules by thin layer chromatography and HPLC. Biodistribution studies show that these labelled benzamides have good affinity to brain tissues. (author)

  2. Exploring the cocrystallization potential of urea and benzamide.

    Science.gov (United States)

    Cysewski, Piotr; Przybyłek, Maciej; Ziółkowska, Dorota; Mroczyńska, Karina

    2016-05-01

    The cocrystallization landscape of benzamide and urea interacting with aliphatic and aromatic carboxylic acids was studied both experimentally and theoretically. Ten new cocrystals of benzamide were synthesized using an oriented samples approach via a fast dropped evaporation technique. Information about types of known bi-component cocrystals augmented with knowledge of simple binary eutectic mixtures was used for the analysis of virtual screening efficiency among 514 potential pairs involving aromatic carboxylic acids interacting with urea or benzamide. Quantification of intermolecular interaction was achieved by estimating the excess thermodynamic functions of binary liquid mixtures under supercooled conditions within a COSMO-RS framework. The smoothed histograms suggest that slightly more potential pairs of benzamide are characterized in the attractive region compared to urea. Finally, it is emphasized that prediction of cocrystals of urea is fairly direct, while it remains ambiguous for benzamide paired with carboxylic acids. The two known simple eutectics of urea are found within the first two quartiles defined by excess thermodynamic functions, and all known cocrystals are outside of this range belonging to the third or fourth quartile. On the contrary, such a simple separation of positive and negative cases of benzamide miscibility in the solid state is not observed. The difference in properties between urea and benzamide R2,2(8) heterosynthons is also documented by alterations of substituent effects. Intermolecular interactions of urea with para substituted benzoic acid analogues are stronger compared to those of benzamide. Also, the amount of charge transfer from amide to aromatic carboxylic acid and vice versa is more pronounced for urea. However, in both cases, the greater the electron withdrawing character of the substituent, the higher the binding energy, and the stronger the supermolecule polarization via the charge transfer mechanism. PMID:27052722

  3. Crystal Structure Prediction could have helped the Experimentalists with Polymorphism in Benzamide!

    OpenAIRE

    2008-01-01

    Abstract Benzamide was the first molecular material for which polymorphism was reported as long as 176 years ago. Unfortunately, due to very similar cell metrics leading to massive peak overlap, the metastable form reported by Liebig escaped structural characterization by XRD until recently. With the help of crystal structure prediction this old riddle of ?Liebig's? polymorph of benzamide could have been solved many years earlier. Performing state of the art crystal structure predi...

  4. The challenging case of the theophylline-benzamide cocrystal.

    Science.gov (United States)

    Fischer, Franziska; Schmidt, Martin U; Greiser, Sebastian; Emmerling, Franziska

    2016-03-01

    Theophylline has been used as an active pharmaceutical ingredient (API) in the treatment of pulmonary diseases, but due to its low water solubility reveals very poor bioavailability. Based on its different hydrogen-bond donor and acceptor groups, theophylline is an ideal candidate for the formation of cocrystals. The crystal structure of the 1:1 benzamide cocrystal of theophylline, C7H8N4O2·C7H7NO, was determined from synchrotron X-ray powder diffraction data. The compound crystallizes in the tetragonal space group P41 with four independent molecules in the asymmetric unit. The molecules form a hunter's fence packing. The crystal structure was confirmed by dispersion-corrected DFT calculations. The possibility of salt formation was excluded by the results of Raman and (1)H solid-state NMR spectroscopic analyses. PMID:26942431

  5. Halogenated benzamides as ligands for cerebral dopamine receptors

    International Nuclear Information System (INIS)

    In the past several years the authors' has synthesized a series of high affinity iodine-123 and fluorine-18 labeled substituted benzamide ligands for SPECT and PET visualization of the dopamine D-2 receptors in brain regions with low receptor density outside the striatum. Radioiodination and radiofluorination in high yield and high specific activity was achieved by using the tributyltin precursor and nucleophilic displacement of the saturation analysis revealed that the optimal striatum-to-cerebellum uptake ratio in the rat brain is highly correlated with the product of Kw and KD. The authors have used [125I] and [123I] epidepride to detect extra striatal dopamine D2 receptors in vitro by saturation analysis and in vivo with high resolution SPECT imaging

  6. Cytotoxicity and characterization of an active metabolite of benzamide riboside, a novel inhibitor of IMP dehydrogenase.

    Science.gov (United States)

    Gharehbaghi, K; Paull, K D; Kelley, J A; Barchi, J J; Marquez, V E; Cooney, D A; Monks, A; Scudiero, D; Krohn, K; Jayaram, H N

    1994-03-15

    Benzamide riboside exhibits significant cytotoxicity against a variety of human tumor cells in culture. On the basis of metabolic studies, the primary target of this drug's action appears to be IMP dehydrogenase (IMPDH). Incubation of human myelogenous leukemia K562 cells with an IC50 concentration of benzamide riboside resulted in an expansion of IMP pools (5.9-fold), with a parallel reduction in the concentration of GMP (90%), GDP (63%), GTP (55%) and dGTP (40%). On kinetic grounds, it was deduced that benzamide riboside (whose Ki versus IMPDH is 6.4 mM, while that of its 5'-monophosphate is 3.9 mM) or its 5'-monophosphate were unlikely to be responsible for inhibition of this target enzyme, IMPDH, since only micromolar concentrations of benzamide riboside were needed to exert potent inhibition of tumor-cell growth. Studies on the metabolism of this C-nucleoside have revealed the presence of a new peak eluting in the nucleoside diphosphate area on HPLC. Treatment of this peak with venom phosphodiesterase degraded it and concurrently nullified its inhibitory activity versus IMPDH; alkaline phosphatase, on the other hand, totally failed to digest the anabolite. These results suggest that the metabolite in question is the phosphodiester, benzamide adenine dinucleotide (BAD). Evidence that the inhibitor was an analog of NAD, wherein the nicotinamide moiety has been replaced by benzamide, was provided by both NMR and mass spectrometric analysis and confirmed by enzymatic synthesis. Further insight into the nature of the active principle was obtained from kinetic studies, which established that BAD competitively inhibited NAD utilization by partially purified IMPDH from K562 cells with a Ki of 0.118 microM. In concert, these studies establish that benzamide riboside exhibits potent antiproliferative activity by inhibiting IMPDH through BAD. PMID:7907081

  7. Discovery of benzamide analogues as a novel class of 5-HT3 receptor agonists

    DEFF Research Database (Denmark)

    Jørgensen, Charlotte Grube; Frølund, Bente Flensborg; Kehler, Jan; Jensen, Anders Asbjørn

    2011-01-01

    A 5-HT(3) receptor agonist based on a benzamide scaffold was identified in a screening of a small commercial compound library, and an elaborate SAR study originating from this hit was performed. The design, synthesis, and functional characterisation of benzamide analogues at the 5-HT(3) A receptor...

  8. Synthesis, characterization and antibacterial studies of 2-chloro-5-fluoro-N-[dibenzyl carbamothioyl] benzamide thiourea

    Energy Technology Data Exchange (ETDEWEB)

    Sapari, Suhaila; Yamin, Bohari M.; Hasbullah, Aishah; Ibrahim, Nazlina [School of Chemical Science and Food Technology, Faculty of Science and Technology, The National University of Malaysia, 43600, Bangi, Selangor (Malaysia)

    2014-09-03

    Synthesis, characterization and antibacterial studies of 2-chloro-5-fluoro-N-[dibenzyl carbamothioyl] benzamide thiourea has been reported. The compound characterized by using elementary analysis CHNS, IR, {sup 1}H NMR and {sup 13}C NMR spectroscopies. The compounds have been screened for their antibacterial studies.

  9. Temperature-controlled redox-neutral ruthenium(ii)-catalyzed regioselective allylation of benzamides with allylic acetates.

    Science.gov (United States)

    Manikandan, Rajendran; Jeganmohan, Masilamani

    2016-08-10

    Substituted aromatic amides reacted efficiently with allylic acetates in the presence of a cationic ruthenium complex in ClCH2CH2Cl at room temperature providing ortho allylated benzamides in a highly regioselective manner without any oxidant and base. The whole catalytic reaction occurred in a Ru(ii) oxidation state and thus the oxidation step is avoided. By tuning the reaction temperature, ortho allyl and vinyl benzamides were prepared exclusively. Later, ortho allyl and vinylated benzamides were converted into biologically useful six- and five-membered benzolactones in the presence of HCl. PMID:27456467

  10. An improved synthesis of an 125I and 211At labelled benzamide for melanoma imaging

    International Nuclear Information System (INIS)

    Recent studies have indicated that benzamides can exhibit affinity for malignant melanoma and may be exploited diagnostically in the treatment of this cancer. Radioiodinated N-(2-diethylaminoethyl)-3-[123I/131I]iodo-4-methoxybenzamide (*I-IMBA) is a benzamide with promising diagnostic properties. A new synthesis procedure was developed to obtain 125I-IMBA suitable for use in vivo. The assets of the procedure include the use of less toxic reagents and better reproducible results when radiolabelling the precursor. The procedure also facilitates the synthesis of the astatinated N-(2-diethylaminoethyl)-3-[211At]astatine-4-methoxybenzamide (211At-AMBA), a new benzamide with a therapeutic potential. The regiospecific no-carrier-added 125I- and 211At-labeling of the benzamide is performed by demetalation of an organotin precursor. Using tributylstannyl as a leaving group, the radiochemical yield obtained after 15 minutes of reaction was 70 %-90 % for both 125I-IMBA and 211At-AMBA. The labelling was performed in a solution of MeOH:AcOH with NCS as the oxidising agent. The organotin precursor N-(2-diethylaminoethyl)-3-(tri-n-butylstannyl)-4-methoxy-benzamide was synthesized from 3-bromo-4-methoxybenzoic acid, with n-BuLi (2 eq) and Bu3SnCl (1 eq) in THF, giving 3-(tri-n-butylstannyl)-4-methoxybenzoic acid. The amide function was introduced by converting the acid group into an active N-succinimidyl-ester, a good leaving group in the reaction with 2-(diethylamino)ethylamine. The overall yield of the organotin precursor was 65 %

  11. Cytotoxicity of a new IMP dehydrogenase inhibitor, benzamide riboside, to human myelogenous leukemia K562 cells.

    Science.gov (United States)

    Jayaram, H N; Gharehbaghi, K; Jayaram, N H; Rieser, J; Krohn, K; Paull, K D

    1992-08-14

    COMPARE computer program suggested that benzamide riboside, BR, 3-(1-deoxy-beta-D-ribofuranosyl)benzamide, should have a similar mechanism of action as that of tiazofurin, an inhibitor of IMP dehydrogenase (IMPDH). This hypothesis was tested in K562 cells in culture. BR was cytotoxic to K562 cells with an IC50 of 2 microM. Incubation of K562 cells with BR resulted in a significant decrease in GMP and GTP levels with a concurrent increase in IMP pools, and with a significant inhibition of IMPDH activity. However, 290-fold higher BR concentration was needed to demonstrate in vitro inhibition of IMPDH activity, suggesting that the agent may require metabolism to exert its action. These results provide evidence that BR is a new inhibitor of IMPDH. This investigation should be helpful to design new analogues having activity against IMPDH. PMID:1354960

  12. Studies on the mechanism of action of benzamide riboside: a novel inhibitor of IMP dehydrogenase.

    Science.gov (United States)

    Gharehbaghi, Kamran; Grünberger, Werner; Jayaram, Hiremagalur N

    2002-04-01

    Benzamide is a well known inhibitor of poly(ADP-ribose)polymerase, an enzyme involved in DNA repair. However, benzamide exhibited neuotoxicity in animals and hence, in the hope of overcoming this problem, benzamide riboside (BR) was synthesized. Our mechanism of action studies on BR suggested that the agent was being metabolized to its 5'-monophosphate and then to its NAD analogue (BAD, benzamide adenine dinucleotide) that inhibits Inosine 5'-monophosphate dehydrogenase (IMPDH). IMPDH is the rate-limiting enzyme of the branched purine nucleotide synthetic pathway that provides guanylates including GTP and dGTP. There are two isoforms of IMPDH, type I that is constitutively present in all cells, and type II that is inducible and is present in highly proliferating cells such as cancer. Ongoing studies with BR analogues suggest that they are more selective in inhibiting IMPDH type II. Our studies have characterized the metabolites of BR, especially its NAD analogue, BAD, by synthesizing this active metabolite by enzymatic means, and identifying its structure by NMR and mass spectrometry. We have partially purified IMPDH from tumor cells and have examined the kinetics of inhibition of IMPDH by BAD. We have also compared biochemical and cytotoxic activities of BR with tiazofurin and selenazofurin, that share similar mechanisms of action with BR. Our studies demonstrated that 2-3-fold more BAD is formed compared to TAD and SAD, the active metabolites of tiazofurin and selenazofurin, respectively. BR has demonstrated potent cytotoxic activity in a diverse group of human tumor cells, specifically more active in sarcomas and CNS neoplasms compared to tiazofurin or selenazofurin. Future in vivo animal studies should set a stage for determining its effectiveness in clinical Phase I studies. PMID:11966437

  13. Synthesis and Pharmacological Activities of N-(3-HydroxyphenylBenzamide and its 3-O-Derivatives

    Directory of Open Access Journals (Sweden)

    M. A. Abbasi

    2014-03-01

    Full Text Available N-(3-hydroxyphenyl benzamide (3 was synthesized by the condensation of 3-hydroxyaniline (1 with benzoyl chloride (2 in aqueous medium. From this parent molecule 3, various 3-O-derivatives, 5a-f, were prepared via O-alkylation, by reacting it with different alkyl halides, 4a-f, for 2 h under reflux conditions in the presence of mixture of Na-ethoxide and C2H5OH as solvent. The synthesized compounds were characterized by using different spectroscopic techniques and were subjected to enzyme inhibition activity against butylcholinesterase, acetylcholinesterase, and lipoxygenase enzymes.

  14. Characterization of Antiviral Activity of Benzamide Derivative AH0109 against HIV-1 Infection

    OpenAIRE

    Chen, Liyu; Ao, Zhujun; Jayappa, Kallesh Danappa; Kobinger, Gary; Liu, ShuiPing; Wu, Guojun; Wainberg, Mark A.; Yao, Xiaojian

    2013-01-01

    In the absence of an effective vaccine against HIV-1 infection, anti-HIV-1 strategies play a major role in disease control. However, the rapid emergence of drug resistance against all currently used anti-HIV-1 molecules necessitates the development of new antiviral molecules and/or strategies against HIV-1 infection. In this study, we have identified a benzamide derivative named AH0109 that exhibits potent anti-HIV-1 activity at an 50% effective concentration of 0.7 μM in HIV-1-susceptible CD...

  15. Synthesis, Characterization, and BSA Binding Studies of Some New Benzamides Related to Schiff Base

    OpenAIRE

    Prashanth, M. K.; Madaiah, M.; Revanasiddappa, H. D.; Amruthesh, K. N.

    2013-01-01

    Condensation of amine 1 with aldehyde 2 gives Schiff base, N-(4-((benzofuran-2-ylmethylene) amino)phenyl)acetamide 3. Schiff base on N-acylation with different substituted acid chlorides in the presence of triethylamine gives the corresponding benzamides, N-acetyl-N-(4-((benzofuran-2-ylmethylene)amino)phenyl)substitutedbenzamide (NABP) 5a–j. The structures of newly synthesized compounds were characterized by elemental analysis, 1H NMR, 13C NMR FT-IR, and mass spectral studies. Compounds 3 and...

  16. High affinity dopamine D2 receptor radioligands. 1. Regional rat brain distribution of iodinated benzamides

    Energy Technology Data Exchange (ETDEWEB)

    Kessler, R.M.; Ansari, M.S.; de Paulis, T.; Schmidt, D.E.; Clanton, J.A.; Smith, H.E.; Manning, R.G.; Gillespie, D.; Ebert, M.H. (Vanderbilt University School of Medicine, Nashville, TN (USA))

    1991-08-01

    Five 125I-labeled substituted benzamides, which are close structural analogues of (S)-sulpiride, eticlopride, and isoremoxipride, were evaluated for their selective in vivo uptake into dopamine D2 receptor rich tissue of the rat brain. Iodopride (KD 0.88 nM), an iodine substituted benzamide structurally related to sulpiride, displayed a maximal striatum: cerebellar uptake ratio of 7.6. Demonstration of saturation of the receptor with (125I)iodopride in striatum required uptake in frontal cortex to be used, rather than cerebellar uptake, to define nonspecific binding. Two other ligands structurally related to eticlopride, iclopride (KD 0.23 nM) and itopride (KD 0.16 nM), displayed maximal striatal: cerebellar uptake ratios of 9.8 and 3.3, respectively. The most potent ligands, epidepride (KD 0.057 nM) and ioxipride (KD 0.070 nM) showed striatal:cerebellar uptake ratios of 234 and 65, respectively. The observed uptake ratios correlated poorly with the affinity constants for the dopamine D2 receptor alone, but were highly correlated (r = 0.92) with the product of the receptor dissociation constant (KD) and the apparent lipophilicity (kw), as determined by reverse-phase HPLC at pH 7.5. Total striatal uptake also appeared dependent on lipophilicity, with maximal uptake occurring for ligands having log kw 2.4-2.8.

  17. High affinity dopamine D2 receptor radioligands. 1. Regional rat brain distribution of iodinated benzamides

    International Nuclear Information System (INIS)

    Five 125I-labeled substituted benzamides, which are close structural analogues of (S)-sulpiride, eticlopride, and isoremoxipride, were evaluated for their selective in vivo uptake into dopamine D2 receptor rich tissue of the rat brain. Iodopride (KD 0.88 nM), an iodine substituted benzamide structurally related to sulpiride, displayed a maximal striatum: cerebellar uptake ratio of 7.6. Demonstration of saturation of the receptor with [125I]iodopride in striatum required uptake in frontal cortex to be used, rather than cerebellar uptake, to define nonspecific binding. Two other ligands structurally related to eticlopride, iclopride (KD 0.23 nM) and itopride (KD 0.16 nM), displayed maximal striatal: cerebellar uptake ratios of 9.8 and 3.3, respectively. The most potent ligands, epidepride (KD 0.057 nM) and ioxipride (KD 0.070 nM) showed striatal:cerebellar uptake ratios of 234 and 65, respectively. The observed uptake ratios correlated poorly with the affinity constants for the dopamine D2 receptor alone, but were highly correlated (r = 0.92) with the product of the receptor dissociation constant (KD) and the apparent lipophilicity (kw), as determined by reverse-phase HPLC at pH 7.5. Total striatal uptake also appeared dependent on lipophilicity, with maximal uptake occurring for ligands having log kw 2.4-2.8

  18. Synthesis of benzamide derivatives of anacardic acid and their cytotoxic activity.

    Science.gov (United States)

    Chandregowda, Venkateshappa; Kush, Anil; Reddy, Goukanapalli Chandrasekara

    2009-06-01

    Several benzamide derivatives were synthesized from anacardic acid (1a) which was the product of hydrogenation of the naturally occurring anacardic acid mixture (1a-d), a major constituent of cashew nut shell liquid. Anacardic acid (1a) was first alkylated followed by hydrolysis of the ester to obtain synthones namely, 2-ethoxy-6-pentadecylbenzoic acid (5) and 2-isopropoxy-6-pentadecylbenzoic acid (6). These salicylic acid derivatives were then coupled with a variety of anilines to obtain novel benzamide compounds (7-39). Cytotoxic effect of these synthesized compounds was tested on HeLa cell line of wild type with relatively high expression of p300 and on HCT-15, which is p300 negative. Of all the compounds, 2-isopropoxy-6-pentadecyl-N-pyridin-4-ylbenzamide (27), 2-ethoxy-N-(3-nitrophenyl)-6-pentadecylbenzamide (22) and 2-ethoxy-6-pentadecyl-N-pyridin-4-ylbenzamide (10) were found to be more potent with the respective IC(50) values 11.02 microM, 13.55 microM, 15.29 microM on HeLa cell line. Their activities are comparable with garcinol which is a cell permeable histone acetyltransferase (HAT) inhibitor and 10 fold more active than p300 HAT activators so far reported. PMID:19246131

  19. Substituted Benzamides Containing Azaspiro Rings as Upregulators of Apolipoprotein A-I Transcription

    Directory of Open Access Journals (Sweden)

    Bin Hong

    2012-06-01

    Full Text Available Apolipoprotein A-I (Apo A-I is the principal protein component of high density lipoprotein (HDL, which is generally considered as a potential therapeutic target against atherosclerosis. The understanding of the Apo A-I regulation mechanism has fuelled the development of novel HDL targeted therapeutic approaches. To identify novel agents that can upregulate Apo A-I expression, we performed a cell-based reporter assay to screen 25,600 small molecules. Based on the dataset obtained from screening, a series of novel analogs of substituted benzamides containing azaspiro rings were assessed for their ability to induce the transcription of the Apo A-I gene, and the structure-activity relationship (SAR around these analogs was also proposed. The results indicated that the trifluoromethyl substituted benzamide containing an azaspiro ring is a promising backbone for designing Apo A-I transcriptional upregulator and could be viable leads for development of new drugs to prevent and treat atherosclerosis in the future.

  20. Terahertz Absorption Spectroscopy of Benzamide, Acrylamide, Caprolactam, Salicylamide, and Sulfanilamide in the Solid State

    Directory of Open Access Journals (Sweden)

    Ye Jiang

    2014-01-01

    Full Text Available Terahertz (THz absorption spectra of the similarly structured molecules with amide groups including benzamide, acrylamide, caprolactam, salicylamide, and sulfanilamide in the solid phase at room temperature and 7.8 K for salicylamide are reported and compared to infrared vibrational spectral calculations using density functional theory. The results of THz absorption spectra show that the molecules have characteristic bands in the region of 0.2–2.6 THz (~7–87 cm−1. THz technique can be used to distinguish different molecules with amide groups. In the THz region benzamide has three bands at 0.83, 1.63, and 1.73 THz; the bands are located at 1.44 and 2.00 THz for acrylamide; the bands at 1.24, 1.66 and 2.12 THz are observed for caprolactam. The absorption bands are located at 1.44, 1.63, and 2.39 THz at room temperature, and at 1.22, 1.46, 1.66, and 2.41 THz at low temperature for salicylamide. The bands at 1.63, 1.78, 2.00, and 2.20 THz appear for sulfanilamide. These bands in the THz region may be related to torsion, rocking, wagging, and other modes of different groups in the molecules.

  1. Removal of Uranium (VI from aqueous solution by Uranium Benzamide Complex using AC_Fe3O4 Nanocomposite

    Directory of Open Access Journals (Sweden)

    Z Akbari Jonoush

    2014-07-01

    Conclusion: The removal of U(VI on AC_Fe3O4 nanocomposite with the aid of benzamide is a rapid and highly pH depended process. The maximum sorption capacity (15/87 mg/g of AC_Fe3O4 nanocomposite shows that this method is a suitable method for Uranium removal.

  2. N-[2-(maleimido)ethyl]-3-(trimethylstannyl)benzamide, a molecule for radiohalogenation of proteins and peptides

    DEFF Research Database (Denmark)

    Aneheim, Emma; Foreman, Mark R StJ; Jensen, Holger;

    2015-01-01

    In this work a new coupling reagent, N-[2-(maleimido)ethyl]-3-(trimethylstannyl)benzamide, for radiohalogenation has been synthesized and characterized. The reagent is intended to either be attached to reduced disulfide bridges of proteins (making the halogenation site-specific) or to free termin...

  3. One-pot synthesis of novel 1, 8-dioxo-decahydroacridines containing phenol and benzamide moiety and their synthetic uses

    Indian Academy of Sciences (India)

    Ali Dorehgiraee; Esmat Tavakolinejad Kermani; Hojatollah Khabazzadeh

    2014-07-01

    An efficient synthesis of some new 1, 8-dioxo-decahydroacridines is achieved via one-pot, threecomponent condensation of aromatic aldehydes, cyclic diketone, and 4-amino benzamide/4-aminophenol. Reaction of these acridines with dimethylacetylene dicarboxylate and triphenylphosphine or cyclohexylisocyanide gives stable phosphorus ylides or 4H-chromene derivatives, respectively, with good yields.

  4. 131/123 iodine labeled benzamides for the detection of melanomas and metastases. Synthesis, labeling, animal experiences and preliminary clinical studies

    International Nuclear Information System (INIS)

    Radioiodine labeled benzamides are being studied as radiopharmaceuticals for the detection of melanomas and metastases. With this purpose the synthesis and labeling of N-(2-diethylaminoethyl)-3-[131I]-4-methoxybenzamide (IMBA) has been carried out. Tissue distribution of the labeled compound has been studied in C 57 mice, showing a fast renal excretion. The labeled benzamide was also injected in mice with previously induced subcutaneous melanomas and lung metastases using B 16-F0 murine melanoma cells. The tumors show a good uptake of the labeled benzamide. The melanoma/other tissues uptake ratio is suitable for scintigraphic detection. Clinical studies in patients are under way. (author)

  5. Comparison of biochemical parameters of benzamide riboside, a new inhibitor of IMP dehydrogenase, with tiazofurin and selenazofurin.

    Science.gov (United States)

    Gharehbaghi, K; Sreenath, A; Hao, Z; Paull, K D; Szekeres, T; Cooney, D A; Krohn, K; Jayaram, H N

    1994-10-01

    The biochemical and cytotoxic activities of the IMP dehydrogenase (IMPDH) inhibitors benzamide riboside, tiazofurin, and selenazofurin were compared. These three C-nucleosides exert their cytotoxicity by forming an analogue of NAD, wherein nicotinamide is replaced by the C-nucleoside base. The antiproliferative activities of these three agents were compared in a panel of 60 human cancer cell lines. To examine the relationship of benzamide riboside and selenazofurin to tiazofurin, COMPARE computer analysis was performed, and correlation coefficients of 0.761 and 0.815 were obtained for benzamide riboside and selenazofurin, respectively. The biochemical activities of these agents were examined in human myelogenous leukemia K562 cells. Incubation of K562 cells for 4 hr with 10 microM each of benzamide riboside, selenazofurin and tiazofurin resulted in a 49, 71, and 26% decrease in IMPDH activity with a concurrent increase in intracellular IMP pools. As a consequence of IMPDH inhibition, GTP and dGTP concentrations were curtailed. These studies demonstrated that selenazofurin was the most potent of the three agents. To compare the cellular synthesis of NAD analogues of these agents, K562 cells were incubated with 10 microM each of benzamide riboside, tiazofurin and selenazofurin after prelabeling the cells with [2,8-3H]adenosine. The results demonstrated that benzamide riboside produced 2- and 3-fold more of NAD analogue (BAD) than tiazofurin and selenazofurin did. To elucidate the effects of the three compounds on other NAD-utilizing enzymes, the inhibitory activities of purified benzamide adenine dinucleotide (BAD), thiazole-4-carboxamide adenine dinucleotide (TAD) and selenazole-4-carboxamide adenine dinucleotide (SAD) were studied in commercially available purified preparations of lactate dehydrogenase, glutamate dehydrogenase and malate dehydrogenase. TAD and SAD did not inhibit these three dehydrogenases. Although BAD did not influence lactate and glutamate

  6. Synthesis and biological evaluation of 99Tcm labelled benzamides for dopamine D2 receptor imaging

    International Nuclear Information System (INIS)

    (S)-(-)-5-mercapto-N-((1-ethyl-2-pyrrolidinyl)methyl)-2-methoxy benz-amide [MBZM] is synthesized by introducing a mercapto group at 5-position of benzene ring to mimic sulpiride ligand. Through the '3 + 1' mixed ligand approach, a neutral radiolabelled compound 99Tcm-MBZM is also prepared as a potential D2 receptor imaging agent, 99Tcm-MBZM exhibits a fast clearance in blood and higher uptake in the liver and kidney (2.148 and 2.184% ID/g at 30 min respectively) but low initial brain uptake (only 0.145% ID/g at 2 min). The results preclude 99Tcm-MBZM from making a brain receptor agent

  7. Crystal structure of N-[(morpholin-4-yl(thiophen-2-ylmethyl]benzamide

    Directory of Open Access Journals (Sweden)

    S. Arun Prabhu

    2015-07-01

    Full Text Available In the title compound, C16H18N2O2S, the morpholine ring adopts a chair conformation. The thiophene ring makes a dihedral angle of 63.54 (14° with the mean plane of the four C atoms [maximum deviation = 0.010 (3 Å] of the morpholine ring. The benzamide ring is disordered, with four C atoms occupying two sets of sites, with a refined occupancy ratio of 0.502 (4:0.498 (4. These two rings are inclined to one another by 85.2 (4° and to the thiophene ring by 72.7 (3 and 13.0 (3° for the major and minor components, respectively. In the crystal, molecules are linked via N—H...O hydrogen bonds, forming chains along [001].

  8. Fragmentation of Protonated N-(3-Aminophenyl)Benzamide and Its Derivatives in Gas Phase

    Science.gov (United States)

    Zu, Chengli; Mukhopadhyay, Sukrit; Hanley, Patrick S.; Xia, Shijing; Bell, Bruce M.; Grigg, David; Gilbert, Jeffrey R.; O'Brien, John P.

    2016-05-01

    An ion of m/ z 110.06036 (ion formula [C6H8NO]+; error: 0.32 mDa) was observed in the collision induced dissociation tandem mass spectrometry experiments of protonated N-(3-aminophenyl)benzamide, which is a rearrangement product ion purportedly through nitrogen-oxygen (N-O) exchange. The N-O exchange rearrangement was confirmed by the MS/MS spectrum of protonated N-(3-aminophenyl)- O 18 -benzamide, where the rearranged ion, [C6H8N O 18 ]+ of m/ z 112 was available because of the presence of O 18 . Theoretical calculations using Density Functional Theory (DFT) at B3LYP/6-31 g(d) level suggest that an ion-neutral complex containing a water molecule and a nitrilium ion was formed via a transition state ( TS- 1), followed by the water molecule migrating to the anilide ring, eventually leading to the formation of the rearranged ion of m/ z 110. The rearrangement can be generalized to other protonated amide compounds with electron-donating groups at the meta position, such as, -OH, -CH3, -OCH3, -NH(CH3)2, -NH-Ph, and -NHCOCH3, all of which show the corresponding rearranged ions in MS/MS spectra. However, the protonated amide compounds containing electron-withdrawing groups, including -Cl, -Br, -CN, -NO2, and -CF3, at the meta position did not display this type of rearrangement during dissociation. Additionally, effects of various acyl groups on the rearrangement were investigated. It was found that the rearrangement can be enhanced by substitution on the ring of the benzoyl with electron-withdrawing groups. [Figure not available: see fulltext.

  9. Fragmentation of Protonated N-(3-Aminophenyl)Benzamide and Its Derivatives in Gas Phase

    Science.gov (United States)

    Zu, Chengli; Mukhopadhyay, Sukrit; Hanley, Patrick S.; Xia, Shijing; Bell, Bruce M.; Grigg, David; Gilbert, Jeffrey R.; O'Brien, John P.

    2016-03-01

    An ion of m/z 110.06036 (ion formula [C6H8NO]+; error: 0.32 mDa) was observed in the collision induced dissociation tandem mass spectrometry experiments of protonated N-(3-aminophenyl)benzamide, which is a rearrangement product ion purportedly through nitrogen-oxygen (N-O) exchange. The N-O exchange rearrangement was confirmed by the MS/MS spectrum of protonated N-(3-aminophenyl)-O 18 -benzamide, where the rearranged ion, [C6H8NO 18 ]+ of m/z 112 was available because of the presence of O 18 . Theoretical calculations using Density Functional Theory (DFT) at B3LYP/6-31 g(d) level suggest that an ion-neutral complex containing a water molecule and a nitrilium ion was formed via a transition state (TS-1), followed by the water molecule migrating to the anilide ring, eventually leading to the formation of the rearranged ion of m/z 110. The rearrangement can be generalized to other protonated amide compounds with electron-donating groups at the meta position, such as, -OH, -CH3, -OCH3, -NH(CH3)2, -NH-Ph, and -NHCOCH3, all of which show the corresponding rearranged ions in MS/MS spectra. However, the protonated amide compounds containing electron-withdrawing groups, including -Cl, -Br, -CN, -NO2, and -CF3, at the meta position did not display this type of rearrangement during dissociation. Additionally, effects of various acyl groups on the rearrangement were investigated. It was found that the rearrangement can be enhanced by substitution on the ring of the benzoyl with electron-withdrawing groups. [Figure not available: see fulltext.

  10. Pyramidamycins A-D and 3-hydroxyquinoline-2-carboxamide; cytotoxic benzamides from Streptomyces sp. DGC1.

    Science.gov (United States)

    Shaaban, Khaled A; Shepherd, Micah D; Ahmed, Tamer A; Nybo, S Eric; Leggas, Markos; Rohr, Jürgen

    2012-12-01

    Four new benzamides, pyramidamycins A-D (2-5) along with the new natural 3-hydroxyquinoline-2-carboxamide (6) were isolated from the crude extract of Streptomyces sp. DGC1. Additionally, five other known compounds, namely 2-aminobenzamide (anthranilamide) (1), 4',7-dihydroxyisoflavanone (7), 2'-deoxy-thymidine, 2'-deoxy-uridine and adenosine were also isolated and identified. The structures of the new compounds 2-6 were elucidated by 1D and 2D NMR studies along with HR MS analyses. The isolated compounds 1-6 contained the same amide side chain. The isolated compounds 1-7 were biologically evaluated in comparison with landomycin A against a prostate cancer cell line (PC3) and non-small cell lung cancer cell line (H460) for 48 h and against several bacterial strains. Pyramidamycin C (4) was the most active compound against both PC3 and H460 cell lines (GI(50)=2.473 and 7.339 μM, respectively). Benzamides (1-3) demonstrated inhibitory activity against Kocuria rosea B-1106 (a diameter halo of 13±2 mm for 1; 10±2 mm for 2 and 3). Compound 6 was slightly active against both Escherichia coli DH5α and Micrococcus luteus NRRL B-2618 (diameter halos 8±2 and 9±2 mm, respectively). Taxonomically, the amplified 500-bp 16 S rRNA fragment of the Streptomyces sp. DGC1 had 99% identity (BLAST search) to the 16S rRNA gene of Streptomyces atrovirens strain NRRL B-16357. PMID:23047245

  11. [125]I-spectramide: A novel benzamide displaying potent and selective effects at the D2 dopamine receptor

    International Nuclear Information System (INIS)

    The new substituted benzamide Spectramide, (N-[2-[4-iodobenzyl-N-methylamino]-2-methoxy-4-ethyl]-5-chloro-methylamine benzamide) labelled with 125I was used as a potent and highly selective dopamine-D2 receptor antagonist in rat striatal homogenates for in vitro receptor binding. Kinetic experiments demonstrated the reversibility of the binding and the estimated Kd from saturation analysis was 25 pM, with a Bmax of 20 pmol/g of tissue. Competition studies showed that spectramide did not interact potently with the D1 or dopamine-uptake site. Drugs known to interact with other receptor system were weak competitors of the binding, while binding was potently inhibited by other D2 antagonists, such as spiperone and eticlopride. These data indicate that Spectramide binds selectively and with high affinity to the dopamine D2 receptors, and may prove to be a useful tool for the study of these receptors in vivo using PET or SPECT

  12. Photocatalytic/Cu-Promoted C-H Activations: Visible-light-Induced ortho-Selective Perfluoroalkylation of Benzamides.

    Science.gov (United States)

    Chen, Xiang; Tan, Ze; Gui, Qingwen; Hu, Liang; Liu, Jidan; Wu, Jing; Wang, Guangwei

    2016-04-25

    A visible-light-induced and copper-promoted perfluoroalkylation of benzamides was successfully developed under the assistance of an 8-aminoquinoline directing group. It provides a straightforward method for the synthesis of ortho-perfluoroalkyl-substituted benzoic acid derivatives. The reaction employs a cheap organic dye eosin Y as the photoredox catalyst and is run under the irradiation of a 26 W fluorescent LED light bulb. PMID:26933840

  13. Synthesis and Evaluation of Astatinated N-[2-(Maleimido)ethyl]-3-(trimethylstannyl)benzamide Immunoconjugates.

    Science.gov (United States)

    Aneheim, Emma; Gustafsson, Anna; Albertsson, Per; Bäck, Tom; Jensen, Holger; Palm, Stig; Svedhem, Sofia; Lindegren, Sture

    2016-03-16

    Effective treatment of metastasis is a great challenge in the treatment of different types of cancers. Targeted alpha therapy utilizes the short tissue range (50-100 μm) of α particles, making the method suitable for treatment of disseminated occult cancers in the form of microtumors or even single cancer cells. A promising radioactive nuclide for this type of therapy is astatine-211. Astatine-211 attached to tumor-specific antibodies as carrier molecules is a system currently under investigation for use in targeted alpha therapy. In the common radiolabeling procedure, astatine is coupled to the antibody arbitrarily on lysine residues. By instead coupling astatine to disulfide bridges in the antibody structure, the immunoreactivity of the antibody conjugates could possibly be increased. Here, the disulfide-based conjugation was performed using a new coupling reagent, maleimidoethyl 3-(trimethylstannyl)benzamide (MSB), and evaluated for chemical stability in vitro. The immunoconjugates were subsequently astatinated, resulting in both high radiochemical yield and high specific activity. The MSB-conjugate was shown to be stable with a long shelf life prior to the astatination. In a comparison of the in vivo distribution of the new immunoconjugate with other tin-based immunoconjugates in tumor-bearing mice, the MSB conjugation method was found to be a viable option for successful astatine labeling of different monoclonal antibodies. PMID:26791409

  14. Could N-(diethylcarbamothioyl)benzamide be a good ionophore for sensor membranes?

    Science.gov (United States)

    Fraga, Ana Rosa Lazo; Destri, Giovanni Li; Forte, Giuseppe; Rescifina, Antonio; Punzo, Francesco

    2010-09-01

    Nuclear Magnetic Resonance, Density Functional Theory and Molecular Dynamics calculations together with X-ray diffraction analysis have been used to enlighten the structural properties of N-(diethylcarbamothioyl)benzamide, a ionophore for sensor applications. Focusing the attention over the molecular conformation in different phases - i.e. solid state, solution and gas - before and after the interaction with a heavy metal ion, the behaviour of the molecule as a ionophore in a typical Ion Selective Electrode membrane was simulated. The whole structural analysis has been carried out as a comparison with an already studied and similar compound also used for the same purpose. To achieve this goal the available single crystal structure has been used to model the X-ray powder diffraction pattern. Although the condensed phase structure was not used as a starting guess for the gas phase model, it fits the possible conformers suggested for the gas phase. As the structure transition solid → gas takes place with a substantial identity preservation, an analogous structure in the liquid phase was suggested. As a consequence, a detailed interaction mechanism between the title compound and the Pb 2+ ion in solution has been depicted. Analogies and differences among the different structures and homologies with compounds of the same class, help the understanding of the ionophore behaviour in the electrode and its potential applications.

  15. Identification of a Benzamide Derivative that Inhibits Stress-Induced Adrenal Corticosteroid Synthesis

    Directory of Open Access Journals (Sweden)

    Jing Xu

    2009-09-01

    Full Text Available Elevated serum glucocorticoid levels contribute to the progression of many diseases, including depression, Alzheimer’s disease, hypertension, and acquired immunodeficiency syndrome. Here we show that the benzamide derivative N-[2-(4-cyclopropanecarbonyl-3-methyl-piperazin-1-yl-1-(tert-butyl-1H-indol-3-yl-methyl-2-oxo-ethyl]-4-nitrobenzamide (SP-10 inhibits dibutyryl cyclic AMP (dbcAMP-induced corticosteroid synthesis in a dose-dependent manner in Y-1 adrenal cortical mouse tumor cells, without affecting basal steroid synthesis and reduced stress-induced corticosterone increases in rats without affecting the physiological levels of the steroid in blood. SP-10 did not affect cholesterol transport and metabolism by the mitochondria but was unexpectedly found to increase 3-hydroxy-3-methylglutaryl-coenzyme A, low density lipoprotein receptor, and scavenger receptor class B type I (SR-BI expression. However, it also markedly reduced dbcAMP-induced NBD-cholesterol uptake, suggesting that this is a compensatory mechanism aimed at maintaining cholesterol levels. SP-10 also induced a redistribution of filamentous (F- and monomeric (G- actin, leading to decreased actin levels in the submembrane cytoskeleton suggesting that SP-10-induced changes in actin distribution might prevent the formation of microvilli–cellular structures required for SRBI-mediated cholesterol uptake in adrenal cells.

  16. Synthesis and evaluation of [18F] labeled benzamides: High affinity sigma receptor ligands for PET imaging

    International Nuclear Information System (INIS)

    We have synthesized and characterized four new fluorinated halobenzamides as sigma receptor ligands for use with positron emission tomography (PET). All the compounds were found to have high sigma-1 affinities (Ki = 0.38-0.98 nM), and the 4-fluoro-substituted benzamides were found to be more potent sigma-2 ligands (Ki = 3.77-4.02 nM) than their corresponding 2-fluoro analogs (Ki = 20.3-22.8 nM). The [18F] radiochemical syntheses of two of the analogs gave overall yields between 3-10% (EOS), radiochemical purities >99%, and specific activities between 800-1200 Ci/mmol (29.6-44.4 TBq/mmol). Rat biodistribution and blocking experiments were performed with 2-[18F](N-fluorobenzylpiperidin-4yl)-4-iodobenzamide, the analog with the best Ki value for sigma-1 sites (0.38 nM). Results of these experiments demonstrate specific uptake of the compound in tissues believed to contain sigma receptors, such as lungs, kidneys, heart, brain, and spleen and indicate its potential as a candidate for use in PET imaging of tissues containing these receptors

  17. Cobalt-Catalyzed Cyclization of N-Methoxy Benzamides with Alkynes using an Internal Oxidant through C-H/N-O Bond Activation.

    Science.gov (United States)

    Sivakumar, Ganesan; Vijeta, Arjun; Jeganmohan, Masilamani

    2016-04-18

    The cyclization of substituted N-methoxy benzamides with alkynes in the presence of an easily affordable cobalt complex and NaOAc provides isoquinolone derivatives in good to excellent yields. The cyclization reaction is compatible with a range of functional group-substituted benzamides, as well as ester- and alcohol-substituted alkynes. The cobalt complex [Co(III) Cp*(OR)2 ] (R=Me or Ac) serves as an efficient catalyst for the cyclization reaction. Later, isoquinolone derivatives were converted into 1-chloro and 1-bromo substituted isoquinoline derivatives in excellent yields in the presence of POCl3 or PBr3 . PMID:26951887

  18. Copper(II)-Mediated Intermolecular C(sp(2))-H Amination of Benzamides with Electron-Rich Anilines.

    Science.gov (United States)

    Singh, Bijaya Kumar; Polley, Arghya; Jana, Ranjan

    2016-05-20

    Despite significant progress, copper-catalyzed/mediated C-H amination reactions with electron-rich anilines remain an unsolved problem due to catalyst deactivation and deleterious side reactions. Herein, we report a copper(II)-mediated C(sp(2))-H amination of benzamides with electronically neutral or electron-rich anilines. A dramatic influence of silver(I) and tetrabutylammonium bromide was observed on the reaction outcome. The present protocol also demonstrates the synthesis of a number of nonsteroidal anti-inflammatory drugs. PMID:27148754

  19. Effect of combined treatment of caffeine benzamide and 137Cs γ-ray on mutation frequency in soybean

    International Nuclear Information System (INIS)

    The results of single treatment of caffeine or benzamide to M1 soybean are as follows. The seedling height, rate of mature plant, fertility, frequency of chromosomal aberration in root tip cells and activity of POD were obviously affected, and the same results were with M2. 137Cs γ-ray had damage and mutagenic effects on soybean. Combined treatment of the three methods enhanced M1 damage effect and M2 mutagenic effect. By the method of 3H-TdR, it was shown that caffeine inhibited the recovery of radiation damage and enforced the damage effect on M1 soybean and obviously increased mutagenic frequency of M2

  20. Assembling an isomer grid: the isomorphous 4-, 3- and 2-fluoro-N'-(4-pyridyl)benzamides

    OpenAIRE

    Donnelly, Katie; Gallagher, John F.; Lough, Alan J.

    2008-01-01

    The three title isomers, 4-, (I), 3-, (II), and 2-fluoro-N'-(4-pyridyl)benzamide, (III), all C₁₂H₉FN₂O, crystallize in the P21/c space group (No. 14) with similar unit-cell parameters and are isomorphous and isostructural at the primary hydrogen-bonding level. An intramolecular C-H...O=C interaction is present in all three isomers [C...O = 2.8681 (17)-2.884 (2) Å and C-H...O117-118°], with an additional N-H...F [N...F = 2.7544 (15) Å] interaction in (III). Intermolecular amide-pyridine N-H......

  1. Effects of organophosphorus donors in the extraction of Uranium(VI) with N-acetyl benzamide in chloroform

    International Nuclear Information System (INIS)

    The liquid-liquid extraction of Uranium(VI) from aqueous nitrate solution by a mixture of N-acetyl benzamide and Organophosphorus donors in chloroform is reported. Concentration of the metal was measured by fluorescence technique and synergism was observed in the extraction of Uranium(VI). Stoichiometries of extracted species in both individual and mixed extraction were ascertained by slope ratio analysis. From the extraction data, overall equilibrium constants for binary and ternary extractions were calculated. Thermodynamic parameters controlling the nature of extraction were also evaluated. (author)

  2. Synthesis, crystal structure, and cytotoxic activity of novel cyclic systems in [1,2,4]thiadiazolo[2,3-a]pyridine benzamide derivatives and their copper(II) complexes.

    Science.gov (United States)

    Adhami, Forogh; Safavi, Maliheh; Ehsani, Maryam; Ardestani, Sussan K; Emmerling, Franziska; Simyari, Farzaneh

    2014-06-01

    Three N-(pyridine-2-ylcarbamothioyl)benzamide derivatives were synthesized by the reaction of potassium thiocyanate, benzoyl chloride, and 2-amino pyridine derivatives in one pot. The obtained derivatives were oxidized using copper(ii) chloride. During the oxidation, two hydrogen atoms were removed, cyclization of the derivatives occurred, and finally, three new N-(2H-[1,2,4]thiadiazolo[2,3-a]pyridine-2-ylidene)benzamide derivatives were produced. Coordination of these three new derivative ligands to the copper(II) ion resulted in the formation of three new complexes: dichlorobis(N-(2H-[1,2,4]thiadiazolo[2,3-a]pyridine-2-ylidene)benzamide)copper(II), dichlorobis(N-(7-methyl-2H-[1,2,4]thiadiazolo[2,3-a]pyridine-2ylidene)benzamide)copper(II), and dichlorobis(N-(5-methyl-2H-[1,2,4]thiadiazolo[2,3-a]pyridine-2-ylidene)benzamide)copper(II). All the synthesized products were characterized by IR, (1)H NMR, and (13)C NMR spectroscopies. Crystal structures of the obtained N-(pyridine-2-ylcarbamothioyl)benzamide derivatives, N-(2H-[1,2,4]thiadiazolo[2,3-a]pyridine-2-ylidene)benzamide derivatives, and complexes were determined using X-ray single-crystal diffraction; the positions of atoms, bond lengths, bond angles, and dihedral angles were also determined. In all complexes, the coordination of two large monodentate ligands and two chloride anions to the copper(ii) ion resulted in the formation of a stable planar geometry around the central ion. Three N-(pyridine-2-ylcarbamothioyl)benzamide derivatives, three N-(2H-[1,2,4]thiadiazolo[2,3-a]pyridine-2-ylidene)benzamide derivatives, and three complexes were evaluated for their cytotoxicity against five human cancer cell lines (breast cancer cell line MDA-MB-231, neuroblastoma cell line SK-N-MC, prostate adenocarcinoma cell line LNCap, nasopharyngeal epidermoid carcinoma cell line KB, and liver cancer cell line HEPG-2) using an in vitro analysis. The N-(pyridine-2-ylcarbamothioyl)benzamide derivatives showed no cytotoxic

  3. Synthesis, in vitro binding and biodistribution in B16 melanoma-bearing mice of new iodine-125 spermidine benzamide derivatives

    Energy Technology Data Exchange (ETDEWEB)

    Moreau, Marie-France [INSERM UMR 484, BP 184, 63000 Clermont-Ferrand cedex (France); Univ d' Auvergne, F-63000 Clermont-Ferrand (France); Centre Jean Perrin, F-63000 Clermont-Ferrand (France); Papon, Janine [INSERM UMR 484, BP 184, 63000 Clermont-Ferrand cedex (France); Univ d' Auvergne, F-63000 Clermont-Ferrand (France); Centre Jean Perrin, F-63000 Clermont-Ferrand (France); Labarre, Pierre [INSERM UMR 484, BP 184, 63000 Clermont-Ferrand cedex (France); Univ d' Auvergne, F-63000 Clermont-Ferrand (France); Centre Jean Perrin, F-63000 Clermont-Ferrand (France); Moins, Nicole [INSERM UMR 484, BP 184, 63000 Clermont-Ferrand cedex (France); Univ d' Auvergne, F-63000 Clermont-Ferrand (France); Centre Jean Perrin, F-63000 Clermont-Ferrand (France)]. E-mail: moins@inserm484.u-clermont1.fr; Borel, Michele [INSERM UMR 484, BP 184, 63000 Clermont-Ferrand cedex (France); Univ d' Auvergne, F-63000 Clermont-Ferrand (France); Centre Jean Perrin, F-63000 Clermont-Ferrand (France); Bayle, Martine [INSERM UMR 484, BP 184, 63000 Clermont-Ferrand cedex (France); Univ d' Auvergne, F-63000 Clermont-Ferrand (France); Centre Jean Perrin, F-63000 Clermont-Ferrand (France); Bouchon, Bernadette [INSERM UMR 484, BP 184, 63000 Clermont-Ferrand cedex (France); Univ d' Auvergne, F-63000 Clermont-Ferrand (France); Centre Jean Perrin, F-63000 Clermont-Ferrand (France); Madelmont, Jean-Claude [INSERM UMR 484, BP 184, 63000 Clermont-Ferrand cedex (France); Univ d' Auvergne, F-63000 Clermont-Ferrand (France); Centre Jean Perrin, F-63000 Clermont-Ferrand (France)

    2005-05-01

    In the course of our investigations aimed at improving the biological characteristics of iodobenzamides for melanoma therapeutic applications, four new derivatives containing a spermidine chain have been prepared and radiolabeled with {sup 125}I. In vitro studies showed that all compounds displayed high affinity for melanin superior to the reference compound BZA, thus validating our experimental approach. In vivo biodistribution was investigated in B16 melanoma-bearing mice. All four compounds, particularly benzamide 3, showed accumulation in the tumor, but lower, however, than that of BZA. Moreover, high concentrations of radioactivity in other organs, namely, the liver and lung, demonstrated nonspecific tumoral uptake. In view of these results, compounds 1 2 3 4 do not appear to be suitable radiopharmaceuticals for melanoma radionuclide therapy.

  4. Species-specific pharmacology of Trichloro(sulfanylethyl benzamides as transient receptor potential ankyrin 1 (TRPA1 antagonists

    Directory of Open Access Journals (Sweden)

    Immke David C

    2007-12-01

    Full Text Available Abstract Agonists of TRPA1 such as mustard oil and its key component AITC cause pain and neurogenic inflammation in humans and pain behavior in rodents. TRPA1 is activated by numerous reactive compounds making it a sensor for reactive compounds in the body. Failure of AITC, formalin and other reactive compounds to trigger pain behavior in TRPA1 knockout mice, as well as the ability of TRPA1 antisense to alleviate cold hyperalgesia after spinal nerve ligation, suggest that TRPA1 is a potential target for novel analgesic agents. Here, we have characterized CHO cells expressing human and rat TRPA1 driven by an inducible promoter. As reported previously, both human and rat TRPA1 are activated by AITC and inhibited by ruthenium red. We have also characterized noxious cold response of these cell lines and show that noxious cold activates both human and rat TRPA1. Further, we have used CHO cells expressing human TRPA1 to screen a small molecule compound library and discovered that 'trichloro(sulfanylethyl benzamides' (AMG2504, AMG5445, AMG7160 and AMG9090 act as potent antagonists of human TRPA1 activated by AITC and noxious cold. However, trichloro(sulfanylethyl benzamides' (TCEB compounds displayed differential pharmacology at rat TRPA1. AMG2504 and AMG7160 marginally inhibited rat TRPA1 activation by AITC, whereas AMG5445 and AMG9090 acted as partial agonists. In summary, we conclude that both human and rat TRPA1 channels show similar AITC and noxious cold activation profiles, but TCEB compounds display species-specific differential pharmacology at TRPA1.

  5. N-[2-(Diethylamino)ethyl]benzamide als melanomaffine Trägermoleküle für Zytostatika und Gadoliniumkomplexe

    OpenAIRE

    Wolf, Markus

    2004-01-01

    Wegen ihrer hohen in vivo Melanomaffinität wurden N-[2-(Diethylamino)ethyl]benzamide als melanomselektive Trägermoleküle für Zytostatika ausgewählt. Es wurden Chlorambucilkon-jugate, Chlorambucilanaloga, Dacarbazinanaloga, Methotrexatkonjugate, ein Platinkomplex und ein Anthrazyklinkonjugat synthetisiert, analytisch charakterisiert und ihre IC50-Werte für murine B16 Melanomzellen, SkMel 28 (humane Melanomzellen), Mausfibroblasten, MH3924A (Morris Hepatom) und HeLa (humanes Zervixkarzinom) er...

  6. In vitro cytotoxicity activity on several cancer cell lines of acridone alkaloids and N-phenylethyl-benzamide derivatives from Swinglea glutinosa (Bl.) Merr.

    Science.gov (United States)

    Braga, P A C; Dos Santos, D A P; Da Silva, M F D G F; Vieira, P C; Fernandes, J B; Houghton, P J; Fang, R

    2007-01-01

    The methanol extract from the stems and fruits of Swinglea glutinosa (Rutaceae) afforded 11 known acridone alkaloids and three N-phenylethyl-benzamide derivatives, glycocitrine-IV, 1,3,5-trihydroxy-4-methoxy-10-methyl-2,8-bis(3-methylbut-2-enyl)acridin-9(10H)-one, 1,3,5- trihydroxy-2,8-bis(3-methylbut-2-enyl)-10-methyl-9-acridone, citbrasine, citrusinine-II, citrusinine-I, 5-dihydroxyacronycine, pyranofoline, 3,4-dihydro-3,5,8-trihydroxy-6-methoxy-2,2,7-trimethyl-2H-pyrano[2,3-a]acridin-12(7H)-one, 2,3-dihydro-4,9-dihydroxy-2-(2-hydroxy-propan-2-yl)-11-methoxy-10-methylfuro[3,2-b]acridin-5(10H)-one, bis-5-hydroxyacronycine, N-(2-{4-[(3,7-dimethylocta-2,6-dien-1-yl)oxy]phenyl}ethyl)benzamide, N-(2-{4-[(3,7-dimethyl-4-acethyl-octa-2,6-dien-1-yl)oxy]phenyl}ethyl)benzamide, and severine acetate. All compounds isolated were examined for their activity against three cancer cell lines: human lung carcinoma (COR-L23), human breast adenocarcinoma (MCF7), human melanoma (C32), and normal human fetal lung cell line, MRC-5. The acridones tested exhibited weak cytotoxicity but the amides showed moderate nonselective cytotoxic activity. PMID:17365689

  7. Substituted benzamides as ligands for visualization of dopamine receptor binding in the human brain by positron emission tomography

    International Nuclear Information System (INIS)

    Two substituted benzamides, FLB 524 and raclopride, were labeled with 11C and examined for their possible use as ligands for positron emission tomography (PET) scan studies on dopamine-2 (D-2) receptors in the brains of monkeys and healthy human subjects. Both ligands allowed the in vivo visualization of D-2 receptor binding in the corpus striatum caudate nucleus/putamen complex in PET-scan images. [11C]Raclopride showed a high ratio of specific striatal to nonspecific cerebellar binding, and the kinetics of binding of this ligand made it optimal for PET studies. The in vivo binding of [11C]raclopride in the striatum of cynomolgus monkeys was markedly reduced by displacement with haloperidol. In healthy human subjects, [11C]raclopride binding in the caudate nucleus/putamen was 4- to 5-fold greater than nonspecific binding in the cerebellum. In comparison with previously available ligands for PET-scan studies on central dopamine receptors in man, [11C]raclopride appears to be advantageous with regard to (i) specificity of binding to D-2 receptors, (ii) the high ratio between binding in dopamine-rich (caudate, putamen) and dopamine-poor (cerebellum) human brain regions, and (iii) rapid association and reversibility of specific binding

  8. Super acid catalysed sequential hydrolysis/cycloisomerization of -(acetylenic)benzamides under microwave condition: Synthesis, antinociceptive and antiinflammatory activity of substituted isocoumarins

    Indian Academy of Sciences (India)

    Chandrasekaran Praveen; P Dheenkumar; P T Perumal

    2013-01-01

    Synthesis of isocoumarins and related compounds via triflic acid promoted hydrolysis/cyclization sequence of 2-(alkynyl)benzamides under microwave condition was achieved. The substrate scope of the reaction was broad to include not only aromatic but also polyaromatic and heteroaromatic motifs, thus highlighting the significance of this methodology. One-pot operation, short reaction time, good chemical yields and excellent regioselectivity are the advantages of this protocol. All the synthesized compounds were evaluated for their antinociceptive and antiinflammatory activities using in vivo rodent models.

  9. Preferential binding of benzo[a]pyrene diol epoxide to the linker DNA of human foreskin fibroblasts in S phase in the presence of benzamide.

    OpenAIRE

    Kurian, P.; Jeffrey, A M; Milo, G E

    1985-01-01

    Addition of benzamide (BZ) at the onset of S phase inhibited expression of the neoplastic phenotype in human foreskin fibroblasts treated in vitro with (+/-)-7 alpha,8 beta-dihydroxy-9 beta,10 beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]P diol epoxide) in early S phase. Analysis of the specific B[a]P diol epoxide-DNA adducts revealed that ca. 65% of the total adducts in BZ and non-BZ carcinogen-treated cells was the B[a]P diol epoxide-deoxyguanine adduct. Limited micrococcal nuclease di...

  10. Radiolabelling of 4-iodo-N-(2-morpholinoethyl)benzamide with Na{sup 123}I and Na{sup 125}I

    Energy Technology Data Exchange (ETDEWEB)

    Tsopelas, C

    1999-07-01

    4-Iodo-N-(2-morpholinoethyl)benzamide (1) is a new benzamide that is an analogue of the antidepressant moclobemide. The synthesis of (1) is described and the radiolabelling conditions with Na{sup 123}I and Na{sup 125}I were optimized using the Cu(I)-added exchange labelling reaction. The reaction was found to perform best in the presence of Cu{sup +} and a stannous reducing agent, in the absence of Cu{sup 2+} and potassium iodide, and at [H{sup +}] = 1.8-7.9 mM with a ligand (1) concentration = 2.6-5.6 mg/mL cold kit. Above a [H{sup +}] of 7.9 mM, the hydrolysis of (1) gave 4-iodo[{sup 125}I]benzoic acid in high amounts. The radiochemical conversion was routinely >95% and >98% after anion exchange Sep-Pak treatment. The radiolabelled product is stable at room temperature for at least 4 h.

  11. Synthesis, crystal structures, luminescence and magnetic properties of lanthanide complexes containing the 1,8-bis(2-hydroxy-benzamide)-3,6-di-oxa-octane ligand

    Energy Technology Data Exchange (ETDEWEB)

    Winnie, Po-Wan Lai; Wing-Tak, Wong [Hong Kong Univ., Dept. of Chemistry, P.R. (China); Wing-Tak, Wong [PKU-PKU Joint Lab. on Rare Earth Materials, Pekin University, Beijing (China); Billy King-Fai, Li; Kwok-Wai, Cheah [Hong Kong Baptist University, Dept. of Physics, Hong Kong, P.R. (China)

    2002-05-01

    The reaction of 1,8-bis(2-hydroxy-benzamide)-3,6-di-oxa-octane (H{sub 2}L) with lanthanide nitrates in MeCN afforded new binuclear lanthanide complexes (Ln=La-Nd, Sm-Yb or Y, 1-13) in high yields, and the molecular structures of 1 and 2 were established by X-ray crystallography. A photophysical study of the ligand H{sub 2}L and of the binuclear complexes (Ln=Nd, Sm, Eu, Tb and Dy) has been performed and the quenching effect of coordinated water molecules was observed. The H{sub 2}L and Tb complex exhibit an up-conversion process under OPO excitation at 660 nm. The magnetic properties of Pr and Gd complexes are also reported. (authors)

  12. In Vitro Bactericidal Activity of 4- and 5-Chloro-2-hydroxy-N-[1-oxo-1-(phenylaminoalkan-2-yl]benzamides against MRSA

    Directory of Open Access Journals (Sweden)

    Iveta Zadrazilova

    2015-01-01

    Full Text Available A series of nine substituted 2-hydroxy-N-[1-oxo-1-(phenylaminoalkan-2-yl]benzamides was assessed as prospective bactericidal agents against three clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA and S. aureus ATCC 29213 as the reference and quality control strain. The minimum bactericidal concentration was determined by subculturing aliquots from MIC determination onto substance-free agar plates. The bactericidal kinetics of compounds 5-chloro-2-hydroxy-N-[(2S-3-methyl-1-oxo-1-{[4-(trifluoromethylphenyl]amino}butan-2-yl]benzamide (1f, N-{(2S-1-[(4-bromophenylamino]-3-methyl-1-oxobutan-2-yl}-4-chloro-2-hydroxybenzamide (1g, and 4-chloro-N-{(2S-1-[(3,4-dichlorophenylamino]-3-methyl-1-oxobutan-2-yl}-2-hydroxybenzamide (1h was established by time-kill assay with a final concentration of the compound equal to 1x, 2x, and 4x MIC; aliquots were removed at 0, 4, 6, 8, and 24 h time points. The most potent bactericidal agent was compound 1f exhibiting remarkable rapid concentration-dependent bactericidal effect even at 2x MIC at 4, 6, and 8 h (with a reduction in bacterial count ranging from 3.08 to 3.75 log10 CFU/mL and at 4x MIC at 4, 6, 8, and 24 h (5.30 log10 CFU/mL reduction in bacterial count after incubation against MRSA 63718. Reliable bactericidal effect against other strains was maintained at 4x MIC at 24 h.

  13. A novel 3-acetoxy-2-methyl-N-(4-methoxyphenyl)benzamide: Molecular structural describe, antioxidant activity with use X-ray diffractions and DFT calculations

    Science.gov (United States)

    Demir, Sibel; Cakmak, Sukriye; Dege, Necmi; Kutuk, Halil; Odabasoglu, Mustafa; Kepekci, R. Aysun

    2015-11-01

    In this work, the structure of a novel 3-acetoxy-2-methyl-N-(4-methoxyphenyl) benzamide, was analyzed both experimentally and theoretically using three methods, X-ray single crystal diffraction technique, IR spectroscopy, and quantum chemical computation. The X-ray diffraction analysis indicates that 3-acetoxy-2-methyl-N-(4-methoxyphenyl) benzamide molecula crystallizes in a triclinic system (space group P-1) and the calculated lattice constants are, a = 5.1205 ± 0.0004 Å, b = 9.8598 ± 0.0008 Å, c = 15.3398 ± 0.0013 Å, α = 80.79(7)°, β = 83.142(6)°, γ= 85.411(6)°, and Z = 2. In addition, the molecular geometry and vibrational frequencies of the title compound in ground state have been calculated using density functional theory (DFT) at B3LYP level 6-31G+(d,p) basis set. The geometrical parameters of the title compound obtained from XRD studies are good in agreement with the calculated values. The electronic properties, such as HOMO and LUMO energies and thermodynamic properties were calculated with DFT (using B3LYP/6-31G+(d,p) basis set) approach. To estimate the chemical reactivity of the molecule, the molecular electrostatic potential (MEP) surface map of the title molecule and PES scan were investigated with theoretical calculations at the B3LYP/6-31+G(d,p) and B3LYP/3-21G levels, respectively. Antioxidant properties are determined using DPPH free radical scavenging test.

  14. Synthesis, radiosynthesis, and in vitro evaluation of [131I]-5-iodo-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-yl)-ethyl] -2-methoxy-benzamide as a potential tumor imaging agent

    International Nuclear Information System (INIS)

    This work reports the synthesis, radiolabeling and preliminary in vitro evaluation of [131I]-5-iodo-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-yl)-ethyl] -2-methoxy-benzamide. The tributylstannylprecursor was synthesized with a yield of 38%. Radiolabeling was performed using an electrophilic iododestannylation. Tracer yield was 94%, radiochemical purity was >95%. The tracer showed high uptake in MCF-7 breast cancer cell line and therefore will be evaluated further

  15. Synthesis, in vitro binding profile and biodistribution of a 125I-labeled N-benzyl pyrrolidinyl benzamide derivative: A potential radioligand for mapping dopamine D2 receptors

    International Nuclear Information System (INIS)

    cis-N-(1-Benzyl-2-methylpyrrolidine-3-yl)-5-iodo-2-methoxy-4-(methylamino) benzamide (IYM), a YM-09151-2 analog iodinated at the 5-position of the benzoyl moiety, was synthesized and evaluated as a potential radiopharmaceutical for investigating brain dopamine D2 receptors by single photon emission computer tomography (SPECT). [125I]IYM was synthesized by a halogen exchange reaction and purified by high-performance liquid chromatography (HPLC). An in vitro competitive binding study with [3H]spiperone using rat striatal synaptosomal membranes revealed that IYM had higher affinity for dopamine D2 receptors than did YM-09151-2 or spiperone. In a saturation binding study using rat striatal synaptosomal membranes, IYM had a Kd of 0.04 nM. Biodistribution studies in mice disclosed that [125I]IYM exhibited high and specific striatal uptake, with the striatal/cerebellar uptake ratio being 14 at 120 min after injection. Furthermore, the striatal uptake of [125I]IYM was saturable, and [125I]IYM was displaced only by dopaminergic compounds. Ex vivo autoradiographic studies in rats further confirmed the high uptake and retention of this agent in the striatum and total blockade of its uptake by YM-09151-2. Thus, IYM showed specific binding to dopamine D2 receptors in the rodent striatum and therefore holds great potential for use in in vivo dopamine D2 receptor studies

  16. Synthesis, Crystal Structure and Biological Activity of 2-Chloro-N-{2-fluoro-5-[N-(phenylsulfonyl) phenyl- sulfonamido] phenyl} benzamide

    Institute of Scientific and Technical Information of China (English)

    LI Wen-ming; WANG Jian-guo; LI Zheng-ming; SONG Hai-bin

    2008-01-01

    2-Chloro-N-{2-fluoro-5-[N-(phenylsulfonyl)phenylsulfonamido]phenyl}benzamide was synthesized and its crystal structure was also determined by X-ray single-crystal diffraction. The title compound(C25H18C1FN2O5S2) belongs to monoclinic, space group P21/n with a=0.7377(3) nm, b=1.2036(5) nm, c=2.6846(11) nm, β=90.895(9)°,V=2.3833(16) nm3, Mr=544.98, Z=4, Dc= 1.519 g/cm3, μ=0.385 mm-1, F(000)=1120, R1=0.0632, and wR2=0. 1438. Its crystal structure belongs to a novel class that has not been reported yet, and its preliminary herbicidal activity was also tested. Its inhibition rate to seedling growth of barnyard grass reaches 15.1% at 100 μg/mL.

  17. Preferential binding of benzo[a]pyrene diol epoxide to linker DNA of human foreskin fibroblasts in S phase in the presence of benzamide

    International Nuclear Information System (INIS)

    Addition of benzamide (BZ) at the onset of S phase inhibited expression of the neoplastic phenotype of human foreskin fibroblasts treated in vitro with (+/-)-7α,8β-dihydroxy-9β,10β-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]P diol epoxide) in early S phase. Analysis of the specific B[a]P diol epoxide-DNA adducts revealed that ca. 65% of the total adducts in BZ and non-BZ carcinogen-treated cells was the B[a]P diol epoxide-deoxyguanine adduct. Limited micrococcal nuclease digestion of the early S phase nuclei from cells treated with B[a]P diol epoxide indicated that the carcinogen binds equally to linker and core DNA. However, when the cells were predominantly in S phase, in the presence of BZ, there was ca. three times more binding of B[a]P diol epoxide to the linker DNA compared to the core region. These data indicate that pretreatment of the cells with BZ at the onset of S phase established a preferential binding pattern in the linker DNA similar to that observed in the cells treated with B[a]P diol epoxide in G1 arrest

  18. Tumor Response and Apoptosis of N1-S1 Rodent Hepatomas in Response to Intra-arterial and Intravenous Benzamide Riboside

    International Nuclear Information System (INIS)

    Purpose: Benzamide riboside (BR) induces tumor apoptosis in multiple cell lines and animals. This pilot study compares apoptosis and tumor response in rat hepatomas treated with hepatic arterial BR (IA) or intravenous (IV) BR. Methods: A total of 106 N1-S1 cells were placed in the left hepatic lobes of 15 Sprague-Dawley rats. After 2 weeks, BR (20 mg/kg) was infused IA (n = 5) or IV (n = 5). One animal in each group was excluded for technical factors, which prevented a full dose administration (1 IA and 1 IV). Five rats received saline (3 IA and 2 IV). Animals were killed after 3 weeks. Tumor volumes after IA and IV treatments were analyzed by Wilcoxon rank sum test. The percentage of tumor and normal liver apoptosis was counted by using 10 fields of TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling)-stained slides at 40× magnification. The percentage of apoptosis was compared between IV and IA administrations and with saline sham-treated rats by the Wilcoxon rank sum test. Results: Tumors were smaller after IA treatment, but this did not reach statistical significance (0.14 IA vs. 0.57 IV; P = 0.138). There was much variability in percentage of apoptosis and no significant difference between IA and IV BR (44.49 vs. 1.52%; P = 0.18); IA BR and saline (44.49 vs. 33.83%; P = 0.66); or IV BR and saline (1.52 vs. 193%; P = 0.18). Conclusions: Although differences in tumor volumes did not reach statistical significance, there was a trend toward smaller tumors after IA BR than IV BR in this small pilot study. Comparisons of these treatment methods will require a larger sample size and repeat experimentation.

  19. Efficacy of the repellent N,N-diethyl-3-methyl-benzamide (DEET) against tabanid flies on horses evaluated in a field test in Switzerland.

    Science.gov (United States)

    Herholz, C; Kopp, C; Wenger, M; Mathis, A; Wägeli, S; Roth, N

    2016-05-15

    Female tabanid flies (Diptera: Tabanidae) can be a serious nuisance for horses because of their painful bites during blood feeding. They also play a primary role in mechanical transmission of a lentivirus causing Equine Infectious Anemia (EIA), a virus that has spread within Europe in recent years. According to the European law for products intended for use as a repellent on horses (recreational and sport horses), a field test is mandatory to demonstrate sufficient repellency of such a substance against the specific target fly species, but currently no agreed protocols are available for testing of potential repellents. The aim of the present study was to establish a protocol for a field test to investigate the efficacy of N,N-diethyl-3-methyl-benzamide (DEET, Brum®, Huebeli-Stud Horse Care AG) in a 15-17% oil-water emulsion against tabanid flies on horses up to four hours. Between July and August 2015, four horses on three farms each were tested on two consecutive days in a cross-over design. The four horses on Farm A were used in the pre-test as well as in the main test. Two and a half hours after repellent application the horses were lunged until sweating. Tabanid fly infestations were both photographed and directly counted during five minutes 3 and 4h after repellent application on the right side of the horses in the area from the head to the flank, belly and first third of the foreleg. Without repellent application, up to 29 tabanid flies were counted on a horse, whereas the maximum for the repellent treated horses was four. In 50% of the horses treated with DEET there were no Tabanids observed (efficacy 100%), and in all horses the tabanid fly counts were lower than in the control horses with one exemption at 4h. The efficacy of the DEET repellent was at least 80% and 71% respectively, three or four hours after application (with a confidence level of 89%). A fly trap (Horse Pal) revealed the presence of the tabanid species Tabanus brominus and Haematopota

  20. Crystal structures of two 18-crown-6 complexes: With the sodium salt of N-(Diiso-propoxyphosphoryl)benzamide and with the potassium salt of N-(Di-iso-propoxyphosphoryl)thiobenzamide

    International Nuclear Information System (INIS)

    Approximately isomorphous crystal structures of two 18-crown-6 complexes were determined: with the sodium salt of N-(diiso-propoxyphosphoryl)benzamide (I) and with the potassium salt of N-(di-iso-propoxyphosphoryl)thiobenzamide (II). Both I and II are (1:1:1) guest-host complexes containing two different hosts (the crown ether and a bidentate organophosphorus anion) and their common guest (an Na+ or K+ cation). Despite a certain similarity between complexes I and II, significant structural distinctions between them resulting from the difference in the ionic radii of Na+ and K+ cations were revealed. In complex I, the Na+ cation is hexacoordinated, and in complex II, the K+ cation is octacoordinated. In I, the crown ether has an asymmetric monoangular conformation, whereas in II, its conformation approximates that described by the D3d symmetry

  1. Discovery of 4-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamides as novel, highly potent and selective, orally bioavailable inhibitors of Tyrosine Threonine Kinase, TTK.

    Science.gov (United States)

    Laufer, Radoslaw; Li, Sze-Wan; Liu, Yong; Ng, Grace; Lang, Yunhui; Feher, Miklos; Brokx, Richard; Beletskaya, Irina; Hodgson, Richard; Mao, Guodong; Plotnikova, Olga; Awrey, Donald E; Mason, Jacqueline M; Wei, Xin; Lin, Dan Chi-Chia; Che, Yi; Kiarash, Reza; Madeira, Brian; Fletcher, Graham C; Mak, Tak W; Bray, Mark R; Pauls, Henry W

    2016-08-01

    TTK/Mps1 is a key kinase controlling progression of cell division via participation in the mitotic spindle assembly checkpoint and is overexpressed in a number of human cancers. Herein we report the discovery of 4-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamides as a potent, novel class of TTK inhibitors. The series was identified by means of bioisosteric replacement of the related imidazopyrazine and imidazopyridazine scaffolds. Optimization led to the identification of compounds with excellent potency (Ki=0.8nM) and exceptional kinase selectivity. The SAR indicates a strong dependence of activity on the presence of the N-cyclopropyl-2-methylbenzamide moiety delineating the geometry for 1½ type kinase inhibitor. Molecular modeling indicates the extensive and optimal contacts, mediated through H-bonds and hydrophobic interactions, are responsible for the selectivity and potency of the inhibitors. The compounds demonstrate a strong anti-proliferative activity in a panel of human cancer cell lines (HCT116 GI50<15nM) and good rodent pharmacokinetics (oral %F 97%). PMID:27335255

  2. Structural Basis for Small Molecule NDB (N-Benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) Benzamide) as a Selective Antagonist of Farnesoid X Receptor α (FXRα) in Stabilizing the Homodimerization of the Receptor.

    Science.gov (United States)

    Xu, Xing; Xu, Xin; Liu, Peng; Zhu, Zhi-yuan; Chen, Jing; Fu, Hai-an; Chen, Li-li; Hu, Li-hong; Shen, Xu

    2015-08-01

    Farnesoid X receptor α (FXRα) as a bile acid sensor plays potent roles in multiple metabolic processes, and its antagonist has recently revealed special interests in the treatment of metabolic disorders, although the underlying mechanisms still remain unclear. Here, we identified that the small molecule N-benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) benzamide (NDB) functioned as a selective antagonist of human FXRα (hFXRα), and the crystal structure of hFXRα ligand binding domain (hFXRα-LBD) in complex with NDB was analyzed. It was unexpectedly discovered that NDB induced rearrangements of helix 11 (H11) and helix 12 (H12, AF-2) by forming a homodimer of hFXRα-LBD, totally different from the active conformation in monomer state, and the binding details were further supported by the mutation analysis. Moreover, functional studies demonstrated that NDB effectively antagonized the GW4064-stimulated FXR/RXR interaction and FXRα target gene expression in primary mouse hepatocytes, including the small heterodimer partner (SHP) and bile-salt export pump (BSEP); meanwhile, administration of NDB to db/db mice efficiently decreased the gene expressions of phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6-pase), small heterodimer partner, and BSEP. It is expected that our first analyzed crystal structure of hFXRα-LBD·NDB will help expound the antagonistic mechanism of the receptor, and NDB may find its potential as a lead compound in anti-diabetes research. PMID:26100621

  3. Development and validation of a sensitive HPLC-MS/MS method for determination of chidamide (epidaza), a new benzamide class of selective histone deacetylase inhibitor, in human plasma and its clinical application.

    Science.gov (United States)

    Gu, Ruolan; Liu, Taoyun; Zhu, Xiaoxia; Gan, Hui; Wu, Zhuona; Li, Jian; Zheng, Ying; Dou, Guifang; Meng, Zhiyun

    2015-09-01

    Chidamide (epidaza), a new oral isotype-selective histone deacetylase inhibitor (HDACi), which is just approved in China for the treatment of recurrent or refractory peripheral T-cell lymphoma (PTCL) in December 2014, is the first listed benzamide class of HDACi in the world, and is currently undergoing global clinical trials for solid tumor treatments. Here, we report a sensitive, rapid and robust HPLC-MS/MS method for determination of chidamide in human plasma. Plasma sample was subjected to a simple acetonitrile protein precipitation containing MS-275 used as an internal standard (IS). Chromatography was performed on a Hypersil GOLD C18 analytical column, using a gradient methanol/water mobile phase containing 0.1% formic acid. A tandem mass spectrometer equipped with electrospray ionization source was used as detector and operated in the positive-ion mode. Selected reaction monitoring (SRM) using the precursor/ product transitions (m/z) of 391.1/265.1 for chidamide and 377.1/359.2 for IS were used for quantification, respectively. Good linearity was obtained in the range of 1-1000ng/mL. The method gave R.S.D.% values for precision always lower than 13.8% and R.E.% values for accuracy between -3.7 and 9.1%. In addition, the specificity, recovery, stability and matrix effect were satisfactory too. The method is now being successfully applied to plasma samples as part of an ongoing chidamide phase Ib clinical trial in patients with solid tumors, and had demonstrated consistent AUClast and t1/2 results with the published phase I pharmacokinetic data, which was also analyzed by this method, thus further confirming the reproducibility and accuracy during its clinical application. Considering the excellent performance of this method, it will continue being utilized for future clinical developments of chidamide and for routine monitoring of plasma exposure of chidamide during its clinical therapy. PMID:26245362

  4. Synthesis and in vivo evaluation of [123I]-4-iodo-N-(4-(4-(2-methoxyphenyl)-piperazin-1-yl)butyl)-benzamide, a potential sigma receptor ligand for SPECT studies

    International Nuclear Information System (INIS)

    the brain (ratio brain to blood after 10 min: 10). Pretreatment with cold product resulted in a decrease of accumulation of the tracer in the brain (ratio brain to blood after 10 min: 1.6). As expected the regional brain distribution showed a homogeneous distribution throughout the brain, pretreatment with FPS resulted in a decrease of the uptake in different brain regions (cortex: 91%, striatum: 88% and hypothalamus: 89% decrease). Conclusion: Both biodistribution and blocking studies in mice and rabbits show that 123I-4-iodo-N-(4-(4-(2-methoxyphenyl)-1-piperazinyl)butyl)-benzamide is a potential tracer for in vivo visualization of the sigma receptor

  5. 2-(Prop-2-enyloxy)benzamide

    Science.gov (United States)

    Bugenhagen, Bernhard; Al Jasem, Yosef; Barkhad, Farah; Hindawi, Bassam al; Thiemann, Thies

    2012-01-01

    In the title mol­ecule, C10H11NO2, the benzene ring forms dihedral angles of 33.15 (2) and 6.20 (2)° with the mean planes of the amide and propen­oxy groups, respectively. The amide –NH2 group is oriented toward the propen­oxy substituent and forms a weak intra­molecular N—H⋯O hydrogen bond to the propen­oxy O atom. The conformation of the propen­oxy group at the Csp 2—Csp 3 and Csp 3—O bonds is synperiplanar and anti­periplanar, respectively. In the crystal, N—H⋯O hydrogen bonds involving the amide groups generate C(4) and R 2 3(7) motifs that organize the mol­ecules into tapes along the a-axis direction. There are C—H⋯π inter­actions between the propen­oxy –CH2 group and the aromatic system of neighboring mol­ecules within the tape. The mean planes of the aromatic ring and the propen­oxy group belonging to mol­ecules located on opposite sites of the tape form an angle of 83.16 (2)°. PMID:23284483

  6. 2-(Prop-2-enyloxy)benzamide

    OpenAIRE

    Bugenhagen, Bernhard; Al Jasem, Yosef; Barkhad, Farah; Hindawi, Bassam al; Thiemann, Thies

    2012-01-01

    In the title mol­ecule, C10H11NO2, the benzene ring forms dihedral angles of 33.15 (2) and 6.20 (2)° with the mean planes of the amide and propen­oxy groups, respectively. The amide –NH2 group is oriented toward the propen­oxy substituent and forms a weak intra­molecular N—H⋯O hydrogen bond to the propen­oxy O atom. The conformation of the propen­oxy group at the Csp 2—Csp 3 and Csp 3—O bonds is synperiplanar and anti­periplanar, respectively. In the crystal, N—H⋯O hydrogen bonds involving th...

  7. Studies on coordination and addition compounds and anti microbial activity of some mixed ligand complexes of Au(III), Mo(II), Co(II) and Cd(II) with dibasic acid and heterocyclic amines and addition compounds of As(III) and Sb(III) halides with benzamide and acetophenon

    International Nuclear Information System (INIS)

    Three new mixed ligand complexes of Au(III) and Mo(II) with dibasic acid e.g., homophthalic acid, oxalic acid and heterocylic amines e.g., quinonine, iso-quinonine, bipyridine, Phenylanaline and the two new addition compounds of As(III) and Sb(III) halides with N-donor ligands viz. benzamide and acetophenone and one complex [Cd(DPH)(IQ)2], where IQ = Iso-quinoline and DPH = Deprotonated phthalic acid have been prepared according to the procedure in the literature. Their conventional physical and chemical analyses have been done. Their antibacterial studies against nine gram positive and five gram negative pathogenic bacteria and antifungal activities against eight plant and three human fungi have been evaluated. Kanamycin and Nystatin have been used as a standard for carrying out experiments of antibacterial and antifungal activities, respectively. The minimum inhibitory concentration (MIC) values of these compounds, as antibiotic against two gram positive and two gram negative pathogenic bacteria, have also been carried out and in this case, Amoxacilin antibiotic has been used as a standard antibiotic. (author)

  8. 对硝基苯甲醛缩对氨基乙酰苯胺希夫碱的室温固相合成及其可逆热致变色研究%Research on Solid State Synthesis and Reversible Thermochromic Behavior of N-methyl-4-(4-nitrobenzylidene amino)Benzamide Schiff Base

    Institute of Scientific and Technical Information of China (English)

    梁小蕊; 张勇; 王磊; 韩红宾; 杨秉东

    2011-01-01

    A Schiff base N-methyl-4-(4-nitrobenzylidene amino)benzamide were prepared by solid state reaction of 4-ni-trobenzaldehyde with 4-amino-N-methylbenzamide at room temperature. Element analysis and H1NMR confirmed the structure of the product and the color change process were studied by DSC spectra. The results indicated that the structure of the synthesized compound were consistent with that of the target product, the productive rate were higher, the melting ranges were narrower, the purity higher, and the reaction effect desirable. As a thermochromatic material the title compound has the advantages such as sharp swift color change speed, obvious color contrast, good reversibility and high color change temperature. In conclusion, the materials have good applied future.%以对硝基苯甲醛和对氨基乙酰苯胺为原料,通过室温固相反应合成了一种希夫碱衍生物,用元素分析、核磁共振等方法对产物进行了表征,并利用DSC技术对其变色过程进行了研究.结果表明,采用室温固相反应的方法合成的化合物结构和目标产物一致,且产率较高,熔程较短,纯度较高,反应效果理想.标题化合物作为热致变色材料具有变色敏锐、颜色对比明显、可逆性好以及变色温度高等特点,是一种具有良好应用前景的可逆热致变色材料.

  9. Synthesis and Crystal Structure of 3,5-Dichloro-N-(2-methoxyphenyl)benzamide

    Institute of Scientific and Technical Information of China (English)

    Aamer Saeed; Ulrich Fl(o)rke

    2013-01-01

    The title compound was synthesized by the direct reaction of 3,5-dichlorobenzoic acid with 2-methoxyaniline in the presence of DCC and HOBT.The structure was supported by the spectroscopic data and unambiguously confirmed by the single-crystal X-ray diffraction studies.It crystallizes from a methanol solution in the monoclinic space group P21/c with unit cell dimensions of a =4.9369(16),b =13.351(5),c =20.168(7) (A),β=96.755(8)°,V=1320.1(8) (A)3 and Z=4.

  10. Substituted 2-hydroxy-N-(arylalkyl)benzamides induce apoptosis in cancer cell lines

    Czech Academy of Sciences Publication Activity Database

    Imramovský, A.; Jorda, Radek; Pauk, K.; Řezníčková, Eva; Dušek, J.; Hanousek, J.; Kryštof, Vladimír

    2013-01-01

    Roč. 68, č. 2013 (2013), s. 253-259. ISSN 0223-5234 R&D Projects: GA ČR GAP305/12/0783; GA ČR GA301/08/1649 Institutional research plan: CEZ:AV0Z50380511 Keywords : Diamides * Apoptosis * Cytotoxicity Subject RIV: CE - Biochemistry Impact factor: 3.432, year: 2013

  11. Crystal structure of 4-fluoro-N-[2-(4-fluorobenzoylhydrazine-1-carbonothioyl]benzamide

    Directory of Open Access Journals (Sweden)

    Syadza Firdausiah

    2014-09-01

    Full Text Available In the title compound, C15H11F2N3O2S, the dihedral angle between the fluorobenzene rings is 88.43 (10° and that between the central semithiocarbazide grouping is 47.00 (11°. The dihedral angle between the amide group and attached fluorobenzene ring is 50.52 (11°; the equivalent angle between the carbonylthioamide group and its attached ring is 12.98 (10°. The major twists in the molecule occur about the C—N—N—C bonds [torsion angle = −138.7 (2°] and the Car—Car—C—N (ar = aromatic bonds [−132.0 (2°]. An intramolecular N—H...O hydrogen bond occurs, which generates an S(6 ring. In the crystal, the molecules are linked by N—H...O and N—H...S hydrogen bonds, generating (001 sheets. Weak C—H...O and C—H...F interactions are also observed.

  12. Synthesis of novel flavone derivatives possessing substituted benzamides and their biological evaluation against human cancer cells.

    Science.gov (United States)

    Yun, Bo Hee; Lee, Young Hun; Park, Kyung Tae; Jung, Su Jin; Lee, Yong Sup

    2016-09-01

    Baicalein is a well-known flavone derivative that possesses diverse biological properties, such as anticancer, antioxidant and anti-inflammatory activities. Numerous baicalein derivatives, including 5,6,7-trimethoxyflavone, have been synthesized with the aim of enhancing its inherent biological activities. In the present work, new flavones, possessing an N-aroylamine-substituent on the B-ring, were synthesized to improve the cytotoxicity of baicalein and 5,6,7-trimethoxyflavone against human cancer cell lines. The majority of the flavones synthesized exhibited greater cytotoxicity than baicalein and 5,6,7-trimethoxyflavone against HepG2 and MCF-7 cells. Among them, compounds 5n, possessing a 3-methoxybenzoylamino group, exhibited great cytotoxic effects on HepG2 (GI50=7.06μM) and MCF-7 (GI50=7.67μM) cells. In contrast, N-aroylamine-substituted 5-hydroxy-6,7-dimethoxyflavone derivatives showed greater cytotoxicity against MCF-7 than HepG2 cells, indicating that the replacement of a 5-methoxy group on the A-ring with a 5-hydroxy group has a marked influence on the cytotoxicity profile. PMID:27503682

  13. First-pass cerebral extraction of benzamide-derivative radiotracers for SPECT

    International Nuclear Information System (INIS)

    Central dopaminergic receptors are widely studied for their importance in the pathophysiology of neurological and psychiatric diseases. We have investigated the cerebral delivery kinetics of three dopaminergic ligands in rats through the use of an indicator fractionation method to measure the tracer's regional influx rate constant with respect to regional blood flow. The aim is to collect the in vivo kinetic parameters of the radioligand cerebral distribution, which are necessary if, dealing with SPECT and 'trapped' tracers, one wishes to analyse data using a graphical approach

  14. Benzamide capped peptidomimetics as non-ATP competitive inhibitors of CDK2 using the REPLACE strategy.

    Science.gov (United States)

    Premnath, Padmavathy Nandha; Craig, Sandra N; Liu, Shu; McInnes, Campbell

    2016-08-01

    Inhibition of cyclin dependent kinase 2 (CDK2) in complex with cyclin A in G1/S phase of the cell cycle has been shown to promote selective apoptosis of cancer cells through the E2F1 pathway. An alternative approach to catalytic inhibition is to target the substrate recruitment site also known as the cyclin binding groove (CBG) to generate selective non-ATP competitive inhibitors. The REPLACE strategy has been applied to identify fragment alternatives and substituted benzoic acid derivatives were evaluated as a promising scaffold to present appropriate functionality to mimic key peptide determinants. Fragment Ligated Inhibitory Peptides (FLIPs) are described which potently inhibit both CDK2/cyclin A and CDK4/cyclin D1 and have preliminary anti-tumor activity. A structural rationale for binding was obtained through molecular modeling further demonstrating their potential for further development as next generation non ATP competitive CDK inhibitors. PMID:27297568

  15. Nicotinamide and other benzamide analogs as agents for overcoming hypoxic cell radiation resistance in tumours

    International Nuclear Information System (INIS)

    Oxygen deficient hypoxic cells, which are resistant to sparsely ionising radiation, have now been identified in most animal and some human solid tumours and will influence the response of those tumours to radiation treatment. This hypoxia can be either chronic, arising from an oxygen diffusion limitation, or acute, resulting from transient stoppages in microregional blood flow. Extensive experimental studies, especially in the last decade, have shown that nicotinamide and structurally related analogs can effectively sensitize murine tumours to both single and fractionated radiation treatments and that they do so in preference to the effects seen in mouse normal tissues. The earliest studies suggested that this enhancement of radiation damage was the result of an inhibition of the repair mechanisms. However, recent studies in mouse tumours have shown that these drugs prevent transient cessations in blood flow, thus inhibiting the development of acute hypoxia. This novel discovery led to the suggestion that the potential role of these agents as radiosensitizers would be when combined with treatments that overcame chronic hypoxia. The combined nicotinamide with hyperthermia proved that the enhancement of radiation damage by both agents together was greater than that seen with each agent alone. Similar results were later seen for nicotinamide combined with a perfluorochemical emulsion, carbogen breathing, and pentoxifylline, and in all these studies the effects in tumours were always greater than those seen in appropriate normal tissues. Of all the analogs, it is nicotinamide itself which has been the most extensively studied as a radiosensitizer in vivo and the one that shows the greatest effect in animal tumours. It is also an agent that has been well established clinically, with daily doses of up to 6 g, associated with a low incidence of side effects. This human dose is equivalent to 100-200 mg/kg in mice and such doses will maximally sensitize murine tumours to radiation. These findings have now resulted in clinical trials of nicotinamide, in combination with carbogen breathing, as a potential radiosensitizing treatment. (EG)

  16. Crystal structure of 4-methoxy-N-[(pyrrolidin-1-ylcarbothioyl]benzamide

    Directory of Open Access Journals (Sweden)

    Khairi Suhud

    2015-04-01

    Full Text Available In the title compound, C13H16N2O2S, the pyrrolidine ring has a twisted conformation on the central –CH2–CH2– bond. Its mean plane is inclined to the 4-methoxybenzoyl ring by 72.79 (15°. In the crystal, molecules are linked by N—H...O and C—H...O hydrogen bonds to the same O-atom acceptor, forming chains along [001]. The chains are linked via slipped parallel π–π interactions [inter-centroid distance = 3.7578 (13 Å], forming undulating slabs parallel to (100.

  17. 4-Chloro-N-(2,3-dimethyl­phen­yl)benzamide

    OpenAIRE

    Rodrigues, Vinola Z.; Kameníček,, Jiří; Gowda, B. Thimme; Kožíšek, Jozef

    2011-01-01

    In the title compound, C15H14ClNO, the ortho- and meta-methyl substituents in the aniline ring are anti to the N—H bond. The dihedral angle between the benzoyl and aniline benzene rings is 95.0 (1)°. N—H⋯O hydrogen bonds and C—H⋯π inter­actions link the mol­ecules in the crystal structure.

  18. Shelf-life of ɛ-lysyl-3-(trimethylstannyl)benzamide immunoconjugates, precursors for 211At labeling of antibodies

    DEFF Research Database (Denmark)

    Aneheim, Emma; Halleröd, Jenny; Albertsson, Per;

    2015-01-01

    Astatine-211 is possibly the most promising radionuclide for targeted α-particle therapy when it comes to the treatment of occult disseminated cancer. Preclinical research has proven effective, and patient studies have been initiated based on these results. However, a lack of production capacity ...

  19. Shelf-Life of ɛ-Lysyl-3-(Trimethylstannyl)Benzamide Immunoconjugates, Precursors for 211At Labeling of Antibodies

    OpenAIRE

    Aneheim, Emma; Halleröd, Jenny; Albertsson, Per; Jensen, Holger; Holgersson, Stellan; Lindegren, Sture

    2015-01-01

    Astatine-211 is possibly the most promising radionuclide for targeted α-particle therapy when it comes to the treatment of occult disseminated cancer. Preclinical research has proven effective, and patient studies have been initiated based on these results. However, a lack of production capacity and the complex radiochemistry of 211At are major obstacles for research and prospective clinical applications. In the present study, astatination of immunoconjugates, already prepared well in advance...

  20. The family of N9-adenine: New entry for adenine-benzamide conjugates linked via versatile spacers

    Indian Academy of Sciences (India)

    Prabhpreet Singh

    2014-01-01

    We have prepared 4-nitrobenzamide-adenine conjugates (8, 13 and 14) linked with versatile spacer such as triethylene glycol (TEG), aminocaproic acid and ethyl chains which were eventually reduced to obtain the corresponding 4-aminobenzamide-adenine conjugates (1-3) in good yields. These conjugates bear a nucleobase for DNA recognition or self-assembly through base-pair complementarity, a biocompatible linker for interfacing with biological system, and a p-aminobenzamide moiety for pharmacological applications. The use of hydrophilic or lipophilic linkers may tune the dispersibility of these conjugates in different solvents, as well as impart different properties. In the preliminary experiments the versatility and application of these linkers has been tested for functionalization of SWCNTs.

  1. Conformational arm-wrestling: battles for stereochemical control in benzamides bearing matched and mismatched chiral 2- and 6-substituents.

    Science.gov (United States)

    Clayden, Jonathan; Foricher, Yann J Y; Helliwell, Madeleine; Johnson, Paul; Mitjans, David; Vinader, Victoria

    2006-02-01

    The orientation of a tertiary amide group adjacent to an aromatic ring may be governed by the stereochemistry of an adjacent chiral substituent. With a chiral substituent in both ortho positions, matched/mismatched pairs of isomers result. Evidence for matched stereochemistry is provided by the clean NMR spectra of single conformers, while mismatching gives poor or unexpected selectivities in the formation of chiral substituents, or mixtures of amide conformers. Attempts to use the match-mismatch effect to select for racemic pairs of enantiomeric substituents, and hence develop a "racemate-sequestering" reagent, are described, along with the use of "matching" to scavenge a single enantiomer of a diamine from material of incomplete enantiomeric purity. PMID:16446801

  2. Design, Synthesis and Biological Activity of Substituted-N-[4- (substituted-phenylsulfamoyl)phenyl]benzamide as Potential AHAS Inhibitors

    Institute of Scientific and Technical Information of China (English)

    Jian Guo WANG; Yong Jun XIAO; Yong Hong LI; Xing Hai LIU; Zheng Ming LI

    2006-01-01

    Based on the crystal structure of AHAS/sulfonylurea complex, we obtained 296compounds with low binding energy towards AHAS via virtual screening. One series of them have been synthesized. Preliminary bioassay indicated that some compounds displayed good herbicidal activity on rape and barnygrass and inhibited AHAS to some extent. This study indicated the rationality of our molecular design based on the crystal structure of target enzyme.

  3. 4-N-pyridin-2-yl-benzamide nanotubes compatible with mouse stem cell and oral delivery in Drosophila

    Energy Technology Data Exchange (ETDEWEB)

    Yadav, Jhillu S; Das, Pragna P; Bag, Indira; Krishnan, Anita; Jagannadh, Bulusu; Mohapatra, Debendra K; Bhadra, Manika Pal [Division of Organic Chemistry-I, Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500007 (India); Lavanya, Madugula P; Bhadra, Utpal [Functional Genomics and Gene Silencing Group, Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500007 (India)

    2010-04-16

    p-aminobenzoic acid (PABA), a structural moiety of many commercial drugs, is self-assembled with linker alkyl side chains to form tubular nanostructures. The tubes exhibited fluorescence either intrinsic or from fluorescent molecules embedded in the wall during self-assembly. Uptake and inter-cellular delivery of the conjugated nanotubes in human cancer cells and in mouse embryonic stem cells were demonstrated by fluorescence imaging and flow cytometry. Biocompatibility, cytotoxicity and clearance were monitored both ex vivo in mouse multipotent embryonic stem cells and in vivo in adult Drosophila. Accumulation of nanotubes had no adverse effects and abnormalities on stem cell morphology and proliferation rate. A distinct distribution of two separate nanotubes in various internal organs of Drosophila interprets that accumulation of nanomaterials might be interdependent on the side chain modifications and physiological settings of cell or tissue types. Unlike carbon nanomaterials, exposure of PABA nanotubes does not produce any hazards including locomotion defects and mortality of adult flies. Despite differential uptake and clearance from multiple live tissues, the use of self-assembled nanotubes can add new dimensions and scope to the development of dual-purpose oral carriers for the fulfilment of many biological promises.

  4. 4-N-pyridin-2-yl-benzamide nanotubes compatible with mouse stem cell and oral delivery in Drosophila

    Science.gov (United States)

    Yadav, Jhillu S.; Lavanya, Madugula P.; Das, Pragna P.; Bag, Indira; Krishnan, Anita; Jagannadh, Bulusu; Mohapatra, Debendra K.; Pal Bhadra, Manika; Bhadra, Utpal

    2010-04-01

    p-aminobenzoic acid (PABA), a structural moiety of many commercial drugs, is self-assembled with linker alkyl side chains to form tubular nanostructures. The tubes exhibited fluorescence either intrinsic or from fluorescent molecules embedded in the wall during self-assembly. Uptake and inter-cellular delivery of the conjugated nanotubes in human cancer cells and in mouse embryonic stem cells were demonstrated by fluorescence imaging and flow cytometry. Biocompatibility, cytotoxicity and clearance were monitored both ex vivo in mouse multipotent embryonic stem cells and in vivo in adult Drosophila. Accumulation of nanotubes had no adverse effects and abnormalities on stem cell morphology and proliferation rate. A distinct distribution of two separate nanotubes in various internal organs of Drosophila interprets that accumulation of nanomaterials might be interdependent on the side chain modifications and physiological settings of cell or tissue types. Unlike carbon nanomaterials, exposure of PABA nanotubes does not produce any hazards including locomotion defects and mortality of adult flies. Despite differential uptake and clearance from multiple live tissues, the use of self-assembled nanotubes can add new dimensions and scope to the development of dual-purpose oral carriers for the fulfilment of many biological promises.

  5. Detection of the Streptomyces coelicolor brgA mutation leading to benzamide resistance and abolishment of differentiation

    Czech Academy of Sciences Publication Activity Database

    Petříček, Miroslav; Kieser, H.; Hopwood, D. A.; Ochi, K.

    SissiHeraklion: Hellenic Society of Biological Sciences, 1999. s. 118. [International Symposium on the Biology of Actinomycetes .. 24.10.1999-28.10.1999, Sissi-Heraklion] Subject RIV: EE - Microbiology, Virology

  6. N-(2-Hydroxy­ethyl)-2-[3-(p-tol­yl)triazen-1-yl]benzamide

    OpenAIRE

    Rocha-Alonzo, Fernando; Aguirre, Gerardo; Parra-Hake, Miguel

    2009-01-01

    In the solid state, the structure of the title compound, C16H18N4O2, is stabilized by inter­molecular N—H⋯O and O—H⋯O hydrogen bonds. These hydrogen bonds arrange the mol­ecules into a double-layer supra­molecular structure. The mol­ecular conformation is is consolidated by an intra­molecular N—H⋯N hydrogen bond. The dihedral angle between the aromatic rings is 8.01 (10)°

  7. Crystal structures of 3-fluoro-N-[2-(tri­fluoro­meth­yl)phen­yl]benzamide, 3-bromo-N-[2-(tri­fluoro­meth­yl)phen­yl]benzamide and 3-iodo-N-[2-(tri­fluoro­meth­yl)phen­yl]benzamide

    Science.gov (United States)

    Suchetan, P. A.; Suresha, E.; Naveen, S.; Lokanath, N. K.

    2016-01-01

    In the title compounds, C14H9F4NO, (I), C14H9BrF3NO, (II), and C14H9F3INO, (III), the two benzene rings are inclined to one another by 43.94 (8)° in mol­ecule A and 55.66 (7)° in mol­ecule B of compound (I), which crystallizes with two independent mol­ecules in the asymmetric unit, but by only 10.40 (12)° in compound (II) and 12.5 (2)° in compound (III). In the crystals of all three compounds, N—H⋯O hydrogen bonds link the mol­ecules to form chains propagating along the a-axis direction for (I), and along the b-axis direction for (II) and (III). In the crystal of (I), –A–B–A–B– chains are linked by C—H⋯O hydrogen bonds, forming layers parallel to (010). Within the layers there are weak offset π–π inter­actions present [inter­centroid distances = 3.868 (1) and 3.855 (1) Å]. In the crystals of (II) and (III), the chains are linked via short halogen–halogen contacts [Br⋯Br = 3.6141 (4) Å in (II) and I⋯I = 3.7797 (5) Å in (III)], resulting in the formation of ribbons propagating along the b-axis direction. PMID:27308050

  8. Crystal structures of 3-fluoro-N-[2-(tri-fluoro-meth-yl)phen-yl]benzamide, 3-bromo-N-[2-(tri-fluoro-meth-yl)phen-yl]benzamide and 3-iodo-N-[2-(tri-fluoro-meth-yl)phen-yl]benzamide.

    Science.gov (United States)

    Suchetan, P A; Suresha, E; Naveen, S; Lokanath, N K

    2016-06-01

    In the title compounds, C14H9F4NO, (I), C14H9BrF3NO, (II), and C14H9F3INO, (III), the two benzene rings are inclined to one another by 43.94 (8)° in mol-ecule A and 55.66 (7)° in mol-ecule B of compound (I), which crystallizes with two independent mol-ecules in the asymmetric unit, but by only 10.40 (12)° in compound (II) and 12.5 (2)° in compound (III). In the crystals of all three compounds, N-H⋯O hydrogen bonds link the mol-ecules to form chains propagating along the a-axis direction for (I), and along the b-axis direction for (II) and (III). In the crystal of (I), -A-B-A-B- chains are linked by C-H⋯O hydrogen bonds, forming layers parallel to (010). Within the layers there are weak offset π-π inter-actions present [inter-centroid distances = 3.868 (1) and 3.855 (1) Å]. In the crystals of (II) and (III), the chains are linked via short halogen-halogen contacts [Br⋯Br = 3.6141 (4) Å in (II) and I⋯I = 3.7797 (5) Å in (III)], resulting in the formation of ribbons propagating along the b-axis direction. PMID:27308050

  9. Design and Synthesis of DiselenoBisBenzamides (DISeBAs) as Nucleocapsid Protein 7 (NCp7) Inhibitors with anti-HIV Activity.

    Science.gov (United States)

    Sancineto, Luca; Mariotti, Alice; Bagnoli, Luana; Marini, Francesca; Desantis, Jenny; Iraci, Nunzio; Santi, Claudio; Pannecouque, Christophe; Tabarrini, Oriana

    2015-12-24

    The interest in the synthesis of Se-containing compounds is growing with the discovery of derivatives exhibiting various biological activities. In this manuscript, we have identified a series of 2,2'-diselenobisbenzamides (DISeBAs) as novel HIV retroviral nucleocapsid protein 7 (NCp7) inhibitors. Because of its pleiotropic functions in the whole viral life cycle and its mutation intolerant nature, NCp7 represents a target of great interest which is not reached by any anti-HIV agent in clinical use. Using the diselenobisbenzoic scaffold, amino acid, and benzenesulfonamide derivatives were prepared and biologically profiled against different models of HIV infection. The incorporation of amino acids such as glycine and glutamate into DISeBAs 7 and 8 resulted in selective anti-HIV activity against both acutely and chronically infected cells as well as an interesting virucidal effect. DISeBAs demonstrated broad antiretroviral activity, encompassing HIV-1 drug-resistant strains including clinical isolates, as well as simian immunodeficiency virus (SIV). Time of addition experiments, along with the observed dose dependent inhibition of the Gag precursor proper processing, confirmed that their mechanism of action is based on NCp7 inhibition. PMID:26613134

  10. Crystal structure of 4-fluoro-N-[2-(4-fluoro­benzo­yl)hydra­zine-1-carbono­thio­yl]benzamide

    Science.gov (United States)

    Firdausiah, Syadza; Salleh Huddin, Ameera Aqeela; Hasbullah, Siti Aishah; Yamin, Bohari M.; Yusoff, Siti Fairus M.

    2014-01-01

    In the title compound, C15H11F2N3O2S, the dihedral angle between the fluoro­benzene rings is 88.43 (10)° and that between the central semithiocarbazide grouping is 47.00 (11)°. The dihedral angle between the amide group and attached fluoro­benzene ring is 50.52 (11)°; the equivalent angle between the carbonyl­thio­amide group and its attached ring is 12.98 (10)°. The major twists in the mol­ecule occur about the C—N—N—C bonds [torsion angle = −138.7 (2)°] and the Car—Car—C—N (ar = aromatic) bonds [−132.0 (2)°]. An intra­molecular N—H⋯O hydrogen bond occurs, which generates an S(6) ring. In the crystal, the mol­ecules are linked by N—H⋯O and N—H⋯S hydrogen bonds, generating (001) sheets. Weak C—H⋯O and C—H⋯F inter­actions are also observed. PMID:25309250

  11. Ring Substituents on Substituted Benzamide Ligands Indirectly Mediate Interactions with Position 7.39 of Transmembrane Helix 7 of the D4 Dopamine Receptor

    OpenAIRE

    Ericksen, Spencer S.; Cummings, David F.; Teer, Michael E.; Amdani, Shahnawaz; Schetz, John A.

    2012-01-01

    In an effort to delineate how specific molecular interactions of dopamine receptor ligand classes vary between D2-like dopamine receptor subtypes, a conserved threonine in transmembrane (TM) helix 7 (Thr7.39), implicated as a key ligand interaction site with biogenic amine G protein-coupled receptors, was substituted with alanine in D2 and D4 receptors. Interrogation of different ligand chemotypes for sensitivity to this substitution revealed enhanced affinity in the D4, but not the D2 recept...

  12. Melanin Targeted Pre-clinical PET Imaging of Melanoma Metastasis

    OpenAIRE

    Ren, Gang; Miao, Zheng; Liu, Hongguang; Jiang, Lei; Limpa-Amara, Naengnoi; Mahmood, Ashfaq; Gambhir, Sanjiv S.; Cheng, Zhen

    2009-01-01

    Dialkylamino-alkyl-benzamide possess affinities for melanin, suggesting that such 18F-labeled benzamides could potentially be used as melanin targeted positron emission tomography (PET) probes to identify melanotic melanoma metastases in vivo with high sensitivity and specificity. In this report, we describe the synthesis, in vitro and in vivo evaluation of 18F-N-[2-(diethylamino)ethyl]-4-fluoro-Benzamide (18F-FBZA) in mouse tumor models.

  13. Fluorinated benzamide neuroleptics--III. Development of (S)-N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-[18F]fluoropropyl)-2,3- dimethoxybenzamide as an improved dopamine D-2 receptor tracer

    International Nuclear Information System (INIS)

    We have prepared five new analogs (n-propyl, iso-propyl, allyl, n-butyl, and iso-butyl) of the dopamine D-2 receptor antagonist, FPMB which result from modifications of the ethyl group at the pyrrolidine nitrogen in FPMB. As expected, all new derivatives showed higher apparent lipophilicity (log kw), with iso-butyl being the most lipophilic (log kw = 2.52), followed by the allyl derivative (log kw = 2.43). The allyl group showed the largest increase in affinity (from 0.26 nM for the ethyl substituent to 0.03 nM for the allyl substituent, almost 10-fold), followed by the n-propyl substituent which showed approximately five-fold better affinity than did the ethyl substituent. Radiosynthesis of (S-N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-[18F]fluoropropyl)-2,3- dimethoxybenzamide ([18F]fallypride) was carried out by nucleophilic substitution reaction of (S)-N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-tosyloxypropyl)-2,3- dimethoxybenzamide with no carrier added 18F-. [18F]Fallypride was obtained in approximately 20-40% yields (EOS/EOB, decay corrected) in specific activities of 900-1700 Ci/mmol after reverse phase HPLC purification in 60 min from EOB. High striatal uptake (upto 2.5% injected dose/g) of [18F]fallypride in rats was observed with striatal/cerebellar ratios of 17, 42, 63 and 122 at 30, 60, 90 and 120 min post-injection, respectively. PET experiments with [18F]fallypride in a cebus monkey showed a brain uptake of 0.10% injected dose/cc. In rhesus monkeys [18F]fallypride showed rapid specific uptake in the striata (0.04-0.06% injected dose/cc) with striata/cerebellum ratios of approx. 3.0 at 14 min, 5.0 at 35 min and 8 at 70 min post-injection. Specifically bound [18F]fallypride was displaced with haloperidol (1 mg/kg) with a half-life of 18 min in the rhesus monkey

  14. Discovery of N-(3-((1-Isonicotinoylpiperidin-4-yl)oxy)-4-methylphenyl)-3-(trifluoromethyl)benzamide (CHMFL-KIT-110) as a Selective, Potent, and Orally Available Type II c-KIT Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs).

    Science.gov (United States)

    Wang, Qiang; Liu, Feiyang; Wang, Beilei; Zou, Fengming; Chen, Cheng; Liu, Xiaochuan; Wang, Aoli; Qi, Shuang; Wang, Wenchao; Qi, Ziping; Zhao, Zheng; Hu, Zhenquan; Wang, Wei; Wang, Li; Zhang, Shanchun; Wang, Yuexiang; Liu, Jing; Liu, Qingsong

    2016-04-28

    c-KIT kinase is a validated drug discovery target for gastrointestinal stromal tumors (GISTs). Clinically used c-KIT kinase inhibitors, i.e., Imatinib and Sunitinib, bear other important targets such as ABL or FLT3 kinases. Here we report our discovery of a more selective c-KIT inhibitor, compound 13 (CHMFL-KIT-110), which completely abolished ABL and FLT3 kinase activity. KinomeScan selectivity profiling (468 kinases) of 13 exhibited a high selectivity (S score (1) = 0.01). 13 displayed great antiproliferative efficacy against GISTs cell lines GIST-T1 and GIST-882 (GI50: 0.021 and 0.043 μM, respectively). In the cellular context, it effectively affected c-KIT-mediated signaling pathways and induced apoptosis as well as cell cycle arrest. In addition, 13 possessed acceptable bioavailability (36%) and effectively suppressed the tumor growth in GIST-T1 cell inoculated xenograft model without apparent toxicity. 13 currently is undergoing extensive preclinical evaluation and might be a potential drug candidate for GISTs. PMID:27077705

  15. Synthesis, in vitro binding, and tissue distribution of radioiodinated 2-[{sup 125}I]N-(N-benzylpiperidin-4-yl)-2-iodo benzamide, 2-[{sup 125}I]BP: a potential {sigma} receptor marker for human prostate tumors

    Energy Technology Data Exchange (ETDEWEB)

    John, Christy S.; Gulden, Mary E.; Li, Jinghua; Bowen, Wayne D.; McAfee, John G.; Thakur, Mathew L

    1998-04-01

    The preclinical evaluation of a {sigma} receptor-specific radiopharmaceutical that binds to human prostate tumor cells with a high affinity is described. We have synthesized and radioiodinated 2-[{sup 125}I]-N-(N-benzylpiperidin-4-yl)-2-iodobenzamide (2-[{sup 125}I]BP) that possesses high affinity for both {sigma}-1 and {sigma}-2 receptor subtypes that are expressed on a variety of tumor cells. 2-IBP was synthesized, purified and characterized by routine spectroscopic and analytical methods. Radioiodination was accomplished using an oxidative iododestannylation reaction in the presence of chloramine T in high yields (76%-93%) with a very high-specific activity (1700-1900 Ci/mmol). The in vitro competition binding studies of 2-[{sup 125}I]BP with various {sigma} receptor ligands in LnCAP human prostate tumor cells showed a dose-dependent saturable binding. The inhibition constants (K{sub i}, nM) for binding of 2-[{sup 125}I]BP to human prostate tumor cells for 4-IBP, haloperidol and 2-IBP were 4.09, 6.34 and 1.6 nM, respectively. The clearance of 2-[{sup 125}I]BP, in Sprague-Dawley rats, was rapid from the blood pool, other normal tissues and the total body. Tissue distribution studies in nude mice bearing human prostate tumor (DU-145) also showed a fast clearance from normal organs. The tumor had the highest percentage of injected dose per gram (%ID/g) of all tissues at 4 h as well as 24 h (2.0 {+-} 0.05 and 0.147 {+-} 0.038 ID/g, respectively) postinjection. The in vivo receptor binding specificity was demonstrated using haloperidol (a known high-affinity {sigma} receptor ligand). A significant decrease (>50%, p = 0.001) was observed in tumor concentration when haloperidol was used as a blocking agent. The high affinity of 2-[{sup 125}I]BP for {sigma} receptor-binding sites, its fast in vivo clearance from normal organs and its high uptake and retention in tumor implies that 2-[{sup 123}I]BP or 2-[{sup 131}I]BP may be a promising tracer for noninvasive imaging of human prostate tumors.

  16. Synthesis, in vitro binding, and tissue distribution of radioiodinated 2-[125I]N-(N-benzylpiperidin-4-yl)-2-iodo benzamide, 2-[125I]BP: a potential σ receptor marker for human prostate tumors

    International Nuclear Information System (INIS)

    The preclinical evaluation of a σ receptor-specific radiopharmaceutical that binds to human prostate tumor cells with a high affinity is described. We have synthesized and radioiodinated 2-[125I]-N-(N-benzylpiperidin-4-yl)-2-iodobenzamide (2-[125I]BP) that possesses high affinity for both σ-1 and σ-2 receptor subtypes that are expressed on a variety of tumor cells. 2-IBP was synthesized, purified and characterized by routine spectroscopic and analytical methods. Radioiodination was accomplished using an oxidative iododestannylation reaction in the presence of chloramine T in high yields (76%-93%) with a very high-specific activity (1700-1900 Ci/mmol). The in vitro competition binding studies of 2-[125I]BP with various σ receptor ligands in LnCAP human prostate tumor cells showed a dose-dependent saturable binding. The inhibition constants (Ki, nM) for binding of 2-[125I]BP to human prostate tumor cells for 4-IBP, haloperidol and 2-IBP were 4.09, 6.34 and 1.6 nM, respectively. The clearance of 2-[125I]BP, in Sprague-Dawley rats, was rapid from the blood pool, other normal tissues and the total body. Tissue distribution studies in nude mice bearing human prostate tumor (DU-145) also showed a fast clearance from normal organs. The tumor had the highest percentage of injected dose per gram (%ID/g) of all tissues at 4 h as well as 24 h (2.0 ± 0.05 and 0.147 ± 0.038 ID/g, respectively) postinjection. The in vivo receptor binding specificity was demonstrated using haloperidol (a known high-affinity σ receptor ligand). A significant decrease (>50%, p = 0.001) was observed in tumor concentration when haloperidol was used as a blocking agent. The high affinity of 2-[125I]BP for σ receptor-binding sites, its fast in vivo clearance from normal organs and its high uptake and retention in tumor implies that 2-[123I]BP or 2-[131I]BP may be a promising tracer for noninvasive imaging of human prostate tumors

  17. Preparation and biological evaluation of cyclopentadienyl-based {sup 99m}Tc-complexes [(Cp-R){sup 99m}Tc(CO){sub 3}] mimicking benzamides for malignant melanoma targeting

    Energy Technology Data Exchange (ETDEWEB)

    Peindy N' Dongo, Harmel W. [Institute of Inorganic Chemistry, University of Zuerich, 190, CH-8057 Zurich (Switzerland); Raposinho, Paula D.; Fernandes, Celia; Santos, Isabel [Unidade de Ciencias Quimicas e Radiofarmaceuticas, Instituto Tecnologico e Nuclear, Estrada Nacional 10, 2686-953 Sacavem (Portugal); Can, Daniel; Schmutz, Paul; Spingler, Bernhard [Institute of Inorganic Chemistry, University of Zuerich, 190, CH-8057 Zurich (Switzerland); Alberto, Roger [Institute of Inorganic Chemistry, University of Zuerich, 190, CH-8057 Zurich (Switzerland)], E-mail: ariel@aci.uzh.ch

    2010-04-15

    The biological evaluation of half-sandwich {sup 99m}Tc-complexes that surrogate iodobenzamide with a high affinity for melanin tumor tissue is described. We have synthesized via retro Diels-Alder reaction two models of {sup 99m}Tc complexes which possess the piano stool [Cp{sup 99m}Tc(CO){sub 3}] motif instead of a phenyl ring as in the original iodobenzamide {sup 123}I-N-(N-benzylpiperidin-4-yl)-2-iodobenzamide (2-IBP) and N-(2-diethylaminoethyl)-4-iodobenzamide (BZA). Diels-Alder products - (HCp-CONHR){sub 2} (, R=2-diethylaminoethyl; , R=benzylpiperidin-4-yl) were prepared and reacted with fac-[{sup 99m}Tc(H{sub 2}O){sub 3}(CO){sub 3})]{sup +}1 in water to produce the corresponding {sup 99m}Tc complexes [(){sup 99m}Tc(CO){sub 3})] and [(){sup 99m}Tc(CO){sub 3})] . The structures of the {sup 99m}Tc complexes on the no-carrier-added level have been confirmed by chromatographic comparison with the corresponding rhenium complexes and , macroscopically characterized by IR, NMR, ESI-MS and X-ray crystallography for [triclinic, P-1, a=7.3518(1) A, b=8.0309(2) A, c=17.5536(3) A, {alpha}=99.1260(5){sup o}, {beta}=90.4215(14){sup o}, {gamma}=117.0187(11){sup o}]. The radioconjugate showed good in vitro stability. In murine melanoma B16F1 cells, significant cellular uptake (43.9% of the total applied activity) was attained after 4 h at 37 deg. C with about 50% of the cell-associated radioactivity being internalized in the cells (22% of the applied activity). Furthermore, in melanoma-bearing C57BL6 mice, tumor uptake values of 3.39{+-}0.50 %ID g{sup -1} and 3.21{+-}0.26 %ID g{sup -1} at 1 and 4 h postinjection, respectively, were observed indicating a good retention of in the tumor.

  18. Synthesis and evaluation of (S)-5-[125I]iodo-2,3-methylenedioxybenzamide

    International Nuclear Information System (INIS)

    Recent reports have demonstrated that benzamides possessing 2,3-dimethoxy-5-iodo- and 2,3-dihydroxybenzofuran-5-iodo- substitution patterns (termed epidepride and IBF, respectively) are potent dopamine D-2 antagonists. A closely related benzamide ((S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,3-methylenedioxy-5-[I-125]iodo-benzamide, termed IMD) has been synthesized and its activity compared to that of epidepride and IBF. The synthetic pathway and both in vitro and in vivo behavior of the compound are discussed

  19. Novas N-benzoiltiraminas de Swinglea glutinosa (Rutaceae)

    OpenAIRE

    Cristovam do Nascimento Cerqueira; Djalma A. P. dos Santos; Karla da Silva Malaquias; Murilo Marinho de Castro Lima; Maria Fátima das Graças Fernandes da Silva; João Batista Fernandes; Paulo Cezar Vieira

    2012-01-01

    Phytochemical studies of the leaves and fruits have led to the identification of the known amides (E)-N-methyl-cinnamamide, N-benzoyltyramine, N-benzoyl-O-geranyltyramine, N-benzoyl-O-(4-acetoxyl)-geranyltyramine, in addition to the new N-{2-[4-(butoxyl-3-one)phenyl]ethyl}benzamide, N-{2-[4-(2,3-dihydroxy-2-methyl-butoxylanal)phenyl]ethyl}benzamide, N-{2-[4-(2,3-dihydroxy-2-methyl-butoxyloic)phenyl]ethyl}benzamide, N-benzoyl-O-(4-acetoxyl-6,7-epoxy)-geranyltyramine, N-benzoyl-O-(4-acetoxyl-6,...

  20. SYNTHESIS AND BIOLOGICAL EVALUATION OF SOME NOVEL 2-CHLORO-4- (METHYLSULFONYL) PHENYL CONTAINING ACYLTHIOUREA AND 1,3- THIAZOLIDIN-4-ONE AS PROMISING ANTIMICROBIAL AGENTS. Synthese und biologische Bewertung einiger NEUE 2-Chlor-4- (Methylsulfonyl) phenyl MIT Acylthioharnstoff und 1,3 - THIAZOLIDIN-4-ONE als aussichtsreiche ANTIMIKROBIELLE MITTEL.

    OpenAIRE

    Chandra Kant Belwal, Kaushik A. Joshi

    2013-01-01

    A series of acylthiourea derivatives, 2-chloro-4-(methylsulfonyl)-N-(arylcarbamothioyl) benzamides were synthesized by reaction of 2-chloro-4-(methylsulfonyl) benzoyl chloride with ammonium thiocyanate and substituted aromatic amines. Cyclocondensation of acylthiourea derivatives, 2-chloro-4-(methylsulfonyl)-N-(arylcarbamothioyl) benzamides with tert-butyl chloroacetate yielded thiazolidinone derivatives, 3-{[2-chloro-4-(methylsulfonyl) phenyl]carbonyl}-2-(imino)-1,3-thiazolidin-4-one. S...

  1. Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of N-[(1R)-1-(3-Cyclopropoxy-4-fluorophenyl)-1-[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)benzamide (BMS-795311).

    Science.gov (United States)

    Qiao, Jennifer X; Wang, Tammy C; Adam, Leonard P; Chen, Alice Ye A; Taylor, David S; Yang, Richard Z; Zhuang, Shaobin; Sleph, Paul G; Li, Julia P; Li, Danshi; Yin, Xiaohong; Chang, Ming; Chen, Xue-Qing; Shen, Hong; Li, Jianqing; Smith, Daniel; Wu, Dauh-Rurng; Leith, Leslie; Harikrishnan, Lalgudi S; Kamau, Muthoni G; Miller, Michael M; Bilder, Donna; Rampulla, Richard; Li, Yi-Xin; Xu, Carrie; Lawrence, R Michael; Poss, Michael A; Levesque, Paul; Gordon, David A; Huang, Christine S; Finlay, Heather J; Wexler, Ruth R; Salvati, Mark E

    2015-11-25

    Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies. PMID:26524347

  2. Novel N-benzoyltyramines of Swinglea glutinosa (Rutaceae); Novas N-benzoiltiraminas de Swinglea glutinosa (Rutaceae).

    Energy Technology Data Exchange (ETDEWEB)

    Cerqueira, Cristovam do Nascimento; Santos, Djalma A.P. dos; Malaquias, Karla da Silva; Lima, Murilo Marinho de Castro; Silva, Maria Fatima das Gracas Fernandes da; Fernandes, Joao Batista; Vieira, Paulo Cezar, E-mail: dmfs@ufscar.br [Universidade Federal de Sao Carlos (UFSCAR), SP (Brazil). Dept. de Quimica

    2012-07-01

    Phytochemical studies of the leaves and fruits have led to the identification of the known amides (E)-N-methyl-cinnamamide, N-benzoyltyramine, N-benzoyl-O-geranyl tyramine, N-benzoyl-O-(4-acetoxyl)-geranyl tyramine, in addition to the new N-{l_brace}2-[4-(butoxyl-3-one)phenyl]ethyl{r_brace}benzamide, N-{l_brace}2-[4-(2,3-dihydroxy-2-methyl-butoxylanal)phenyl]ethyl{r_brace}benzamide, N-{l_brace}2-[4-(2,3-dihydroxy-2-methyl-butoxyloic) phenyl]ethyl{r_brace}benzamide, N-benzoyl-O-(4-acetoxyl-6,7-epoxy)-geranyltyramine, N-benzoyl-O-(4-acetoxyl-6,7-dihydroxy)-geranyltyramine and N-benzoyl-O-(6-acetoxyl-4,7-dihydroxy)-geranyltyramine. The isolated compounds clearly point to Swinglea phytochemical affinities with other Aurantioideae species. (author)

  3. Novas N-benzoiltiraminas de Swinglea glutinosa (Rutaceae

    Directory of Open Access Journals (Sweden)

    Cristovam do Nascimento Cerqueira

    2012-01-01

    Full Text Available Phytochemical studies of the leaves and fruits have led to the identification of the known amides (E-N-methyl-cinnamamide, N-benzoyltyramine, N-benzoyl-O-geranyltyramine, N-benzoyl-O-(4-acetoxyl-geranyltyramine, in addition to the new N-{2-[4-(butoxyl-3-onephenyl]ethyl}benzamide, N-{2-[4-(2,3-dihydroxy-2-methyl-butoxylanalphenyl]ethyl}benzamide, N-{2-[4-(2,3-dihydroxy-2-methyl-butoxyloicphenyl]ethyl}benzamide, N-benzoyl-O-(4-acetoxyl-6,7-epoxy-geranyltyramine, N-benzoyl-O-(4-acetoxyl-6,7-dihydroxy-geranyltyramine and N-benzoyl-O-(6-acetoxyl-4,7-dihydroxy-geranyltyramine. The isolated compounds clearly point to Swinglea phytochemical affinities with other Aurantioideae species.

  4. Novel N-benzoyltyramines of Swinglea glutinosa (Rutaceae)

    International Nuclear Information System (INIS)

    Phytochemical studies of the leaves and fruits have led to the identification of the known amides (E)-N-methyl-cinnamamide, N-benzoyltyramine, N-benzoyl-O-geranyl tyramine, N-benzoyl-O-(4-acetoxyl)-geranyl tyramine, in addition to the new N-{2-[4-(butoxyl-3-one)phenyl]ethyl}benzamide, N-{2-[4-(2,3-dihydroxy-2-methyl-butoxylanal)phenyl]ethyl}benzamide, N-{2-[4-(2,3-dihydroxy-2-methyl-butoxyloic) phenyl]ethyl}benzamide, N-benzoyl-O-(4-acetoxyl-6,7-epoxy)-geranyltyramine, N-benzoyl-O-(4-acetoxyl-6,7-dihydroxy)-geranyltyramine and N-benzoyl-O-(6-acetoxyl-4,7-dihydroxy)-geranyltyramine. The isolated compounds clearly point to Swinglea phytochemical affinities with other Aurantioideae species. (author)

  5. Aromatic oligoamides with a rare ortho-connectivity

    DEFF Research Database (Denmark)

    Hjelmgaard, T.; Nielsen, John

    2013-01-01

    Even though aromatic oligoamides composed of aromatic amino acids in a "one-way sequence" attract ever increasing research interest, backbones connected through ortho-linked aromatics remain rare. Herein, we present the first synthesis and study of N-alkylated ortho-aminomethyl- benzamides termed...

  6. C-Terminally modified peptides via cleavage of the HMBA linker by O-, N- or S-nucleophiles

    DEFF Research Database (Denmark)

    Hansen, Jonas; Diness, Frederik; Meldal, Morten Peter

    2016-01-01

    A large variety of C-terminally modified peptides was obtained by nucleophilic cleavage of the ester bond in solid phase linked peptide esters of 4-hydroxymethyl benzamide (HMBA). The developed methods provided peptides, C-terminally functionalized as esters, amides and thioesters, with high puri...

  7. Structural analysis of the positive AMPA receptor modulators CX516 and Me-CX516 in complex with the GluA2 ligand-binding domain

    DEFF Research Database (Denmark)

    Krintel, Christian; Harpsøe, Kasper; Zachariassen, Linda G; Peters, Dan; Frydenvang, Karla; Pickering, Darryl S; Gajhede, Michael; Kastrup, Jette S

    Positive allosteric modulators of the ionotropic glutamate receptor A2 (GluA2) can serve as lead compounds for the development of cognitive enhancers. Several benzamide-type (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor modulators such as aniracetam, CX516 and CX61...

  8. Drug: D07310 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07310 Drug Amisulpride (INN); Deniban (TN); Solian (TN) C17H27N3O4S 369.1722 369.4...n [BR:br08303] N NERVOUS SYSTEM N05 PSYCHOLEPTICS N05A ANTIPSYCHOTICS N05AL Benzamides N05AL05 Amisulpride D07310 Amisulpride

  9. Drug: D07311 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07311 Drug Veralipride (INN); Agreal (TN) C17H25N3O5S 383.1515 383.4625 D07311.gif...N NERVOUS SYSTEM N05 PSYCHOLEPTICS N05A ANTIPSYCHOTICS N05AL Benzamides N05AL06 Veralipride D07311 Veralipride

  10. 4-Acylamino-and 4-ureidobenzamides as melanin-concentrating hormone (MCH) receptor 1 antagonists

    DEFF Research Database (Denmark)

    Receveur, Jean-Marie; Bjurling, Emelie; Ulven, Trond;

    2004-01-01

    Synthesis, in vitro biological evaluation and structure-activity relationships of 4-acylamino-and 4-ureidobenzamides as novel hMCH1R-antagonists are disclosed. The nature of the amine side chains could be varied considerably in contrast to the central benzamide scaffold and aromatic substituents....

  11. The first X-ray crystal structure of the glucocorticoid receptor bound to a non-steroidal agonist

    Energy Technology Data Exchange (ETDEWEB)

    Madauss, Kevin P.; Bledsoe, Randy K.; Mclay, Iain; Stewart, Eugene L.; Uings, Iain J.; Weingarten, Gordon; Williams, Shawn P. (GSKNC); (GSK)

    2009-07-23

    The amino-pyrazole 2,6-dichloro-N-ethyl benzamide 1 is a selective GR agonist with dexamethasone-like in vitro potency. Its X-ray crystal structure in the GR LBD (Glucocorticoid ligand-binding domain) is described and compared to other reported structures of steroidal GR agonists in the GR LBD (3E7C).

  12. Synthesis of encainide-13C hydrochloride from 2-nitrobenzaldehyde-formyl-13C

    International Nuclear Information System (INIS)

    A facile synthesis of 2-nitrobenzaldehyde-formyl-13C was developed. This compound was converted to the labelled antiarrhythmic agent, encainide-13C hydrochloride, 4-methoxy-N-[2-(1-methyl-2-piperidinyl)ethyl-1-13C]phenyl]benzamide hydrochloride. (author)

  13. Analysis of Pyrolysates for Polysulphoneamide Fiber by Py-GC/MS

    Institute of Scientific and Technical Information of China (English)

    QIAN He-sheng; LIN Dan-li

    2006-01-01

    Pyrolysis of polysulphoneamide fiber has been investigated using pyrolysis gas chromatography-mass spectroscopy at the different temperatures from 420℃ to 750℃. Its compositions of pyrolysates have been analyzed. At 420 ℃,pyrolysis of molecular chain could not completely take place, 12 compounds of pyrolysis have only been identified.When the temperature increases, the compositions of pyrolysate increase sharply. Several compounds, especially sulfur dioxide, benzene, aniline, benzoic acid, 1,4-benzene dicaronitrile, N-phenyl-acetamide, diphenylamine, benzo[g]isoquinoline, N-phenyl-benzamide, N-( 4-cyanophenyl )benzamide, could be formed. The degradation mechanisms which are determined by structure and amount of the thermal decomposition products are described. During pyrolysis, for polysulphoneamide, polymeric chain scissions take place as a successive removal of the monomer units from the polymeric chain. The chain scissions are followed by secondary reactions, which lead to a variety of compounds.Additional reactions can also take place during pyrolysis.

  14. SYNTHESIS AND BIOLOGICAL EVALUATION OF SOME NOVEL 2-CHLORO-4- (METHYLSULFONYL PHENYL CONTAINING ACYLTHIOUREA AND 1,3- THIAZOLIDIN-4-ONE AS PROMISING ANTIMICROBIAL AGENTS. Synthese und biologische Bewertung einiger NEUE 2-Chlor-4- (Methylsulfonyl phenyl MIT Acylthioharnstoff und 1,3 - THIAZOLIDIN-4-ONE als aussichtsreiche ANTIMIKROBIELLE MITTEL.

    Directory of Open Access Journals (Sweden)

    Chandra Kant Belwal, Kaushik A. Joshi

    2013-07-01

    Full Text Available A series of acylthiourea derivatives, 2-chloro-4-(methylsulfonyl-N-(arylcarbamothioyl benzamides were synthesized by reaction of 2-chloro-4-(methylsulfonyl benzoyl chloride with ammonium thiocyanate and substituted aromatic amines. Cyclocondensation of acylthiourea derivatives, 2-chloro-4-(methylsulfonyl-N-(arylcarbamothioyl benzamides with tert-butyl chloroacetate yielded thiazolidinone derivatives, 3-{[2-chloro-4-(methylsulfonyl phenyl]carbonyl}-2-(imino-1,3-thiazolidin-4-one. Structure elucidation of the synthesized compounds has been accomplished on the basis of elemental analysis, mass, IR, 1H-NMR and 13C-NMR data. Synthesized compounds were screened for their antimicrobial activity against gram-positive, gram-negative bacteria and some selected fungal stains.

  15. Reversal by Dithiothreitol Treatment of the Block in Murine Leukemia Virus Maturation Induced by Disulfide Cross-Linking

    OpenAIRE

    Campbell, Stephen; Oshima, Masamichi; Mirro, Jane; Nagashima, Kunio; Rein, Alan

    2002-01-01

    We previously reported that if murine leukemia virus particles are produced in the presence of the mild oxidizing agent disulfide-substituted benzamide-2, they fail to undergo the normal process of virus maturation. We now show that treatment of these immature particles with a reducing agent (dithiothreitol) induces their maturation in vitro, as evidenced by proteolytic cleavage of Gag, Gag-Pol, and Env proteins and by their morphology. The identification of partial cleavage products in these...

  16. Characterization of the 5-HT4 receptor mediating tachycardia in piglet isolated right atrium.

    OpenAIRE

    Medhurst, A. D.; Kaumann, A J

    1993-01-01

    1. In order to explore whether 5-HT4 receptor subtypes exist, we have characterized further the 5-HT4 receptor that mediates tachycardia in the piglet isolated right atrium. All experiments were carried out in the presence of propranolol (400 nM) and cocaine (6 microM). We used tryptamine derivatives, substituted benzamides and benzimidazolone derivatives as pharmacological tools. 2. Tachycardia responses to 5-hydroxytryptamine (5-HT) were mimicked by other tryptamine derivatives with the fol...

  17. Regulation of dopamine D2 receptors by sodium and pH

    International Nuclear Information System (INIS)

    The role of Na+ and H+ in the regulation of D2 receptor affinity for ligands was studied to determine the molecular mechanisms of this phenomenon. The potency of substituted benzamide derivatives and agonists at D2 receptors depended on the concentration of Na+ and H+, whereas the potency of other antagonists was relatively unaltered by changes in pH or Na+ concentration. The potency of agonists was generally decreased in the presence of NaCl or lowered pH. For example, in the absence of sodium the affinity of D2 receptors for dopamine was decreased 17-fold by lowering of the pH from 8.0 to pH 6.8. Addition of NaCl caused 2-4-fold decreases in affinity for most agonists. The affinity of the receptors for two substituted benzamide derivatives, on the other hand, was reduced 6-44-fold by elevated concentrations of H+ but was enhanced 7-24-fold in the presence of Na+. The regulation by H+ of the potency of dopamine was selective for D2 receptors, because binding of dopamine to neostriatal D1 receptors was unaffected by changes in pH. Decreasing of the pH from 8.0 or 7.3 to 6.8 facilitated the dissociation of the substituted benzamide ligand 125I epidepride from D2 receptors but inhibited dissociation of 3H spiperone. Furthermore, the presence of NaCl or lowered pH slowed inactivation of D2 receptors by N-ethylmaleimide. Together, these data suggest that the conformation of D2 receptors is regulated by both Na+ and H+. The affinity of D2 receptors for agonists and substituted benzamide antagonists varies according to the conformational state of the receptors, whereas other antagonists bind to both forms with approximately equal potency. Amiloride is a compound that interacts with many sodium-binding macromolecules

  18. Regulation of dopamine D2 receptors by sodium and pH

    Energy Technology Data Exchange (ETDEWEB)

    Neve, K.A. (VA Medical Center, Portland, OR (USA))

    1991-04-01

    The role of Na+ and H+ in the regulation of D2 receptor affinity for ligands was studied to determine the molecular mechanisms of this phenomenon. The potency of substituted benzamide derivatives and agonists at D2 receptors depended on the concentration of Na+ and H+, whereas the potency of other antagonists was relatively unaltered by changes in pH or Na+ concentration. The potency of agonists was generally decreased in the presence of NaCl or lowered pH. For example, in the absence of sodium the affinity of D2 receptors for dopamine was decreased 17-fold by lowering of the pH from 8.0 to pH 6.8. Addition of NaCl caused 2-4-fold decreases in affinity for most agonists. The affinity of the receptors for two substituted benzamide derivatives, on the other hand, was reduced 6-44-fold by elevated concentrations of H+ but was enhanced 7-24-fold in the presence of Na+. The regulation by H+ of the potency of dopamine was selective for D2 receptors, because binding of dopamine to neostriatal D1 receptors was unaffected by changes in pH. Decreasing of the pH from 8.0 or 7.3 to 6.8 facilitated the dissociation of the substituted benzamide ligand {sup 125}I epidepride from D2 receptors but inhibited dissociation of {sup 3}H spiperone. Furthermore, the presence of NaCl or lowered pH slowed inactivation of D2 receptors by N-ethylmaleimide. Together, these data suggest that the conformation of D2 receptors is regulated by both Na+ and H+. The affinity of D2 receptors for agonists and substituted benzamide antagonists varies according to the conformational state of the receptors, whereas other antagonists bind to both forms with approximately equal potency. Amiloride is a compound that interacts with many sodium-binding macromolecules.

  19. Chemical constituents from red algae Bostrychia radicans (Rhodomelaceae): new amides and phenolic compounds

    OpenAIRE

    Ana Lígia Leandrini de Oliveira; Denise B. da Silva; Norberto P. Lopes; Debonsi, Hosana M.; Yokoya, Nair S

    2012-01-01

    This study describes the isolation and structural determination of two amides, isolated for the first time: N,4-dihydroxy-N-(2'-hydroxyethyl)-benzamide (0.019%) and N,4-dihydroxy-N-(2'-hydroxyethyl)-benzeneacetamide (0.023%). These amides, produced by the red macroalgae Bostrychia radicans, had their structures assigned by NMR spectral data and MS analyses. In addition, this chemical study led to the isolation of cholesterol, heptadecane, squalene, trans-phytol, neophytadiene, tetradecanoic a...

  20. Carboxylate-Assisted Iridium-Catalyzed C-H Amination of Arenes with Biologically Relevant Alkyl Azides.

    Science.gov (United States)

    Zhang, Tao; Hu, Xuejiao; Wang, Zhen; Yang, Tiantian; Sun, Hao; Li, Guigen; Lu, Hongjian

    2016-02-24

    An iridium-catalyzed C-H amination of arenes with a wide substrate scope is reported. Benzamides with electron-donating and -withdrawing groups and linear, branched, and cyclic alkyl azides are all applicable. Cesium carboxylate is crucial for both reactivity and regioselectivity of the reactions. Many biologically relevant molecules, such as amino acid, peptide, steroid, sugar, and thymidine derivatives can be introduced to arenes with high yields and 100 % chiral retention. PMID:26712274

  1. Synthesis and characterization of oligo(thiophene carboxamide)s

    OpenAIRE

    Klos, Johannes

    2010-01-01

    Die vorliegende Arbeit besteht aus zwei Teilen: Im ersten Teil der Arbeit werden supramolekulare Strukturen betrachtet, die durch unterschiedliche Fällungsbedingungen von Polyethylenoxid-block-oligo-p-benzamid-copolymeren erhalten wurden. Durch tropfenweise Zugabe des gelösten Polymers zu Chloroform, ein für Polyethylenoxid selektives Lösemittel, konnten verschiedenste Aggregate hergestellt werden. Von großen Hohlkugel mit einem Durchmesser von mehreren Mikrometern, bis zu kleinen Stäbchen mi...

  2. Drug: D02208 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D02208 Drug Sultopride hydrochloride (JAN); Sultopride monohydrochloride; Barnetil ...sensory organs 11 Agents affecting central nervous system 117 Psychotropics 1179 Others D02208 Sultopride hy...3] N NERVOUS SYSTEM N05 PSYCHOLEPTICS N05A ANTIPSYCHOTICS N05AL Benzamides N05AL02 Sultopride D02208 Sultopride...sin family Dopamine dopamine D2-receptor [HSA:1813] [KO:K04145] Sultopride [ATC:N05AL02] D02208 Sultopride

  3. Drug: D08549 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08549 Drug Sultopride (INN) C17H26N2O4S 354.1613 354.4643 D08549.gif Neuroleptic S...:br08303] N NERVOUS SYSTEM N05 PSYCHOLEPTICS N05A ANTIPSYCHOTICS N05AL Benzamides N05AL02 Sultopride D08549 Sultopride...ily Dopamine dopamine D2-receptor [HSA:1813] [KO:K04145] Sultopride [ATC:N05AL02] D08549 Sultopride

  4. In Vitro Effects of Thiazolides on Giardia lamblia WB Clone C6 Cultured Axenically and in Coculture with Caco2 Cells

    OpenAIRE

    Müller, Joachim; Rühle, Géraldine; Müller, Norbert; Rossignol, Jean-François; Hemphill, Andrew

    2006-01-01

    The thiazolides represent a novel class of anti-infective drugs, with the nitrothiazole nitazoxanide [2-acetolyloxy-N-(5-nitro 2-thiazolyl) benzamide] (NTZ) as the parent compound. NTZ exhibits a broad spectrum of activities against a wide variety of helminths, protozoa, and enteric bacteria infecting animals and humans. In vivo, NTZ is rapidly deacetylated to tizoxanide (TIZ), which exhibits similar activities. We have here comparatively investigated the in vitro effects of NTZ, TIZ, a numbe...

  5. Use of dimetpramid for the prophylaxis and treatment of neurotoxic reactions during radio- and chemotherapy of patients with Hodgkin's disease

    International Nuclear Information System (INIS)

    A study was made of the efficacy of a new Soviet drug dimetpramid of the group of substituted benzamides for the prophylaxis and treatment of neurotoxic reactions in radio- and chemotherapy of patients with the Hodgiin disease. It has been established that the use of dimetpramid before and during specific therapy helps to prevent nausea and vomiting in 96 % of cases. The drug does not produce a negative effect either on the general status of patients or hemodynamics, peripheral blood and urine

  6. A Convenient Method for the Synthesis of 1,3,2-Oxazaphospholidin-[3,2-a]-8-oxo-10-thio(or seleno)-[1,3,2]-benzodiazaphosphorines

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    A Convenient method for the synthesis of fused phosphorusheterocycle 1,3,2-oxazaphosphorin-[3,2-a]-8-oxo-10-thio(or seleno)-[1,3,2]-benzodiazaphosphorines was carried out in one pot by the reaction of Tris(diethylamino)phosphine with multifunctional compounds 2-(N-(βor γ-hydroxyl) alkylene) amino-benzamides 1.When PCL3 was used, only chlorinated product was obtained.

  7. Radioiodinated N-(alkylaminoalkyl)-substituted 4-methoxy-, 4-hydroxy-, and 4-aminobenzamides: Biological investigations for the improvement of melanoma-imaging agents

    International Nuclear Information System (INIS)

    The synthesis and radiolabeling of 27 new N-(alkylaminoalkyl)-4-methoxy-, 4-hydroxy-, and -4-aminobenzamides are described and evaluated in C57Bl/6 mice with subcutaneously transplanted B16 melanoma in order to screen the optimal chemical structure for melanoma scintigraphy. Using Tl(TFA)3 for 131I- labeling, a series of radioiodinated 4-methoxy benzamide derivatives proved to exhibit superior melanoma uptake with outstanding melanoma/non-target-tissue ratios. From the benzamide derivatives tested, N-(2-(1'-piperidinyl)ethyl)-3-[131I]iodo-4-methoxybenzamide (1) and N-(2-diethylaminoethyl)-3-[131I]iodo-4-methoxybenzamide (2) demonstrated best results. The introduction of 4-hydroxy and 4-amino groups led to less favourable benzamides. While the former compounds showed little melanoma uptake, the latter revealed unfavourable melanoma/non-target-tissue ratios. Additionally, it could be shown that an amino group was inevitably necessary for melanoma uptake, and that dialkylation of the amide nitrogen and replacing CONH by CH2NH revealed less advantageous results

  8. Effect of cyclosporin A on the uptake of D{sub 3}-selective PET radiotracers in rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Tu Zhude; Li Shihong; Xu Jinbin; Chu Wenhua; Jones, Lynne A. [Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110 (United States); Luedtke, Robert R. [Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107 (United States); Mach, Robert H., E-mail: rhmach@mir.wustl.edu [Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110 (United States); Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110 (United States); Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110 (United States)

    2011-07-15

    Introduction: Four benzamide analogs having a high affinity and selectivity for D{sub 3} versus D{sub 2} receptors were radiolabeled with {sup 11}C or {sup 18}F for in vivo evaluation. Methods: Precursors were synthesized, and the four D{sub 3} selective benzamide analogs were radiolabeled. The tissue distribution and brain uptake of the four compounds were evaluated in control rats and rats pretreated with cyclosporin A, a modulator of P-glycoprotein and an inhibitor of other ABC efflux transporters that contribute to the blood brain barrier. Micro-positron emission tomographic (PET) imaging was carried out for [{sup 11}C]6 in a control and a cyclosporin A pretreated rat. Results: All four compounds showed low brain uptake in control rats at 5 and 30 min post-injection; despite recently reported rat behavioral studies conducted on analogs 6 (WC-10) and 7 (WC-44). Following administration of cyclosporin A, increased brain uptake was observed with all four PET radiotracers at both 5 and 30 min post-intravenous injection. An increase in brain uptake following modulation/inhibition of the ABC transporters was also observed in the microPET study. Conclusions: These data suggest that D3 selective conformationally-flexible benzamide analogs which contain a N-2-methoxyphenylpiperazine moiety are substrates for P-glycoprotein or other adenosine triphosphate (ATP)-binding cassette transporters expressed at the blood-brain barrier, and that PET radiotracers containing this pharmacophore may display low brain uptake in rodents due to the action of these efflux transporters.

  9. Nuclear medicine and imaging research (quantitative studies in radiopharmaceutical science). Progress report, January 1, 1992--December 31, 1992

    Energy Technology Data Exchange (ETDEWEB)

    Cooper, M.; Beck, R.N.

    1992-06-01

    This report describes three studies aimed at using radiolabeled pharmaceuticals to explore brain function and anatomy. The first section describes the chemical preparation of [F18]fluorinated benzamides (dopamine D-2 receptor tracers), [F18]fluorinated benzazepines (dopamine D-1 receptor tracers), and tissue distribution of [F18]-fluoxetine (serotonin reuptake site tracer). The second section relates pharmacological and behavioral studies of amphetamines. The third section reports on progress made with processing of brain images from CT, MRI and PET/SPECT with regards to brain metabolism of glucose during mental tasks.

  10. Nuclear medicine and imaging research (quantitative studies in radiopharmaceutical science)

    Energy Technology Data Exchange (ETDEWEB)

    Cooper, M.; Beck, R.N.

    1992-06-01

    This report describes three studies aimed at using radiolabeled pharmaceuticals to explore brain function and anatomy. The first section describes the chemical preparation of (F18)fluorinated benzamides (dopamine D-2 receptor tracers), (F18)fluorinated benzazepines (dopamine D-1 receptor tracers), and tissue distribution of (F18)-fluoxetine (serotonin reuptake site tracer). The second section relates pharmacological and behavioral studies of amphetamines. The third section reports on progress made with processing of brain images from CT, MRI and PET/SPECT with regards to brain metabolism of glucose during mental tasks.

  11. Formation of a Six-Coordinate fac-[Re(Co)3]+ Complex by the N-C bond cleavage of a potentially tetradentate ligand

    International Nuclear Information System (INIS)

    The rhenium(I) compound fac-[Re(CO)3(daa)]. Hpab.H2O (Hpab N,N'-(l,2-phenylene)bis(2'-aminobenzamide); Hdaa 2-amino-N-(2-aminophenyl)benzamide) was synthesized from the reaction of [Re(CO)5,Br] with two equivalent of Hpab in toluene. The monoanionic tridentate ligand daa was formed by the rhenium-mediated cleavage of an amido N-C bond of the potentially tetradentate ligand Hpab. The compound was characterized by IR spectroscopy and X-ray crystallography, and daa is coordinated as a diamino amide via three nitrogen-donor atoms

  12. Nuclear medicine and imaging research (quantitative studies in radiopharmaceutical science)

    International Nuclear Information System (INIS)

    This report describes three studies aimed at using radiolabeled pharmaceuticals to explore brain function and anatomy. The first section describes the chemical preparation of [F18]fluorinated benzamides (dopamine D-2 receptor tracers), [F18]fluorinated benzazepines (dopamine D-1 receptor tracers), and tissue distribution of [F18]-fluoxetine (serotonin reuptake site tracer). The second section relates pharmacological and behavioral studies of amphetamines. The third section reports on progress made with processing of brain images from CT, MRI and PET/SPECT with regards to brain metabolism of glucose during mental tasks

  13. Drug: D08590 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08590 Drug Tiapride (INN); Tiapridal (TN) C15H24N2O4S 328.1457 328.4271 D08590.gif...ANTIPSYCHOTICS N05AL Benzamides N05AL03 Tiapride D08590 Tiapride (INN) Target-based classification of drugs ...[BR:br08310] G Protein-coupled receptors Rhodopsin family Dopamine dopamine D2-receptor [HSA:1813] [KO:K04145] Tiapride... [ATC:N05AL03] D08590 Tiapride (INN) CAS: 51012-32-9 PubChem: 96025274

  14. Drug: D01522 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D01522 Drug Tiapride hydrochloride (JP16); Gramalil (TN) C15H24N2O4S. HCl 364.1224 ...eous 1190 Miscellaneous D01522 Tiapride hydrochloride (JP16) Anatomical Therapeutic Chemical (ATC) classific...ation [BR:br08303] N NERVOUS SYSTEM N05 PSYCHOLEPTICS N05A ANTIPSYCHOTICS N05AL Benzamides N05AL03 Tiaprid...e D01522 Tiapride hydrochloride (JP16) Target-based classification of drugs [BR:br0...8310] G Protein-coupled receptors Rhodopsin family Dopamine dopamine D2-receptor [HSA:1813] [KO:K04145] Tiapride

  15. Drug: D02682 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D02682 Drug Remoxipride (USAN) C16H23BrN2O3 370.0892 371.2694 D02682.gif Antipsycho...TICS N05A ANTIPSYCHOTICS N05AL Benzamides N05AL04 Remoxipride D02682 Remoxipride (USAN) Target-based classif...A:1813] [KO:K04145] Remoxipride [ATC:N05AL04] D02682 Remoxipride (USAN) Opioid si...gma1-opioid receptor [HSA:10280] Remoxipride [ATC:N05AL04] D02682 Remoxipride (USAN) CAS: 80125-14-0 PubChem

  16. Drug: D02683 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D02683 Drug Remoxipride hydrochloride (USAN) C16H23BrN2O3. HCl. H2O 424.0764 425.74...OUS SYSTEM N05 PSYCHOLEPTICS N05A ANTIPSYCHOTICS N05AL Benzamides N05AL04 Remoxipride D02683 Remoxipride hyd...mily Dopamine dopamine D2-receptor [HSA:1813] [KO:K04145] Remoxipride [ATC:N05AL04] D02683 Remoxipride... hydrochloride (USAN) Opioid sigma1-opioid receptor [HSA:10280] Remoxipride [ATC:N05AL04] D02683 Remoxipride

  17. (E)-N′-[1-(Thiophen-2-yl)ethylidene]benzohydrazide

    OpenAIRE

    Shang Shan; Yan-Lan Huang; Han-Qi Guo; Deng-Feng Li; Jian Sun

    2011-01-01

    The title compound, C13H12N2OS, was obtained from the condensation reaction of 2-acetylthiophene and benzohydrazide. In the molecule, the formohydrazide fragment is approximately planar (r.m.s deviation = 0.0146 Å) and the mean plane is oriented at dihedral angles of 24.47 (11) and 28.86 (13)°, respectively, to the phenyl and thiophene rings. The thiophene and phenyl rings make a dihedral angle of 53.21 (8)°. The benzamide fra...

  18. Copper-promoted synthesis of 1,4-benzodiazepinones via alkene diamination

    Science.gov (United States)

    Karyakarte, Shuklendu D.; Sequeira, Fatima C.; Zibreg, Garrick H.; Huang, Guoqing; Matthew, Josiah P.; Ferreira, Marina M. M.

    2015-01-01

    A new method for the synthesis of 2-aminomethyl functionalized 1,4-benzodiazepin-5-ones is presented. The benzodiazepine core is well-known to interact with biological receptors and many pharmaceutical drugs are derived from this structure. The alkene diamination strategy is employed for the first time for the synthesis of 1,4-benzodiazepinones. In this reaction, copper(2-ethylhexanoate)2 serves as promoter and a range of external amines can be coupled with 2-sulfonamido-N-allyl benzamides to generate the 1,4-benzodiazepinones in good yields. PMID:26034340

  19. Nuevas aplicaciones del cloral en la síntesis de compuestos heterocíclicos nitrogenados

    OpenAIRE

    Alarcón Belmonte, Enrique

    2015-01-01

    Se han desarrollado nuevos métodos de síntesis para varias clases de compuestos heterocíclicos nitrogenados partiendo de derivados del cloral: pirimidinas, imidazo[1,5-b]pirazoles, imidazo[1,5-b][1,2,4]triazoles, 1,2,4-triazinas y 1,2,4-triazoles. Se efectuaron reacciones entre cloral y acetofenonas que dieron lugar a cloralacetofenonas con elevados rendimientos, las cuales fueron eficazmente deshidratadas para dar 2,2,2-tricloroetilidenacetofenonas, que se hicieron reaccionar con benzamid...

  20. Synthesis and antileishmanial activity of C7- and C12-functionalized dehydroabietylamine derivatives.

    Science.gov (United States)

    Dea-Ayuela, M Auxiliadora; Bilbao-Ramos, Pablo; Bolás-Fernández, Francisco; González-Cardenete, Miguel A

    2016-10-01

    Abietane-type diterpenoids, either naturally occurring or synthetic, have shown a wide range of pharmacological actions, including antiprotozoal properties. In this study, we report on the antileishmanial evaluation of a series of (+)-dehydroabietylamine derivatives functionalized at C7 and/or C12. Thus, the activity in vitro against Leishmania infantum, Leishmania donovani, Leishmania amazonensis and Leishmania guyanensis, was studied. Most of the benzamide derivatives showed activities at low micromolar concentration against cultured promastigotes of Leishmania spp. (IC50 = 2.2-46.8 μM), without cytotoxicity on J774 macrophage cells. Compound 15, an acetamide, was found to be the most active leishmanicidal agent, though it presented some cytotoxicity on J774 cells. Among the benzamide derivatives, compounds 8 and 10, were also active against L. infantum intracellular amastigotes, being 18- and 23-fold more potent than the reference compound miltefosine, respectively. Some structure-activity relationships have been identified for the antileishmanial activity in these dehydroabietylamine derivatives. PMID:27318121

  1. Quinuclidine compounds differently act as agonists of Kenyon cell nicotinic acetylcholine receptors and induced distinct effect on insect ganglionic depolarizations.

    Science.gov (United States)

    Mathé-Allainmat, Monique; Swale, Daniel; Leray, Xavier; Benzidane, Yassine; Lebreton, Jacques; Bloomquist, Jeffrey R; Thany, Steeve H

    2013-12-01

    We have recently demonstrated that a new quinuclidine benzamide compound named LMA10203 acted as an agonist of insect nicotinic acetylcholine receptors. Its specific pharmacological profile on cockroach dorsal unpaired median neurons (DUM) helped to identify alpha-bungarotoxin-insensitive nAChR2 receptors. In the present study, we tested its effect on cockroach Kenyon cells. We found that it induced an inward current demonstrating that it bounds to nicotinic acetylcholine receptors expressed on Kenyon cells. Interestingly, LMA10203-induced currents were completely blocked by the nicotinic antagonist α-bungarotoxin. We suggested that LMA10203 effect occurred through the activation of α-bungarotoxin-sensitive receptors and did not involve α-bungarotoxin-insensitive nAChR2, previously identified in DUM neurons. In addition, we have synthesized two new compounds, LMA10210 and LMA10211, and compared their effects on Kenyon cells. These compounds were members of the 3-quinuclidinyl benzamide or benzoate families. Interestingly, 1 mM LMA10210 was not able to induce an inward current on Kenyon cells compared to LMA10211. Similarly, we did not find any significant effect of LMA10210 on cockroach ganglionic depolarization, whereas these three compounds were able to induce an effect on the central nervous system of the third instar M. domestica larvae. Our data suggested that these three compounds could bind to distinct cockroach nicotinic acetylcholine receptors. PMID:23884575

  2. New SPECT tracers: Example of tracers of proteoglycans and melanin

    International Nuclear Information System (INIS)

    The majority of research program on new radiopharmaceuticals turn to tracers used for positron emission tomography (PET). Only a few teams work on new non fluorine labeled tracers. However, the coming of SPECT/CT gamma cameras, the arrival of semi-conductors gamma cameras should boost the development of non-PET tracers. We exhibit in this article the experience acquired by our laboratory in the conception and design of two new non fluorine labelled compounds. The 99mTc-N.T.P. 15-5 (N.T.P. 15-5 for N-[tri-ethyl-ammonium]-3-propyl-[15]ane-N5) which binds to proteoglycans could be used for the diagnosis and staging of osteoarthritis and chondrosarcoma. The iodo benzamides, specific to the melanin, are nowadays compared to 18F-fluorodeoxyglucose in a phase III clinical trial for the diagnosis and detection of melanoma metastasis. Our last development focus on N-[2-(diethyl-amino)ethyl]-4 and 2-iodo benzamides respectively B.Z.A. and B.Z.A.2 hetero-aromatic analogues usable for melanoma treatment. (authors)

  3. New SPECT tracers: Example of tracers of proteoglycans and melanin; Nouveaux traceurs TEMP: exemple des traceurs des proteoglycanes et de la melanine

    Energy Technology Data Exchange (ETDEWEB)

    Cachin, F.; Mestas, D.; Kelly, A.; Merlin, C.; Veyre, A.; Maublant, J. [CRLCC Jean-Perrin, Service de Medecine Nucleaire, 63 - Clermont-Ferrand (France); Cachin, F.; Chezal, J.M.; Miot-Noirault, E.; Moins, N.; Auzeloux, P.; Vidal, A.; Bonnet-Duquennoy, M.; Boisgard, S.; D' Incan, M.; Madelmont, J.C.; Maublant, J. [Universite d' Auvergne, EA 4231, 63 - Clermont-Ferrand (France); Boisgard, S. [CHRU Gabriel-Montpied, Service d' Orthopedie, 63 - Clermont-Ferrand (France); D' Incan, M. [CHRU Gabriel-Montpied, Service de Dermatologie, 63 - Clermont-Ferrand (France); Redini, F. [Inserm, U957-EA3822, Faculte de Medecine, 44 - Nantes (France); Filaire, M. [Universite d' Auvergne, Lab. d' Anatomie, 63 - Clermont-Ferrand (France)

    2009-02-15

    The majority of research program on new radiopharmaceuticals turn to tracers used for positron emission tomography (PET). Only a few teams work on new non fluorine labeled tracers. However, the coming of SPECT/CT gamma cameras, the arrival of semi-conductors gamma cameras should boost the development of non-PET tracers. We exhibit in this article the experience acquired by our laboratory in the conception and design of two new non fluorine labelled compounds. The {sup 99m}Tc-N.T.P. 15-5 (N.T.P. 15-5 for N-[tri-ethyl-ammonium]-3-propyl-[15]ane-N5) which binds to proteoglycans could be used for the diagnosis and staging of osteoarthritis and chondrosarcoma. The iodo benzamides, specific to the melanin, are nowadays compared to {sup 18}F-fluorodeoxyglucose in a phase III clinical trial for the diagnosis and detection of melanoma metastasis. Our last development focus on N-[2-(diethyl-amino)ethyl]-4 and 2-iodo benzamides respectively B.Z.A. and B.Z.A.2 hetero-aromatic analogues usable for melanoma treatment. (authors)

  4. Partial molar volumes of some drug and pro-drug substances in 1-octanol at T = 298.15 K

    Energy Technology Data Exchange (ETDEWEB)

    Manin, Alex N.; Shmukler, Liudmila E.; Safonova, Liubov P. [Institute of Solution Chemistry, Russian Academy of Sciences, 153045 Ivanovo (Russian Federation); Perlovich, German L., E-mail: glp@isc-ras.r [Institute of Solution Chemistry, Russian Academy of Sciences, 153045 Ivanovo (Russian Federation)

    2010-03-15

    The article deals with measuring the densities of phenol, acetanilide, benzamide, benzoic acid, phenacetin, i-(acetylamino)-benzoic acid, i-hydroxy-benzamide, and i-acetaminophen (where i = 1, 2, 3) in 1-octanol in the wide concentration interval at T = 298.15 K. It also concerns the evaluation of apparent molar volumes and partial molar volumes at infinite dilution, V{sub 2}{sup 0}-bar as well as comparative analysis of the free volumes per molecule in the octanolic solutions, V{sub 2}{sup free}, and in the crystal lattices, V{sub 2}{sup free} (cr), from the nature and position of the substitutes. Also described is the evaluation of the increments of V{sub 2}{sup 0}-bar andV{sub 2}{sup free} for the unsubstituted molecules and isomers and the methods to obtain partial molar volumes for various functional groups at infinite dilution in 1-octanol at T = 298.15 K. Also considered is the limiting partial molar volume of the solutes in terms of the scaled particle theory.

  5. Thermolysis of some N-arylbenzamidoximes: Mechanistic studies for formation of anilide, oxazole and imidazole derivatives

    Indian Academy of Sciences (India)

    ABDEL-AAL GABER; LAYLA TAIB

    2016-05-01

    The thermolysis of N-2-pyridylbenzamidoxime I under nitrogen atmosphere for 5 hours givesrise to 2-phenyl-1H-imidazo[4,5-b]pyridine and N-(pyridin-2-yl)benzamide as the major products (52.4and 18.11%, respectively), in addition to 2-hydroxy pyridine, benzonitrile, benzoic acid, 2-aminopyridine,2-phenyloxazolo[4,5-b]pyridine, 9H-pyrrolo[2,3-b:5,4-b']dipyridine and 2,4,6-triphenyl-1,3,5-triazine. Also,heating N-Α-naphthylbenzamidoxime II under the same conditions gave N-(Α-Naphthyl)benzamide, 2-Phenyl-3H-naphtho[2,1-d] imidazole as the major products besides benzonitrile, benzoic acid, Α-naphthylamine and2-phenylnaphtho[1,2-d]oxazole. In the presence of tetralin, I gave 1-hydroxytetralin, Α-tetralone and 1,1'-bitetrayl besides the previous products. The reaction and isolated products have been interpreted in terms of afree radical mechanism involving the homolysis of N-O and/or C-N bonds.

  6. Synthesis and characterization of novel dopamine-derivative:Application of modified multi-wall carbon nanotubes paste electrode for electrochemical investigation

    Institute of Scientific and Technical Information of China (English)

    Shadpour Mallakpour; Mehdi Hatami; Ali A. Ensafi; Hassan Karimi-Maleh

    2011-01-01

    Novel dopamine-derivative compound, 3,5-diamino-N-(3,4-dihydroxyphenethyl)benzamide (3,5-DAB) was prepared in two steps. In the first step dopamine hydrochloride was reacted with 3,5-dinitrobenzoyl chloride in the presence of propylene oxide. In the second step reduction of nitro groups resulted in preparation of 3,5-DAB in quantitative yield. This material was characterized using conventional spectroscopic methods such as FT-IR and 1H NMR. In addition, the redox response of a modified carbon nanotubes paste electrode of 3,5-DAB was investigated in aqueous solution at a neutral pH. The result showed that the electrode process has a guasi-reversible response, with △Ep, greater than the (59/n) mV expected for a reversible system. Finally, the diffusion coefficient for redox process in paraffin oil matrix obtained using chronoamperometry methods.

  7. Fluorescence enhancement of Er3+ ion by Glibenclamide: A practical probe

    International Nuclear Information System (INIS)

    Glibenclamide, 5-chloro-N-[2-[4-(cyclohexylcarbamoyl-sulfamoyl) phenyl]ethyl]-2-methoxy-benzamide, is an important anti-diabetic drug that can enhance the erbium (Er) intrinsic fluorescence intensity. Based on that fact, Glibenclamide can be monitored using simple and sensitive fluorimetric probes. For this research, an interest arose in using lanthanides as probing biochemical reactions, and to study the interactions between Ca2+ and biologically important molecules. Methodologies employed are based on the unique fluorescence properties of lanthanides due to their unfilled 4fn electronic orbital, and formation of a complex between Er3+ and Glibenclamide. The proposed method was found to be simple, accurate and precise, thus allowing it to be used as a detector for high performance liquid chromatography in the future.

  8. Research into aroma changes in irradiated foodstuffs. I.- Studies on Fish; Investigacion de Alteraciones de Aroma en alimentos irradiados. I Estudio sobre Pescado

    Energy Technology Data Exchange (ETDEWEB)

    Barreiro Pinero, R.; Gasco Sanchez, L.; Valverde Garcia, F.

    1972-07-01

    Radiolytic formation of volatile compounds have been investigated in fillets of hake, codfish and bonito gamma-irradiated at a dose range of 0.1-5 Mrads. Analytical methods have been developed by gas chromatography of functional group derivatives: carbonyls as 2,4,-dinitrophenyl hydrazones, primary and secondary amines as N-alkyl benzamides, and thiols as 2,4-dinitrophenyl alkyl thioethers. The main results are as follows: increasing with the integral dose of the whole carbonyls, the most significant components being acetaldehyde, propional dehyde and formaldehyde; no significant variations with the integral dose od the traces of ammonia, methylamine, trimethylamine, ethylamine, diethylamine, propylamine, butylamine and pentylamine found in unirradiated samples; and radiolytic formation of methanethiol and dimethyl disulfide. (Author) 98 refs.

  9. Field evaluation of commercial repellents against the floodwater mosquito Psorophora columbiae (Diptera: Culicidae) in St. Johns County, Florida.

    Science.gov (United States)

    Qualls, Whitney A; Xue, Rui-De; Holt, J Adam; Smith, Mike L; Moeller, Jeanne J

    2011-11-01

    Three plant-based repellents-REPEL LEMON Eucalyptus Insect Repellent Lotion (active ingredient [AI] 30% oil of eucalyptus), Bite Blocker Xtreme Sportsman Organic Insect Repellent ([AI] 3% soybean oil, 6% geranium oil, and 8% castor oil), and Bite Blocker BioUD Insect Repellent ([AI] 7.75% 2-undecanone)--were evaluated against OFF! ([AI] 15% N,N-diethyl-m-toluamide or N,N-diethyl-3-methyl-benzamide, also called DEET) at a field site in Elkton, FL, to determine the mean protection time provided against Psorophora columbiae (Dyar & Knab). These products provided different protection times against biting Ps. columbiae. REPEL provided the longest protection time (330 min) followed by Bite Blocker Xtreme Sportsman (163 min), Bite Blocker BioUD (140 min), and OFF! (130 min). This study provides the first information about plant-based insect repellent protection times against Ps. columbiae. PMID:22238886

  10. Dopamine D(2) receptor quantification in extrastriatal brain regions using [(123)I]epidepride with bolus/infusion

    DEFF Research Database (Denmark)

    Pinborg, L H; Videbaek, C; Knudsen, G M;

    2000-01-01

    The iodinated benzamide epidepride, which shows a picomolar affinity binding to dopamine D(2) receptors, has been designed for in vivo studies using SPECT. The aim of the present study was to apply a steady-state condition by the bolus/infusion approach with [(123)I]epidepride for the...... bolus/infusion (B/I) experiment was applied. It was predicted that a B/I protocol with infusion of one-third of the initial bolus per hour would be appropriate. Steady-state conditions were attained in extrastriatal regions within 3-4 h but the infusion continued up to 7 h in order to minimize the...... has a unique signal-to-noise ratio compared to [(123)I]IBZM but present difficulties for steady-state measurements of striatal regions. The bolus/infusion approach is particularly feasible for quantification of the binding potential in extrastriatal regions....

  11. Autoradiographic comparison of [125I]epidepride and [125I]NCQ 298 binding to human brain extrastriated dopamine receptors.

    Science.gov (United States)

    Hall, H; Halldin, C; Jerning, E; Osterlund, M; Farde, L; Sedvall, G

    1997-07-01

    Extrastriatal D2-dopamine receptors can be visualised in the monkey and human brain using the benzamides [11C]- and [76Br]FLB 457 in PET and [123I]epidepride in SPECT but not with the salicylamide analogues [76Br]FLB 463 and [123I]NCQ 298. To clarify the background for the differences in binding seen in vivo, we have compared the in vitro binding of [125I]epidepride and [123I]NCQ 298, using human whole hemisphere autoradiography. The images obtained with any radioligand showed detailed distribution with very dense binding in the putamen and the caudate nucleus and with the same detailed extrastriatal distribution. Thus, the divergent results obtained in vivo cannot be explained by different binding properties of the extrastriatal receptors. PMID:9290072

  12. Autoradiographic comparison of [125I]epidepride and [125I]NCQ 298 binding to human brain extrastriated dopamine receptors

    International Nuclear Information System (INIS)

    Extrastriatal D2-dopamine receptors can be visualized in the monkey and human brain using the benzamides [11C]- and [76Br]FLB 457 in PET and [123I]epidepride in SPECT but not with the salicylamide analogues [76Br]FLB 463 and [123I]NCQ 298. To clarify the background for the differences in binding seen in vivo, we have compared the in vitro binding of [125I]epidepride and [125I]NCQ 298, using human whole hemisphere autoradiography. The images obtained with any radioligand showed detailed distribution with very dense binding in the putamen and the caudate nucleus and with the same detailed extrastriatal distribution. Thus, the divergent results obtained in vivo cannot be explained by different binding properties of the extrastriatal receptors

  13. Autoradiographic comparison of [{sup 125}I]epidepride and [{sup 125}I]NCQ 298 binding to human brain extrastriated dopamine receptors

    Energy Technology Data Exchange (ETDEWEB)

    Hall, Haakan; Halldin, Christer; Jerning, Eva; Oesterlund, Marie; Farde, Lars; Sedvall, Goeran

    1997-07-01

    Extrastriatal D{sub 2}-dopamine receptors can be visualized in the monkey and human brain using the benzamides [{sup 11}C]- and [{sup 76}Br]FLB 457 in PET and [{sup 123}I]epidepride in SPECT but not with the salicylamide analogues [{sup 76}Br]FLB 463 and [{sup 123}I]NCQ 298. To clarify the background for the differences in binding seen in vivo, we have compared the in vitro binding of [{sup 125}I]epidepride and [{sup 125}I]NCQ 298, using human whole hemisphere autoradiography. The images obtained with any radioligand showed detailed distribution with very dense binding in the putamen and the caudate nucleus and with the same detailed extrastriatal distribution. Thus, the divergent results obtained in vivo cannot be explained by different binding properties of the extrastriatal receptors.

  14. Synthesis and reactions with a midines of derivates cycles and of open chain of 2-bromo-3, 4-dioxobutanoic; Sintesis y reacciones con amidinas de derivados ciclicos y de cadena abierta del acido 2-bromo-3, 4-dioxobutanoico

    Energy Technology Data Exchange (ETDEWEB)

    Ancos, B. de; Delgado, F.; Martin, M.R. [Departamento de Quimica Organica, Facultad de Ciencias, Universidad Autonoma, Madrid (Spain)

    1995-12-31

    Bromination of enaminoesters 1 and 5, in appropriate conditions, affords in good yield enamines of the corresponding 2-bromo-3.4-dioxobutanoic acid derivatives 2-3 and 6 or dibromocompounds 4 and 6. The open chain enaminoesters (1-3) are more easily hydrolyzed that enaminofuranones 5 and 6. Prolongated treatment of 6 with hydrochloric acid affords the chlorinated enamine 11. The synthesis of 3-Bromo-4-hydroxy-5-methoxyfuran-2(5H)-one 10 can be achieved by bromination of 12, obtained by hydrolysis of 5. The reaction of methyl 3-bromo-4, 4-dimethoxy-3-oxobutanoate with amidines is a good method for the synthesis of 5-bromo-6-(dimethoxymethyl) pyrimidine-4(3H)-ones substituted at 2 position. Under the same conditions the reaction of furanone 10 with benzamide does not lead to the corresponding imidazoline. (Author) 12 refs.

  15. Research into aroma changes in irradiated foodstuffs. I.- Studies on Fish

    International Nuclear Information System (INIS)

    Radiolytic formation of volatile compounds have been investigated in fillets of hake, codfish and bonito gamma-irradiated at a dose range of 0.1-5 Mrads. Analytical methods have been developed by gas chromatography of functional group derivatives: carbonyls as 2,4,-dinitrophenyl hydrazones, primary and secondary amines as N-alkyl benzamides, and thiols as 2,4-dinitrophenyl alkyl thioethers. The main results are as follows: increasing with the integral dose of the whole carbonyls, the most significant components being acetaldehyde, propional dehyde and formaldehyde; no significant variations with the integral dose od the traces of ammonia, methylamine, trimethylamine, ethylamine, diethylamine, propylamine, butylamine and pentylamine found in unirradiated samples; and radiolytic formation of methanethiol and dimethyl disulfide. (Author) 98 refs

  16. Enhancement of the radiosensitivity of cultured lymphoma cells by 6(5H)-phenanthridinone, a novel poly (ADP-ribose) polymerase inhibitor

    International Nuclear Information System (INIS)

    Poly(ADP-ribose)polymerase (PARP, EC 2.4.2.30) is a chromatin-bound enzyme involved in a number of cellular processes linked to DNA metabolism such as proliferation, differentiation, DNA repair and apoptosis. Therefore, its inhibition, by preventing DNA repair to occur, has been proposed to potentiate radiotherapy or chemotherapy of tumors. However, the inhibitors used so far, mostly benzamide derivatives, gave un-conclusive results due to their weak inhibition potency and to their poor specificity. Recently, a new generation of PARP inhibitors has emerged, much more specific and active. We previously characterized one of them, namely 6(5H)-phenanthridinone (Phen), and showed its ability to potentiate the effects of anticancer drugs upon cultured tumor cells. These results prompted us to investigate whether Phen could also potentiate the effects of γ-radiations. (authors)

  17. Chemical constituents from red algae Bostrychia radicans (Rhodomelaceae: new amides and phenolic compounds

    Directory of Open Access Journals (Sweden)

    Ana Lígia Leandrini de Oliveira

    2012-01-01

    Full Text Available This study describes the isolation and structural determination of two amides, isolated for the first time: N,4-dihydroxy-N-(2'-hydroxyethyl-benzamide (0.019% and N,4-dihydroxy-N-(2'-hydroxyethyl-benzeneacetamide (0.023%. These amides, produced by the red macroalgae Bostrychia radicans, had their structures assigned by NMR spectral data and MS analyses. In addition, this chemical study led to the isolation of cholesterol, heptadecane, squalene, trans-phytol, neophytadiene, tetradecanoic and hexadecanoic acids, methyl hexadecanoate and methyl 9-octadecenoate, 4-(methoxymethyl-phenol, 4-hydroxybenzaldehyde, methyl 4-hydroxybenzeneacetate, methyl 2-hydroxy-3-(4-hydroxyphenyl-propanoate, hydroquinone, methyl 4-hydroxymandelate, methyl 4-hydroxybenzoate, 4-hydroxybenzeneacetic acid and (4-hydroxyphenyl-oxo-acetaldehyde. This is the first report concerning these compounds in B. radicans, contributing by illustrating the chemical diversity within the Rhodomelaceae family.

  18. Synthetic studies on axial chiral biaryls and functional materials utilizing arene-metal complexes; aren kinzokusakutai no tokusei wo riyo shita jikufusai biariru, oyobi shinki kinosei zairyo no gosei kenkyu

    Energy Technology Data Exchange (ETDEWEB)

    Uemura, Motokazu [Osaka Prefecture University, Osaka (Japan). Faculty of Integrated Arts and Sceinces

    1999-12-16

    Axially chiral biaryls compounds are of importance not only as chiral ligands for asymmetric reactions but also as biologically active natural products, e. g., korupensamine, michellamine and vancomycin. (Arene) chromium complex exists in two enantiomeric forms based on a planar chirality. Axially chiral biaryls were stereoselectively prepared by palladium(0)-catalyzed cross-coupling of (aryl halide)Cr(CO){sub 3} complexes with arylboronic acids. This method was applied for the total synthesis of antimaralial agent korupensamine A, naphthyltetrahydro-isoquinoline alkaloid. Furthermore, chiral 1,2-diols and diamines are important compounds for asymmetric reactions. These enantionerically pure 1,2-diols and 1,2-diamines were stereoselectively prepared by pinacol coupling of planar chiral chromium complexes of benzaldehydes and benzaldimines with samarium iodide. Moreover, non-biaryl axial compounds, N,N-dialkyl 2,6-disubstituted benzamides were synthesized in enantiomerically pure form utilizing planar chiral arene chromium complex. (author)

  19. Derivatives of (phenylsulfonamido-methyl)nicotine and (phenylsulfonamido-methyl)thiazole as novel 11β-hydroxysteroid dehydrogenase type 1 inhibitors: synthesis and biological activities in vitro

    Institute of Scientific and Technical Information of China (English)

    Xu ZHANG; Yang ZHOU; Yu SHEN; Li-li DU; Jun-hua CHEN; Ying LENG; Jian-hua SHEN

    2009-01-01

    Aim: To design and synthese a novel class of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors, featuring the (phenylsul-fonamido-methyl)pyridine and (phenyisulfonamido-methyl)thiazole framework. Methods: Our initial lead 4-(phenylsulfonamido-methyl)benzamides were modified. Inhibition of human and mouse 11β-HSD1 enzy-matic activities by the new compounds was determined by a scintillation proximity assay (SPA) using microsomes containing 11β-HSD1.Results: Sixteen new compounds (6a-6h, 7a-7h) were designed, synthesized and bioassayed. In dose-response studies, several com-pounds showed strong inhibitory activities with IC_(50) values at nanomolar or low nanomolar concentrations. Structure-activity relation-ships are also discussed with respect to molecular docking results. Conclusion: This study provides two promising new templates for 11β-HSD1 inhibitors.

  20. 3-(Benzodioxan-2-ylmethoxy)-2,6-difluorobenzamides bearing hydrophobic substituents at the 7-position of the benzodioxane nucleus potently inhibit methicillin-resistant Sa and Mtb cell division.

    Science.gov (United States)

    Straniero, Valentina; Pallavicini, Marco; Chiodini, Giuseppe; Zanotto, Carlo; Volontè, Luca; Radaelli, Antonia; Bolchi, Cristiano; Fumagalli, Laura; Sanguinetti, Maurizio; Menchinelli, Giulia; Delogu, Giovanni; Battah, Basem; De Giuli Morghen, Carlo; Valoti, Ermanno

    2016-09-14

    Lipophilic substituents at benzodioxane C (7) of 3-(benzodioxan-2-ylmethoxy)-2,6-difluorobenzamide improve the antibacterial activity against methicillin-resistant Staphylococcus aureus strains to MIC values in the range of 0.2-2.5 μg/mL, whereas hydrophilic substituents at the same position and modifications at the benzodioxane substructure, excepting for replacement with 2-cromanyl, are deleterious. Some of the lead compounds also exhibit good activity against Mtb. Parallel SARs to those of 3-(2-benzothiazol-2-ylmethoxy)-2,6-difluorobenzamide, well known FtsZ inhibitor, and cells alterations typical of FtsZ inhibition indicate such a protein as the target of these potent antibacterial benzodioxane-benzamides. PMID:27191617

  1. Cytotoxic T lymphocyte control during ectromelia (mousepox) virus infection: Interaction between MHC-restricted cells analyzed by non-radioactive-fluorimetry

    International Nuclear Information System (INIS)

    Cytotoxic T lymphocyte activity of draining lymph node cells isolated from BALB/c mice infected with ectromelia virus (EV) was examined using a fluorometric cell-mediated cytotoxicity (CMC) assay. Specific lysis of target cells A20 and EMT-6 primed with EV was demonstrated. The classical CD8+ cytolytic pathway (72.7%) as compared to that of CD4+ (27.3%) in the cellular response during acute infection. Also an alternative method for determining CMC, employing a bis-benzamide dye for labelling target cells, is described. Coefficient variations of relative fluorescence were below 6%, that makes the method sensitive and reliable. Comparison of the assay demonstrated with to that of the 51Cr-release assay is discussed

  2. Chemical constituents from red algae Bostrychia radicans (Rhodomelaceae): new amides and phenolic compounds

    International Nuclear Information System (INIS)

    This study describes the isolation and structural determination of two amides, isolated for the first time: N,4-dihydroxy-N-(2'-hydroxyethyl)-benzamide (0.019%) and N,4-dihydroxy-N-(2'-hydroxyethyl)-benzeneacetamide (0.023%). These amides, produced by the red macroalgae Bostrychia radicans, had their structures assigned by NMR spectral data and MS analyses. In addition, this chemical study led to the isolation of cholesterol, heptadecane, squalene, trans-phytol, neophytadiene, tetradecanoic and hexadecanoic acids, methyl hexadecanoate and methyl 9-octadecenoate, 4-(methoxymethyl)-phenol, 4-hydroxybenzaldehyde, methyl 4-hydroxybenzeneacetate, methyl 2-hydroxy-3-(4-hydroxyphenyl)-propanoate, hydroquinone, methyl 4-hydroxymandelate, methyl 4-hydroxybenzoate, 4-hydroxybenzeneacetic acid and (4-hydroxyphenyl)-oxo-acetaldehyde. This is the first report concerning these compounds in B. radicans, contributing by illustrating the chemical diversity within the Rhodomelaceae family. (author)

  3. Inorganic-organic hybrid silica based tin complex as a novel, highly efficient and recyclable heterogeneous catalyst for the one-pot preparation of spirooxindoles in water.

    Science.gov (United States)

    Ghahremanzadeh, Ramin; Rashid, Zahra; Zarnani, Amir-Hassan; Naeimi, Hossein

    2014-11-14

    In the present study, a tin complex immobilized on silica gel as a novel, green, highly efficient and heterogeneous reusable catalyst was synthesized by grafting 2-amino benzamide onto the silica gel surface as a result of the reaction between isatoic anhydride and 3-aminopropyl-functionalized silica gel, followed by complexing with tin chloride. The resulting organic-inorganic hybrid material was evaluated in the one-pot three-component synthesis of spiro[indoline-pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine]trione derivatives in water via the condensation reaction of isatins, barbituric acids, and 1H-pyrazol-5-amines. All the reactions were completed in short reaction times and all the products were obtained in high to excellent yields with high purity. In addition, the synthesized novel catalyst could be separated from the reaction mixture by simple filtration and can be reused up to seven runs without significant loss in activity. PMID:25215454

  4. Schedules of Controlled Substances: Placement of AH-7921 Into Schedule I. Final order.

    Science.gov (United States)

    2016-04-14

    With the issuance of this final order, the Administrator of the Drug Enforcement Administration places the substance AH-7921 (Systematic IUPAC Name: 3,4-dichloro-N-[(1dimethylamino)cyclohexylmethyl]benzamide), including its isomers, esters, ethers, salts, and salts of isomers, esters and ethers, into schedule I of the Controlled Substances Act. This scheduling action is pursuant to the Controlled Substances Act and is required in order for the United States to discharge its obligations under the Single Convention on Narcotic Drugs, 1961. This action imposes the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule I controlled substances on persons who handle (manufacture, distribute, import, export, engage in research or conduct instructional activities with, or possess), or propose to handle, AH-7921. PMID:27101639

  5. Antibacterial activity of Capsicum annuum extract and synthetic capsaicinoid derivatives against Streptococcus mutans.

    Science.gov (United States)

    Santos, Moema Mocaiber Peralva; Vieira-da-Motta, Olney; Vieira, Ivo José Curcino; Braz-Filho, Raimundo; Gonçalves, Paula Santos; Maria, Edmilsom José; Terra, Wagner Silva; Rodrigues, Rosana; Souza, Claudio Luiz Melo

    2012-04-01

    The inhibitory effects of the ethyl acetate extract and capsaicin (1) and dihydrocapsaicin (2) isolated from fruits of Capsicum annuum chili pepper type, and synthetic capsaicinoid derivatives (N-(4-hydroxyphenylethyl)decamide (3), (E)-N-(4-hydroxy-3-methoxybenzyl)-3,7-dimethylocta- 2,6-dienamide (4), 4-hydroxy-3-methoxy-N-((E)-3, 7-dimethylocta-2,6-dienyl)benzamide (5) andN-(4-hydroxy- 3-methoxybenzyl)decamide (6) at different concentrations were evaluated against Streptococcus mutans. The minimum inhibitory concentration at which the ethyl acetate extract prevented the growth of S. mutans was 2.5 mg/mL; those of the isolated compounds 1 and 2 were 1.25 μg/mL, while 3 was 5.0 μg/mL, and 4, 5 and 6 were 2.5 μg/mL, respectively. PMID:21858615

  6. Preparation and characterization of monosubstituted porphyrins immobilized on nanosilica

    Indian Academy of Sciences (India)

    Ebrahim Ahmadi; Ali Ramazani; Asemeh Mashhadi-Malekzadeh; Zahra Hamdi; Zahra Mohamadnia

    2014-08-01

    Three kinds of heteroaldehydes, -(3-triethoxysilylpropyl)-4-formyl benzamide (TPHA/SiO2), were prepared by the reaction of terephthalaldehydic acid with different silica supports such as hexagonal SBA-15, spherical SBA-15 and amorphous SiO2 for comparison purposes. Anchoring of this aldehyde to different supports allows the synthesis of mono-substituted porphyrins without the production of di-, tri- and tetra-substituted porphyrin side products. The exclusion of the aforementioned side products during the synthesis of monosubstituted porphyrins greatly reduced the complexity during purification of the product. Absorption spectrophotometry was performed on silica gel immobilizing porphyrin (CPTTP), free base tetraphenylporphyrin (H2TPP) and heteroaldehydes (TPHA/SiO2) using UV–Visible instrument and confirmed the presence of porphyrin on the structure of CPTTP.

  7. [Chemical constituents from Chenopodium ambrosioides].

    Science.gov (United States)

    Song, Kun; Wang, Hong-Qing; Liu, Chao; Kang, Jie; Li, Bao-Ming; Chen, Ruo-Yun

    2014-01-01

    Twelve compounds were isolated from the herb of Chenopodium ambrosioides, and their structures were identified by spectroscopic methods as kaempferol-7-O-alpha-L-rhamnopyranoside (1), kaempferol-3,7-di-O-alpha-L-rhamnopyranoside (2), patuletin (3), quercetin-7-O-alpha-L-rhamnopyranoside (4), grasshopper ketone (5), 4-hydroxy-4-methyl-2-cyclohexen-1-one (6), syringaresinol (7), benzyl beta-D-glucopyranoside (8), dendranthemoside B (9), N-trans-feruloyl tyramine (10), N-trans-feruloyl 4'-O-methyldopamine (11), and 4-hydroxy-N-[2-(4-hydroxyphenyl) ethyl] benzamide (12). Among them,compounds 3, 6-8,10, and 12 were isolated from the genus Chenopodium for the first time, and compounds 2-12 were isolated from this plant for the first time. PMID:24761641

  8. (E)-N′-[1-(Thio­phen-2-yl)ethyl­idene]benzohydrazide

    OpenAIRE

    Shan, Shang; Huang, Yan-Lan; Guo, Han-Qi; Li, Deng-feng; Sun, Jian

    2011-01-01

    The title compound, C13H12N2OS, was obtained from the condensation reaction of 2-acetyl­thio­phene and benzohydrazide. In the mol­ecule, the formohydrazide fragment is approximately planar (r.m.s deviation = 0.0146 Å) and the mean plane is oriented at dihedral angles of 24.47 (11) and 28.86 (13)°, respectively, to the phenyl and thio­phene rings. The thio­phene and phenyl rings make a dihedral angle of 53.21 (8)°. The benzamide fragment and thio­phene ring are located on the opposite sides of...

  9. Chemical constituents from red algae Bostrychia radicans (Rhodomelaceae): new amides and phenolic compounds

    Energy Technology Data Exchange (ETDEWEB)

    Oliveira, Ana Ligia Leandrini de; Silva, Denise B. da; Lopes, Norberto P.; Debonsi, Hosana M. [Universidade de Sao Paulo (FCFRP/USP), Ribeirao Preto, SP (Brazil). Fac. de Ciencias Farmaceuticas de Ribeirao Preto. Dept. de Quimica e Fisica; Yokoya, Nair S., E-mail: hosana@fcfrp.usp.br [Instituto de Botanica, Sao Paulo, SP (Brazil). Secao de Ficologia

    2012-07-01

    This study describes the isolation and structural determination of two amides, isolated for the first time: N,4-dihydroxy-N-(2'-hydroxyethyl)-benzamide (0.019%) and N,4-dihydroxy-N-(2'-hydroxyethyl)-benzeneacetamide (0.023%). These amides, produced by the red macroalgae Bostrychia radicans, had their structures assigned by NMR spectral data and MS analyses. In addition, this chemical study led to the isolation of cholesterol, heptadecane, squalene, trans-phytol, neophytadiene, tetradecanoic and hexadecanoic acids, methyl hexadecanoate and methyl 9-octadecenoate, 4-(methoxymethyl)-phenol, 4-hydroxybenzaldehyde, methyl 4-hydroxybenzeneacetate, methyl 2-hydroxy-3-(4-hydroxyphenyl)-propanoate, hydroquinone, methyl 4-hydroxymandelate, methyl 4-hydroxybenzoate, 4-hydroxybenzeneacetic acid and (4-hydroxyphenyl)-oxo-acetaldehyde. This is the first report concerning these compounds in B. radicans, contributing by illustrating the chemical diversity within the Rhodomelaceae family. (author)

  10. Induction of repair functions by hydrogen peroxide in Chinese hamster cells

    International Nuclear Information System (INIS)

    Hydrogen peroxide has been found to kill Chinese hamster V79 cells as an exponential function of dose. When a small dose (0.9 μg/ml for 1 h) was used as a pretreatment, before exposure to higher concentrations of the same agent, the cells became more resistant to killing than those which were not so pretreated. The presence of cycloheximide or benzamide, during this pretreatment, inhibited this observed increase in resistance. This pretreatment also resulted in decreased killing efficiency by MNNG and gamma-rays, but had no effect upon UV-light-induced killing. The results suggest that proteins (repair enzymes?) are synthesized after treatment with the small dose of hydrogen peroxide, and that these induced proteins enhance the cellular repair functions for agents causing DNA breaks. (author)

  11. Synthesis and evaluation of novel serotonin 4 receptor radiotracers for single photon emission computed tomography.

    Science.gov (United States)

    Lalut, Julien; Tournier, Benjamin B; Cailly, Thomas; Lecoutey, Cédric; Corvaisier, Sophie; Davis, Audrey; Ballandonne, Céline; Since, Marc; Millet, Philippe; Fabis, Frédéric; Dallemagne, Patrick; Rochais, Christophe

    2016-06-30

    Despite its implication in several physiological and pathological processes the serotonin subtype-4 receptor (5-HT4R) has seen limited effort for the development of radiolabeling agent especially concerning single photon emission computed tomography (SPECT). Bearing an ester function, the available ligands are rapidly susceptible to hydrolysis which limits their use in vivo. In this study the synthesis of iodinated benzamide and ketone analogs were described. Their affinity for the 5-HT4R and their lipophilicity were evaluated and the most promising derivatives were evaluated ex vivo for their binding to the receptor and for their ability to displace the reference ligand [(125)I]-SB207710. PMID:27060761

  12. Impact of hydrolysis-mediated clearance on the pharmacokinetics of novel anaplastic lymphoma kinase inhibitors.

    Science.gov (United States)

    Teffera, Yohannes; Berry, Loren M; Brake, Rachael L; Lewis, Richard T; Saffran, Douglas C; Moore, Earl; Liu, Jingzhou; Zhao, Zhiyang

    2013-01-01

    Compound 1 [(E)-4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-((1S,4S)-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide], a new, potent, selective anaplastic lymphoma kinase (ALK) inhibitor with potential application for the treatment of cancer, was selected as candidate to advance into efficacy studies in mice. However, the compound underwent mouse-specific enzymatic hydrolysis in plasma to a primary amine product (M1). Subsequent i.v. pharmacokinetics studies in mice showed that compound 1 had high clearance (CL) and a short half-life. Oral dose escalation studies in mice indicated that elimination of compound 1 was saturable, with higher doses achieving sufficient exposures above in vitro IC(50). Chemistry efforts to minimize hydrolysis resulted in the discovery of several analogs that were stable in mouse plasma. Three were taken in vivo into mice and showed decreased CL corresponding to increased in vitro stability in plasma. However, the more stable compounds also showed reduced potency against ALK. Kinetic studies in NADPH-fortified and unfortified microsomes and plasma produced submicromolar K(m) values and could help explain the saturation of elimination observed in vivo. Predictions of CL based on kinetics from hydrolysis and NADPH-dependent pathways produced predicted hepatic CL values of 3.8, 3.0, 1.6, and 1.2 l/h⋅kg for compound 1, compound 2 [(E)-3,5-difluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-((1s,4s)-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide], compound 3 [(E)-3-chloro-5-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-((1s,4s)-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide], and compound 4 [(E)-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-((1s,4s)-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-3-(trifluoromethyl)benzamide], respectively. The in vivo observed CLs for

  13. Electrostatic assembly/disassembly of nanoscaled colloidosomes for light-triggered cargo release

    KAUST Repository

    Li, Song

    2015-04-27

    Colloidosome capsules possess the potential for the encapsulation and release of molecular and macromolecular cargos. However, the stabilization of the colloidosome shell usually requires an additional covalent crosslinking which irreversibly seals the capsules, and greatly limits their applications in large-cargos release. Herein we report nanoscaled colloidosomes designed by the electrostatic assembly of organosilica nanoparticles (NPs) with oppositely charged surfaces (rather than covalent bonds), arising from different contents of a bridged nitrophenylene-alkoxysilane [NB; 3-nitro-N-(3-(triethoxysilyl)propyl)-4-(((3-(triethoxysilyl)propyl)-amino)methyl)benzamid] derivative in the silica. The surface charge of the positively charged NPs was reversed by light irradiation because of a photoreaction in the NB moieties, which impacted the electrostatic interactions between NPs and disassembled the colloidosome nanosystems. This design was successfully applied for the encapsulation and light-triggered release of cargos. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Two dodecanuclear heterometallic [Zn6Ln6] clusters constructed by a multidentate salicylamide salen-like ligand: synthesis, structure, luminescence and magnetic properties.

    Science.gov (United States)

    Song, Xue-Qin; Liu, Pan-Pan; Liu, Yuan-Ang; Zhou, Jing-Jing; Wang, Xiao-Long

    2016-05-10

    The employment of a multidentate salicylamide salen-like ligand, 2-hydroxy-N-(2-(2-hydroxybenzylidene)amino)ethyl)benzamide (H3L), in aid of NO3(-) anions under weak basic conditions in Zn(II)-Ln(III) chemistry (Ln = Eu, and Dy, ) led to the isolation of two novel butterfly heterometallic dodecanuclear clusters with six Ln(III) ions occupying the body position and six Zn(II) ions the outer wing-tip sites. All of them are fully characterized by elemental analysis, FT-IR spectroscopy, TG analysis, single-crystal X-ray diffraction, and X-ray powder diffraction (XRPD) techniques. Luminescence studies indicate that exhibits dual emission, while exhibits a bright blue emission under visible light excitation. Furthermore, magnetic susceptibility studies carried out for indicate that the magnetic exchange between Dy(III) ions revealed ferromagnetic interactions with interesting slow relaxation of magnetization of the SMM behavior. PMID:27092471

  15. In vivo and in vitro detection of dopamine d2 receptors in uveal melanomas.

    Science.gov (United States)

    Bodei, Lisa; Hofland, Leo J; Ferone, Diego; Mooy, Cornelia M; Kros, Johan M; Paridaens, Dion A; Baarsma, Seerp G; Ferdeghini, Marco; Van Hagen, Martin P; Krenning, Eric P; Kwekkeboom, Dik J

    2003-12-01

    Scintigraphy with radiolabeled benzamides was used in melanoma patients. Studies with a newer benzamide called 123I-epidepride, a high-affinity D2 receptor (D2R) antagonist, showed high sensitivity in D2R-positive pituitary adenomas. We evaluated the presence of D2R in patients with uveal melanomas in vivo with 123I-epidepride, and in vitro in melanomas, using immunohistochemistry (IHC) and 125I-epidepride autoradiography. We studied the in vivo tumor-to-background (TB) ratios in six patients with posterior uveal melanoma (one previously enucleated). IHC was performed in 3 of 6 tumors after enucleation and in another 20 uveal melanomas, 7 metastatic lymph nodes from skin melanoma, and 2 normal specimens. 125I-epidepride autoradiography was performed in 10 uveal melanomas (3 of which were studied in vivo), 7 metastases, and 2 normal samples. Radioligand uptake was present in the affected eye of 5 patients with uveal melanoma (TB = 3.1-6.1) and absent in the operated one (TB = 1). Eight uveal tumors were positive at IHC (35%), 14 weakly positive (61%), and 1 negative (4%). Two metastases were positive (29%), 2 weakly positive (29%), and 3 negative (42%). Two uveal tumors were positive at autoradiography (20%), 7 had nonspecific binding (70%), and 1 was negative (10%). One metastasis was positive (14%), while 6 were negative (86%). 123I-epidepride scintigraphy in uveal melanomas seems promising for sensitivity and image quality. D2R was demonstrated in a significant proportion of the melanomas, although 123I-epidepride uptake might also be nonspecific and unrelated to D2R binding. Although further studies on larger series are needed, 123I-epidepride could represent a future tool to study the expression of D2R in other classes of neuroendocrine tumors. PMID:14969602

  16. Synthesis and in Vitro and in Vivo Anticoagulant and Antiplatelet Activities of Amidino- and Non-Amidinobenzamides

    Directory of Open Access Journals (Sweden)

    Soo Hyun Lee

    2016-05-01

    Full Text Available Three amidino- and ten non-amidinobenzamides were synthesized as 3-aminobenzoic acid scaffold-based anticoagulant and antiplatelet compounds. The anticoagulant activities of thirteen synthesized compounds 1–13, and 2b and 3b as prodrugs were preliminary evaluated by screening the prolongation of activated partial thromboplastin time (aPTT and prothrombin time (PT in vitro. From the aPTT results obtained, two amidinobenzamides, N-(3′-amidinophenyl-3-(thiophen-2′′-ylcarbonylamino benzamide (1, 33.2 ± 0.7 s and N-(4′-amidinophenyl-3-(thiophen-2′′-ylcarbonylamino benzamide (2, 43.5 ± 0.6 s were selected to investigate the further anticoagulant and antiplatelet activities. The aPTT results of 1 (33.2 ± 0.7 s and 2 (43.5 ± 0.6 s were compared with heparin (62.5 ± 0.8 s in vitro at 30 μM. We investigated the effect of 1 and 2 on blood anticoagulant activity (ex vivo and on tail bleeding time (in vivo on mice. A tail cutting/bleeding time assay revealed that both 1 and 2 prolonged bleeding time in mice at a dose of 24.1 g/mouse and above. Compounds 1 and 2 dose-dependently inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation. In addition, 1 and 2 were evaluated on the inhibitory activities of thrombin and FXa as well as the generation of thrombin and FXa in human umbilical vein endothelial cells (HUVECs. Collectively, 1 and 2 possess some antiplatelet and anticoagulant activities and offer a basis for development of a novel antithrombotic product.

  17. Strati-bis porphyrins: a promising gauge for study of photo-induced electron transfer. Final summary report

    Energy Technology Data Exchange (ETDEWEB)

    Mauzerall, D.

    1982-02-01

    The synthesis of a new series of strati-bisporphyrins (sbPs) is reported. The synthesis via the preparation of the first amide-linked sbP, tetra-meso-(m,m' (N-benzyl benzamide)) strati-bisporphyrin, III. This highly symmetric and well defined staked porphyrin dimer of two meso-substituted tetra phenyl porphyrins joined at the meta positions of all eight phenyl groups by four methyl formamide linkages, -CH/sub 2/NHCO-. This sbP is being prepared by the de-novo coupling procedure where a second porphyrin ring is constructed upon an initial porphyrin ring by way of the internal condensation of a porphyrin tetraaldehyde with four pyrrole molecules. This is the same general scheme which was successfully used in the synthesis of the first sbP system which had ester linkages. The necessary porphyrin tetraaldehyde for this new amide-linked dimer has already been synthesized. The porphyrin, tetraaldehyde, T-meso (m-N-benzyl(m'-formyl)benzamide) porphyrin, II, was prepared by the acylation of a porphyrin tetraamine with m-chlorocarbonyl benzaldehyde. The porphyrin tetraamine, tetra-meso-(m-aminomethyl-phenyl porphyrin, I, was prepared by the condensation of the shiff-base polymer of m-amino-methyl benzaldehyde with pyrrole in the usual way. The most effective synthetic scheme for the sbP III begins with the preparation of the essential benzaldehydes 5 and 9 by the bromination of commercially available toluene derivatives. The fluorescence and other photophysical properties of these molecules will be studied as purified samples are prepared. 3 figures. (DMC)

  18. Synthesis and evaluation of a bromine-76-labeled PPAR{gamma} antagonist 2-bromo-5-nitro-N-phenylbenzamide

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Hsiaoju [Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110 (United States); Finck, Brian N. [Department of Internal Medicine, Division of Geriatrics and Nutritional Science, Washington University School of Medicine, St. Louis. MO 63110 (United States); Jones, Lynne A. [Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110 (United States); Welch, Michael J. [Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110 (United States); Mach, Robert H. [Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110 (United States)]. E-mail: rhmach@mir.wustl.edu

    2006-10-15

    Peroxisome proliferator activated-receptor gamma (PPAR{gamma}) binds to peroxisome receptor response elements with its heterodimeric partner, retinoid X receptor, and regulates downstream gene expression. PPAR{gamma} transcriptionally modulates fat metabolism, and receptor agonists have been developed to treat type II diabetes. PPAR{gamma} is also overexpressed in some tumor cell lines and primary tumors, including breast and prostate tumors. Two PPAR{gamma} antagonists, 2-chloro-5-nitro-N-phenylbenzamide (GW9662) and 2-chloro-5-nitro-N-pyridin-4-yl-benzamide (T0070907), represent good lead compounds for radiotracer development. In the current study, four additional halogen substituted analogs were synthesized and evaluated in a whole cell screening assay for PPAR{gamma} binding activity. Two bromine-containing analogs having EC{sub 5} values <5 nM were chosen for bromine-76 radiolabeling. Bromine-76-labeled 2-bromo-5-nitro-N-phenyl-benzamide was selected for subsequent in vitro and in vivo studies due to its superior radiolabeling yield ({approx}70%) and the well-characterized pharmacological properties of its analog GW9662. An in vitro stability study showed that 40% of the compound remained intact in plasma and about 25% in whole blood after 30 min. Biodistribution studies in MDA-MB-435 human breast tumor-bearing nude mice were carried out at 5 min, 30 min, 2 h and 24 h post injection of the radiotracer. Although in vivo metabolite studies demonstrated rapid compound degradation, at least 10% of the parent compound was delivered to the tumor. We are currently exploring second generation analogs of these lead compounds for the development of radiolabeled antagonists of the PPAR{gamma} receptor.

  19. Radiation sensitizations at DNA-level by chemical and biological agents. Coordinated programme on improvement of radiotherapy of cancer using modifiers of radiosensitivity of cells

    International Nuclear Information System (INIS)

    Radiation sensitization by chemical agents at DNA level is discussed. Procaine, Halothan and Metronidazole showed no significant effect on unscheduled DNA synthesis (UDS) in mouse spleen cells, investigated by autoradiography and no effect on rejoining of DNA single strand breaks after gamma or UV irradiation. Oxyphenbutazon and prednisolone reduced the replicative DNA synthesis in vitro and in vivo but there was only little effect on DNA repair in the in vivo experiments. These two substances showed also a small reduction in poly(ADP-ribose) synthesis (PAR synthesis). 5-methoxypsoralen (5-MOP) and 8-methoxypsoralen (8-MOP) in combination with UV irradiation showed that 5-MOP was more toxic than mutagen, but induced much less DNA crosslinks than 8-MOP. Autoradiographic studies of radiation sensitization by biological agents showed significant inhibition of UDS in Yoshida tumor cells after acute mycoplasma infection in rats. Nucleoid sedimentation studies showed only in the case of Yoshida tumor cells after mycoplasma infection a dramatic effect in the sedimentation behaviour. Sensitization of cells by changing chromatin structure was also studied. Benzamide, 3-NH2-benzamide, 3-Methoxybenzamide, Spermine, Theophyllin and Caffeine were tested in different concentrations on replicative DNA synthesis, UDS after UV irradiation and PAR synthesis Chinese hamster ovary cells. 5-Methoxybenzamide was the strongest sensitizer and inhibitor of the PAR synthesis, and was used in further experiments. Results of KFA Juelich on sensitization of a mamma-adenocarcinoma EO 771 on C57 B1 mice are given. Replicative DNA synthesis, DNA repair and PAR synthesis were compared in spleen cells and adenocarcinoma cells after treatment with 5-Methoxybenzamide. An inhibitory effect on UDS could be shown only in adenocarcinoma cells but not in the mice spleen cells

  20. Preparation and characterization of a novel Al(18)F-NOTA-BZA conjugate for melanin-targeted imaging of malignant melanoma.

    Science.gov (United States)

    Chang, Chih-Chao; Chang, Chih-Hsien; Lo, Yi-Hsuan; Lin, Ming-Hsien; Shen, Chih-Chieh; Liu, Ren-Shyan; Wang, Hsin-Ell; Chen, Chuan-Lin

    2016-08-15

    Melanin is an attractive target for the diagnosis and treatment of malignant melanoma. Previous studies have demonstrated the specific binding ability of benzamide moiety to melanin. In this study, we developed a novel (18)F-labeled NOTA-benzamide conjugate, Al(18)F-NOTA-BZA, which can be synthesized in 30min with a radiochemical yield of 20-35% and a radiochemical purity of >95%. Al(18)F-NOTA-BZA is highly hydrophilic (logP=-1.96) and shows good in vitro stability. Intravenous administration of Al(18)F-NOTA-BZA in two melanoma-bearing mouse models revealed highly specific uptake in B16F0 melanotic melanoma (6.67±0.91 and 1.50±0.26%ID/g at 15 and 120min p.i., respectively), but not in A375 amelanotic melanoma (0.87±0.21 and 0.24±0.09%ID/g at 15 and 120min p.i., respectively). The clearance from most normal tissues was fast. A microPET scan of Al(18)F-NOTA-BZA-injected mice also displayed high-contrast tumor images as compared with normal organs. Owing to the favorable in vivo distribution of Al(18)F-NOTA-BZA after intravenous administration, the estimated absorption dose was low in all normal organs and tissues. The melanin-specific binding ability, sustained tumor retention, fast normal tissues clearance and thelow projected human dosimetry supported that Al(18)F-NOTA-BZA is a very promising melanin-specific PET probe for melanin-positive melanoma. PMID:27445169

  1. Preliminary biological evaluation of acridinic compounds for a targeted combined chemo and internal radionuclide therapy for melanoma

    International Nuclear Information System (INIS)

    The increasing incidence of melanoma and a lack of effective therapy on the disseminated form induces the development of selective tissue-targeted therapies. The aim of the present work was a targeting approach combining a bimodality therapy with the same compound exhibiting both chemo and internal radionuclide therapeutic properties. Benzamides are known to present a specific affinity for melanoma tissue. Former studies have shown that with aromatic and hetero-aromatic analogues of N-(2-diethylaminoethyl)- 4-iodo benzamide (B.Z.A.), the affinity for melanoma was maintained. In this context, new compounds have been designed and synthesized conjugating a cytotoxic hetero-aromatic moiety, an amino-alkyl amidic side chain for melanoma targeting and a radioiodine for internal radionuclide therapy. Acridinic derivatives known as cytotoxic DNA-intercalating agents have been chosen for this study. The cytotoxic activity of fifteen new compounds has been tested in vitro on a panel of cell lines and the I.C.50 values were determined. The three first selected compounds have been further evaluated: in vivo, on B 16 F0 melanoma bearing C 57 B.L.6 mice to determine the pharmacological kinetic and namely the tumoral affinity. Two compounds exhibited a high, specific and long lasting concentration in melanoma tumor giving them a kinetic profile favourable for an application to radionuclide therapy; in vitro, using the 'colony forming' test on melanoma cells, for a first approach of association of chemo toxicity and radiotoxicity. Assessed on the ability of cells to form colonies, the inhibition observed with the association for a same molecule of chemo toxic and radio toxic doses was quite exactly the sum of the two separate effects, a result providing a first validation of the radio chemotherapy concept; in vitro, by a preliminary determination of molecular mechanisms. Compared to parent compounds, results confirmed a maintain of DNA-intercalating properties. These first results

  2. Radiation damages in chemical components of organic scintillator detectors; Danos de radiacao em componentes quimicos de detectores cintiladores organicos

    Energy Technology Data Exchange (ETDEWEB)

    Fernandes Neto, Jose Maria

    2003-07-01

    Samples containing PPO (1%, g/ml), diluted in toluene, they were irradiated in a {sup 60}Co irradiator (6.46 kGy/h) at different doses. The PPO concentration decay bi-exponentially with the dose, generating the degradation products: benzoic acid, benzamide and benzilic alcohol. The liquid scintillator system was not sensitive to the radiation damage until 20 kGy. Otherwise, the pulse height analysis showed that dose among 30 to 40 kGy generate significant loss of quality of the sensor (liquid scintillating) and the light yield was reduced in half with the dose of (34.04 {+-} 0.80) kGy. This value practically was confirmed by the photo peak position analysis that resulted D{sub 1/2} = (31.7 {+-} 1,4) kGy, The transmittance, at 360 nm, of the irradiated solution decreased exponentially. The compartmental model using five compartments (fast decay PPO, slow decay PPO, benzamide, benzoic acid and benzilic alcohol) it was satisfactory to explain the decay of the PPO in its degradation products in function of the dose. The explanation coefficient r{sup 2} = 0.985636 assures that the model was capable to explain 98.6% of the experimental variations. The Target Theory together with the Compartmental Analysis showed that PPO irradiated in toluene solution presents two sensitive molecular diameters both of them larger than the true PPO diameter. >From this analysis it showed that the radiolytic are generated, comparatively, at four toluene molecules diameter far from PPO molecules. For each one PPO-target it was calculated the G parameter (damage/100 eV). For the target expressed by the fast decay the G value was (418.4 {+-} 54.1) damages/100 eV, and for the slow decay target the G value was (54.5 {+-} 8.9) damages/100 eV. The energies involved in the chemical reactions were w (0.239 {+-} 0.031) eV/damage (fast decay) and w = (1 834 {+-} 0.301) eV/damage (slow decay). (author)

  3. Characterization of novel MPS1 inhibitors with preclinical anticancer activity.

    Science.gov (United States)

    Jemaà, M; Galluzzi, L; Kepp, O; Senovilla, L; Brands, M; Boemer, U; Koppitz, M; Lienau, P; Prechtl, S; Schulze, V; Siemeister, G; Wengner, A M; Mumberg, D; Ziegelbauer, K; Abrieu, A; Castedo, M; Vitale, I; Kroemer, G

    2013-11-01

    Monopolar spindle 1 (MPS1), a mitotic kinase that is overexpressed in several human cancers, contributes to the alignment of chromosomes to the metaphase plate as well as to the execution of the spindle assembly checkpoint (SAC). Here, we report the identification and functional characterization of three novel inhibitors of MPS1 of two independent structural classes, N-(4-{2-[(2-cyanophenyl)amino][1,2,4]triazolo[1,5-a]pyridin-6-yl}phenyl)-2-phenylacetamide (Mps-BAY1) (a triazolopyridine), N-cyclopropyl-4-{8-[(2-methylpropyl)amino]-6-(quinolin-5-yl)imidazo[1,2-a]pyrazin-3-yl}benzamide (Mps-BAY2a) and N-cyclopropyl-4-{8-(isobutylamino)imidazo[1,2-a]pyrazin-3-yl}benzamide (Mps-BAY2b) (two imidazopyrazines). By selectively inactivating MPS1, these small inhibitors can arrest the proliferation of cancer cells, causing their polyploidization and/or their demise. Cancer cells treated with Mps-BAY1 or Mps-BAY2a manifested multiple signs of mitotic perturbation including inefficient chromosomal congression during metaphase, unscheduled SAC inactivation and severe anaphase defects. Videomicroscopic cell fate profiling of histone 2B-green fluorescent protein-expressing cells revealed the capacity of MPS1 inhibitors to subvert the correct timing of mitosis as they induce a premature anaphase entry in the context of misaligned metaphase plates. Hence, in the presence of MPS1 inhibitors, cells either divided in a bipolar (but often asymmetric) manner or entered one or more rounds of abortive mitoses, generating gross aneuploidy and polyploidy, respectively. In both cases, cells ultimately succumbed to the mitotic catastrophe-induced activation of the mitochondrial pathway of apoptosis. Of note, low doses of MPS1 inhibitors and paclitaxel (a microtubular poison) synergized at increasing the frequency of chromosome misalignments and missegregations in the context of SAC inactivation. This resulted in massive polyploidization followed by the activation of mitotic catastrophe. A

  4. Radiation damages in chemical components of organic scintillator detectors

    International Nuclear Information System (INIS)

    Samples containing PPO (1%, g/ml), diluted in toluene, they were irradiated in a 60Co irradiator (6.46 kGy/h) at different doses. The PPO concentration decay bi-exponentially with the dose, generating the degradation products: benzoic acid, benzamide and benzilic alcohol. The liquid scintillator system was not sensitive to the radiation damage until 20 kGy. Otherwise, the pulse height analysis showed that dose among 30 to 40 kGy generate significant loss of quality of the sensor (liquid scintillating) and the light yield was reduced in half with the dose of (34.04 ± 0.80) kGy. This value practically was confirmed by the photo peak position analysis that resulted D1/2 = (31.7 ± 1,4) kGy, The transmittance, at 360 nm, of the irradiated solution decreased exponentially. The compartmental model using five compartments (fast decay PPO, slow decay PPO, benzamide, benzoic acid and benzilic alcohol) it was satisfactory to explain the decay of the PPO in its degradation products in function of the dose. The explanation coefficient r2 = 0.985636 assures that the model was capable to explain 98.6% of the experimental variations. The Target Theory together with the Compartmental Analysis showed that PPO irradiated in toluene solution presents two sensitive molecular diameters both of them larger than the true PPO diameter. >From this analysis it showed that the radiolytic are generated, comparatively, at four toluene molecules diameter far from PPO molecules. For each one PPO-target it was calculated the G parameter (damage/100 eV). For the target expressed by the fast decay the G value was (418.4 ± 54.1) damages/100 eV, and for the slow decay target the G value was (54.5 ± 8.9) damages/100 eV. The energies involved in the chemical reactions were w (0.239 ± 0.031) eV/damage (fast decay) and w = (1 834 ± 0.301) eV/damage (slow decay). (author)

  5. A novel radioligand for glycine transporter 1: characterization and use in autoradiographic and in vivo brain occupancy studies

    Energy Technology Data Exchange (ETDEWEB)

    Zeng Zhizhen [Imaging, Merck Research Laboratories, West Point, PA 19486 (United States)], E-mail: zhizhen_zeng@merck.com; O' Brien, Julie A. [Sleep and Psychiatric Disorders, Merck Research Laboratories, West Point, PA 19486 (United States); Lemaire, Wei [Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486 (United States); O' Malley, Stacey S.; Miller, Patricia J. [Imaging, Merck Research Laboratories, West Point, PA 19486 (United States); Zhao Zhijian [Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486 (United States); Wallace, Michael A. [Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065 (United States); Raab, Conrad [Drug Metabolism, Merck Research Laboratories, West Point, PA 19486 (United States); Lindsley, Craig W. [Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486 (United States); Departments of Pharmacology and Chemistry, Vanderbilt University, Nashville, TN 37232 (United States); Sur, Cyrille; Williams, David L. [Imaging, Merck Research Laboratories, West Point, PA 19486 (United States)

    2008-04-15

    Introduction: In an effort to develop agents to test the NMDA hypofunction hypothesis of schizophrenia, benchmark compounds from a program to discover potent, selective, competitive glycine transporter 1 (GlyT1) inhibitors were radiolabeled in order to further study the detailed pharmacology of these inhibitors and the distribution of GlyT1 in brain. We here report the in vitro characterization of [{sup 35}S](S)-2-amino-4-chloro-N-(1-(4-phenyl-1-(propylsulfonyl)piperidin-4-yl) ethyl)benzamide ([{sup 35}S]ACPPB), a radiotracer developed from a potent and selective non-sarcosine-derived GlyT1 inhibitor, its use in autoradiographic studies to localize (S)-2-amino-6-chloro-N-(1-(4-phenyl-1-(propylsulfonyl)piperidin-4-yl)ethyl) benzamide (ACPPB) binding sites in rat and rhesus brain and for in vivo occupancy assays of competitive GlyT1 inhibitors. Methods: Functional potencies of unlabeled compounds were characterized by [{sup 14}C]glycine uptake into JAR (human placental choriocarcinoma) cells and synaptosomes. Radioligand binding studies were performed with tissue homogenates. Autoradiographic studies were performed on tissue slices. Results: ACPPB is a potent (K{sub d}=1.9 nM), selective, GlyT1 inhibitor that, when radiolabeled with [{sup 35}S], is a well-behaved radioligand with low nondisplaceable binding. Autoradiographic studies of rat and rhesus brain slices with this ligand showed that specific binding sites were plentiful and nonhomogeneously distributed, with high levels of binding in the brainstem, cerebellar white matter, thalamus, cortical white matter and spinal cord gray matter. In vivo studies demonstrate displaceable binding of [{sup 35}S]ACPPB in rat brain tissues following iv administration of this radioligand. Conclusions: This is the first report of detailed anatomical localization of GlyT1 using direct radioligand binding, and the first demonstration that an in vivo occupancy assay is feasible, suggesting that it may also be feasible to develop

  6. 抗痴呆药物CPI-1189的合成工艺改进%Improved synthesis of anti-dementia drug CPI-1189

    Institute of Scientific and Technical Information of China (English)

    赵金会; 王亚楼; 魏臻

    2013-01-01

    4-Acetamide-N-(tert-butyl)benzamide(CPI-1189) treatment of dementia,associated with AIDS virus(HIV-l) infection was synthesized from 4-nitrobenzoic acid via 4-step reactions, including chlorina-tion, amidation, reduction and N-acylation. The 4-nitrobenzoic acid reacted with thionyl chloride to give 4-ni-trobenzoyl chloride, which was condensed with tert-butyl amine to give N-( tert-butyl) 4-nitrobenzamide (2). The nitro group of compound2 was then reduced to amino group[4-amino-N(tert-butyl)benzamide, 3] by transfer hydrogenation with hydrazine and 5% Pd/C. Finally, acylation of amino group compound 3 with acetyl chloride provided the title compound. The overall yield of the target compound was 67. 9% ,and its structure was confirmed by elemental analysis,MS,and 'H-NMR. In comparison with the reported procedure , the improved process has the advantage of low cost, simple operation, short reaction time and aptness for industrial production.%目的 合成抗痴呆药物4-乙酰氨基-N-(叔丁基)苯甲酰胺(CPI-1189)并优化其合成工艺.方法 以4-硝基苯甲酸为起始原料,经过酰氯化、酰胺化、催化转移氢化和N-乙酰化4步反应合成目标化合物.结果 目标化合物的总收率为67.9%,其化学结构经元素分析、1H-NMR、MS谱确证.结论 与文献报道的方法相比较,本工艺以氯化亚砜为氯化剂,降低了成本,并改进了硝基还原反应工艺,缩短了反应时间,使操作条件更为简单、实用.

  7. Imaging malignant melanoma with {sup 18}F-5-FPN

    Energy Technology Data Exchange (ETDEWEB)

    Feng, Hongyan; Xia, Xiaotian; Li, Chongjiao; Song, Yiling; Qin, Chunxia; Liu, Qingyao; Zhang, Yongxue; Lan, Xiaoli [Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (China); Hubei Key Laboratory of Molecular Imaging (China)

    2016-01-15

    Radiolabelled benzamides are attractive candidates for targeting melanoma because they bind to melanin and exhibit high tumour uptake and retention. {sup 18}F-5-Fluoro-N-(2-[diethylamino]ethyl)picolinamide ({sup 18}F-5-FPN), a benzamide analogue, was prepared and its pharmacokinetics and binding affinity evaluated both in vitro and in vivo to assess its clinical potential in the diagnosis and staging of melanoma. {sup 18}F-5-FPN was prepared and purified. Its binding specificity was measured in vitro in two different melanoma cell lines, one pigmented (B16F10 cells) and one nonpigmented (A375m cells), and in vivo in mice xenografted with the same cell lines. Dynamic and static PET images using {sup 18}F-5-FPN were obtained in the tumour-bearing mice, and the static images were also compared with those acquired with {sup 18}F-FDG. PET imaging with {sup 18}F-5-FPN was also performed in B16F10 tumour-bearing mice with lung metastases. {sup 18}F-5-FPN was successfully prepared with radiochemical yields of 5 - 10 %. Binding of {sup 18}F-5-FPN to B16F10 cells was much higher than to A375m cells. On dynamic PET imaging B16F10 tumours were visible about 1 min after injection of the tracer, and the uptake gradually increased over time. {sup 18}F-5-FPN was rapidly excreted via the kidneys. B16F10 tumours were clearly visible on static images acquired 1 and 2 h after injection, with high uptake values of 24.34 ± 6.32 %ID/g and 16.63 ± 5.41 %ID/g, respectively, in the biodistribution study (five mice). However, there was no visible uptake by A375m tumours. {sup 18}F-5-FPN and {sup 18}F-FDG PET imaging were compared in B16F10 tumour xenografts, and the tumour-to-background ratio of {sup 18}F-5-FPN was ten times higher than that of {sup 18}F-FDG (35.22 ± 7.02 vs. 3.29 ± 0.53, five mice). {sup 18}F-5-FPN PET imaging also detected simulated lung metastases measuring 1 - 2 mm. {sup 18}F-5-FPN specifically targeted melanin in vitro and in vivo with high retention and affinity

  8. Preliminary biological evaluation of acridinic compounds for a targeted combined chemo and internal radionuclide therapy for melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Gardette, M.; Papon, J.; Desbois, N.; Labarre, P.; Maisonial, A.; Maublant, J.; Madelmont, J.C.; Moins, N.; Chezal, J.M. [Centre Jean Perrin, Inserm-Universite d' Auvergne, 63 - Clermont Ferrand (France)

    2008-02-15

    The increasing incidence of melanoma and a lack of effective therapy on the disseminated form induces the development of selective tissue-targeted therapies. The aim of the present work was a targeting approach combining a bimodality therapy with the same compound exhibiting both chemo and internal radionuclide therapeutic properties. Benzamides are known to present a specific affinity for melanoma tissue. Former studies have shown that with aromatic and hetero-aromatic analogues of N-(2-diethylaminoethyl)- 4-iodo benzamide (B.Z.A.), the affinity for melanoma was maintained. In this context, new compounds have been designed and synthesized conjugating a cytotoxic hetero-aromatic moiety, an amino-alkyl amidic side chain for melanoma targeting and a radioiodine for internal radionuclide therapy. Acridinic derivatives known as cytotoxic DNA-intercalating agents have been chosen for this study. The cytotoxic activity of fifteen new compounds has been tested in vitro on a panel of cell lines and the I.C.50 values were determined. The three first selected compounds have been further evaluated: in vivo, on B 16 F0 melanoma bearing C 57 B.L.6 mice to determine the pharmacological kinetic and namely the tumoral affinity. Two compounds exhibited a high, specific and long lasting concentration in melanoma tumor giving them a kinetic profile favourable for an application to radionuclide therapy; in vitro, using the 'colony forming' test on melanoma cells, for a first approach of association of chemo toxicity and radiotoxicity. Assessed on the ability of cells to form colonies, the inhibition observed with the association for a same molecule of chemo toxic and radio toxic doses was quite exactly the sum of the two separate effects, a result providing a first validation of the radio chemotherapy concept; in vitro, by a preliminary determination of molecular mechanisms. Compared to parent compounds, results confirmed a maintain of DNA-intercalating properties. These

  9. A novel radioligand for glycine transporter 1: characterization and use in autoradiographic and in vivo brain occupancy studies

    International Nuclear Information System (INIS)

    Introduction: In an effort to develop agents to test the NMDA hypofunction hypothesis of schizophrenia, benchmark compounds from a program to discover potent, selective, competitive glycine transporter 1 (GlyT1) inhibitors were radiolabeled in order to further study the detailed pharmacology of these inhibitors and the distribution of GlyT1 in brain. We here report the in vitro characterization of [35S](S)-2-amino-4-chloro-N-(1-(4-phenyl-1-(propylsulfonyl)piperidin-4-yl) ethyl)benzamide ([35S]ACPPB), a radiotracer developed from a potent and selective non-sarcosine-derived GlyT1 inhibitor, its use in autoradiographic studies to localize (S)-2-amino-6-chloro-N-(1-(4-phenyl-1-(propylsulfonyl)piperidin-4-yl)ethyl) benzamide (ACPPB) binding sites in rat and rhesus brain and for in vivo occupancy assays of competitive GlyT1 inhibitors. Methods: Functional potencies of unlabeled compounds were characterized by [14C]glycine uptake into JAR (human placental choriocarcinoma) cells and synaptosomes. Radioligand binding studies were performed with tissue homogenates. Autoradiographic studies were performed on tissue slices. Results: ACPPB is a potent (Kd=1.9 nM), selective, GlyT1 inhibitor that, when radiolabeled with [35S], is a well-behaved radioligand with low nondisplaceable binding. Autoradiographic studies of rat and rhesus brain slices with this ligand showed that specific binding sites were plentiful and nonhomogeneously distributed, with high levels of binding in the brainstem, cerebellar white matter, thalamus, cortical white matter and spinal cord gray matter. In vivo studies demonstrate displaceable binding of [35S]ACPPB in rat brain tissues following iv administration of this radioligand. Conclusions: This is the first report of detailed anatomical localization of GlyT1 using direct radioligand binding, and the first demonstration that an in vivo occupancy assay is feasible, suggesting that it may also be feasible to develop positron emission tomography tracers

  10. Synthesis and Biological Evaluation of Novel Urea- and Guanidine-Based Derivatives for the Treatment of Obesity-Related Hepatic Steatosis

    Directory of Open Access Journals (Sweden)

    Xiaolin Liang

    2014-05-01

    Full Text Available Leptin, the product of the obese gene, is an adipocyte-secreted protein hormone playing a key role in the progression of obesity and hepatic steatosis. In this study, 28 novel (thiourea and guanidine-based analogues have been synthesized and N-(1-(4-(3-(2-chloroethylureidobenzylpiperidin-4-yl-3-(trifluoromethyl benzamide (7i was found to be a potent regulator of leptin expression in 3T3-L1 adipocytes. Treatment with 7i at a dose of 50 mg/kg/day for 35 days reduced the body weight and liver weight of diet-induced obesity mice by 13.5% and 18.4%, respectively, while also improving the serum levels of triglyceride, total cholesterol, leptin, adiponectin, LDL-c, HDL-c. Hematoxylin-eosin (H&E and Oil Red O staining also confirmed that 7i ameliorated fat deposition in liver tissue and restricted the size of adipocytes in obesity-related fatty liver disease.

  11. On the clinical impact of cerebral dopamine D2 receptor scintigraphy

    International Nuclear Information System (INIS)

    The present review describes findings and clinical indications for the dopamine D2 receptor scintigraphy. Methods for the examination of D2 receptors are positron emission tomography (PET) using 11C- or 18F-labelled butyrophenones or benzamides or single photon emission tomography (SPECT) using 123I-iodobenzamide (IBZM) respectively. The most important indication in neurology is the differential diagnosis of Parkinsonism: Patients with early Parkinson's disease show an increased D2 receptor binding (D2-RB) compared to control subjects. However, patients suffering from Steele-Richardson-Olszewski-Syndrome or Multiple System Atrophy show a decreased D2-RB and are generally non-responsive to treatment. Postsynaptic blockade of D2 receptors results in a drug induced Parkinsonian syndrome, which can be diagnosed by D2 scintigraphy. Further possible indications occur in psychiatry: The assessment of receptor occupancy is useful in schizophrenic patients treated with neuroleptics. Additionally, D2 receptor scintigraphy might help to clarify the differential diagnosis between neuroleptic malignant syndrome and lethal catatonia. The method might be useful for supervising neurobiochemical changes in drug dependency and during withdrawal. Assessment of dopamine D2 receptor binding can simplify the choice of therapy in depressive disorder: Patients showing a low D2 binding are likely to improve following an antidepressive drug treatment whereas sleep deprivation is promising in patients with high D2 binding. (orig.)

  12. Microwave assisted synthesis of novel acridine-acetazolamide conjugates and investigation of their inhibition effects on human carbonic anhydrase isoforms hCA I, II, IV and VII.

    Science.gov (United States)

    Ulus, Ramazan; Aday, Burak; Tanç, Muhammet; Supuran, Claudiu T; Kaya, Muharrem

    2016-08-15

    4-Amino-N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)benzamide was condensed with cyclic-1,3-diketones (dimedone and cyclohexane-1,3-dione) and aromatic aldehydes under microwave irradiation, leading to a series of acridine-acetazolamide conjugates. The new compounds were investigated as inhibitors of carbonic anhydrases (CA, EC 4.2.1.1), and more precisely cytosolic isoforms hCA I, II, VII and membrane-bound one hCA IV. All investigated isoforms were inhibited in low micromolar and nanomolar range by the new compounds. hCA IV and VII were inhibited with KIs in the range of 29.7-708.8nM (hCA IV), and of 1.3-90.7nM (hCA VII). For hCA I and II the KIs were in the range of 6.7-335.2nM (hCA I) and of 0.5-55.4nM (hCA II). The structure-activity relationships (SAR) for the inhibition of these isoforms with the acridine-acetazolamide conjugates reported here were delineated. PMID:27298005

  13. EFFECT OF NANOSILICA ON THE KINETICS OF CURE REACTION AND THERMAL DEGRADATION OF EPOXY RESIN

    Institute of Scientific and Technical Information of China (English)

    M. Ghaemy; M. Bazzar; H. Mighani

    2011-01-01

    Nanocomposites from nanoscale silica particles (NS), diglycidylether of bisphenol-A based epoxy (DGEBA), and 3,5-diamino-N-(4-(quinolin-8-yloxy) phenyl) benzamide (DQPB) as curing agent were obtained from direct blending of these materials. The effect of nanosilica (NS) particles as catalyst on the cure reaction of DGEBA/DQPB system was studied by using non-isothermal DSC technique. The activation energy (Ea) was obtained by using Kissinger and Ozawa equations.The Ea value of curing of DGEBA/DQPB/10% NS system showed a decrease of about 10 KJ/mol indicating the catalytic effect of NS particles on the cure reaction. The Ea values of thermal degradation of the cured samples of both systems were 148 KJ/mol and 160 KJ/mol, respectively. The addition of 10% of NS to the curing mixture did not have much effect on the initial decomposition temperature (Ti) but increased the char residues from 20% to 28% at 650℃.

  14. Metabolism of nitazoxanide in rats, pigs, and chickens: Application of liquid chromatography coupled to hybrid linear ion trap/Orbitrap mass spectrometer.

    Science.gov (United States)

    Huang, Xianhui; Guo, Chunna; Chen, Zhangliu; Liu, Yahong; He, Limin; Zeng, Zhenling; Yan, Chaoqun; Pan, Guangfang; Li, Shuaipeng

    2015-09-01

    Nitazoxanide (NTZ) is a nitrothiazole benzamide compound with a broad activity spectrum against parasites, Gram-positive and Gram-negative anaerobic bacteria, and viruses. In this study, hybrid linear ion trap/Orbitrap mass spectrometer providing a high mass resolution and accuracy was used to investigate the metabolism of NTZ in rats, pigs, and chickens. The results revealed that acetylation and glucuronidation were the main metabolic pathways in rats and pigs, whereas acetylation and sulfation were the major metabolic pathways in chickens, which indicated interspecies variations in drug metabolism and elimination. With the accurate mass data and the characteristic MS(n) product ions, we identified six metabolites in which tizoxanide and hydroxylated tizoxanide were phase I metabolites and tizoxanide glucuronide, tizoxanide glucose, tizoxanide sulfate and hydroxyl tizoxanide sulfate were phase II metabolites. Hydroxylated tizoxanide and tizoxanide glucose were identified for the first time. All the comprehensive data were provided to make out the metabolism of NTZ in rats, pigs and chickens more clearly. PMID:26231678

  15. Repellency of oils of lemon eucalyptus, geranium, and lavender and the mosquito repellent MyggA natural to Ixodes ricinus (Acari: Ixodidae) in the laboratory and field.

    Science.gov (United States)

    Jaenson, Thomas G T; Garboui, Samira; Palsson, Katinka

    2006-07-01

    MyggA Natural (Bioglan, Lund, Sweden) is a commercially available repellent against blood-feeding arthropods. It contains 30% of lemon-scented eucalyptus, Corymbia citriodora (Hook.) K. D. Hill & L. A. S. Johnson (Myrtaceae), oil with a minimum of 50% p-menthane-3,8-diol. MyggA Natural also contains small amounts of the essential oils of lavender, Lavandula angustifolia Mill. (Lamiaceae), and geranium, Pelargonium graveolens L'Her. (Geraniaceae). In laboratory bioassays, MyggA Natural and C. citriodora oil exhibited 100% repellency against host-seeking nymphs of Ixodes ricinus (L.) (Acari: Ixodidae). Lavender oil and geranium oil, when diluted to 1% in 1,2-propanediol, had weak repellent activities on I. ricinus nymphs, but when diluted to 30% in 1,2-propanediol had 100% repellencies. 1,2-Propanediol (100%) had no significant repellent activity in comparison with that of the control. In field tests in tick-infested areas in central Sweden, tick repellency of MyggA Natural and C. citriodora oil was tested by the blanket-dragging technique for 4 d during a 6-d period. The repellencies (74 and 85%, respectively) on day 1 are similar (89%) to that of blankets treated in a similar manner with 19% diethyl-methyl-benzamide, based on previous work. Repellencies declined significantly from day 1 to day 6 (74 to 45% for MyggA Natural; 85 to 42% for C. citriodora oil). PMID:16892632

  16. Effects of cisapride on ulcer formation and gastric secretion in rats: comparison with ranitidine and omeprazol.

    Science.gov (United States)

    Alarcón de la Lastra, C; Martin, M J; La Casa, M; López, A; Motilva, V

    1996-12-01

    1. The antiulcerogenic effects of cisapride, a potent benzamide-stimulating gastrointestinal motility agent, were studied on cold-resistant and pylorus-ligated gastric ulcers. Acidity, composition of gastric secretion, and quantitative and qualitative changes on mucus glycoprotein content were also determined. These effects were compared with those of ranitidine (50 mg/kg) and omeprazol (10 mg/kg). 2. Oral cisapride (10-100 mg/kg) dose-relatedly and significantly (P < 0.01, P < 0.05) decreased the severity of the lesions induced by cold-resistant stress. In stressed rats, cisapride increased the amount of mucus secretion and markedly enhanced the glycoprotein content. Morphometric evaluation of mucus secretion revealed a significant increase in both the PAS area (neutral glycoproteins) and Alcian blue area (sulfated glycoproteins). 3. In 4 h pyloric-ligated animals, cisapride (10-100 mg/kg) showed a significant reduction in the number and severity of ulcers (P < 0.01) and histamine concentration (P < 0.01, P < 0.001). In addition, at the highest doses (50-100 mg/kg), cisapride produced a significant decreases in acidity; however, it did not alter the gastric volume secretion or pepsin concentrations. 4. These results suggest that cisapride shows antiulcerogenic effects which could possibly be explained through antisecretory and cytoprotective mechanisms involving an enhancement of cuality and production of gastric mucus. PMID:9304418

  17. Evaluation of Hexane Extract of Tuber of Root of Cyperus rotundus Linn (Cyperaceae for Repellency against Mosquito Vectors

    Directory of Open Access Journals (Sweden)

    S. P. Singh

    2009-01-01

    Full Text Available Hexane extract of tuber of plant Cyperus rotundus (Cyperaceae was screened under laboratory conditions for repellent activity against mosquito vector Anopheles culicifacies Giles species A (Diptera: Culicidae, Anopheles stephensi Liston (Diptera: Culicidae, and Culex quinquefasciatus Say (Diptera: Culicidae. The Cyperus rotundus tuber extract was used to determine their effect on mosquito vector, and comparison with the DEET (NN Diethyl 1-3 methyl Benzamide, formerly known as diethyl 1-m-toluamide. The tuber extracts showed more effective at all the dose. Result obtained from the laboratory experiment showed that the tuber extracts are more effective for repellency of allthe mosquito vector even at low dose. Clear dose response relationships were established with the highest dose of 10% tuber extract evoking 100% repellency. Percent protection obtained against An. culicifacies Giles species A 100% repellency in 4 hours, 6 hours, An. stephensi 100% repellency in 6 hours and Cx. quinquefasciatus was 100% repellency in 6 hours at the 10% concentration. Against DEET- 2.5% An. culicifacies A 100% repellency in 1 hour, 2 hours, 6 hours, An. stephensi have shown 100% repellency in 6 hours, and Culex quinquefasciatus have shown 100% repellency in 1 hour, 2 hours, 6 hours. The consolidated data of the repellency observed in different species is given and it is evident that the over all repellency rates varied between 80 and 100% for different repellents concentrations (2.5%, 5%, and 10%. The extract can be applied as an effective personal protective measure against mosquito bites.

  18. Imaging dopamine transmission in schizophrenia

    International Nuclear Information System (INIS)

    Over the last ten years, several positron emission tomography (PET) and single photon computerized tomography (SPECT) studies of the dopamine (DA) system in patients with schizophrenia were performed to test the hypothesis that DA hyperactivity is associated with this illness. In this paper are reviewed the results of fifteen brain imaging studies comparing indices of DA function in drug naive or drug free patients with schizophrenia and healthy controls: thirteen studies included measurements of Da D2 receptor density, two studies compared amphetamine-induced DA release, and two studies measured DOPA decarboxylase activity, an enzyme involved in DA synthesis. It was conducted a meta-analysis of the studies measuring D2 receptor density parameters, under the assumption that all tracers labeled the same population of D2 receptors. This analysis revealed that, compared to healthy controls, patients with schizophrenia present a significant but mild elevation of D2 receptor density parameters and a significant larger variability of these indices. It was found no statistical evidence that studies performed with radiolabeled butyrophenones detected a larger increase in D2 receptor density parameters than studies performed with other radioligands, such as benzamides. Studies of presynaptic activity revealed an increase in DA transmission response to amphetamine challenge, and an increase in DOPA decarboxylase activity. Together, these data are compatible with both pre- and post-synaptic alterations of DA transmission in schizophrenia. Future studies should aim at a better characterization of these alterations, and at defining their role in the pathophysiology of the illness

  19. Bis(2-{2-[2-(benzylcarbamoylphenoxy]acetamido}ethylammonium nitrate ethanol disolvate

    Directory of Open Access Journals (Sweden)

    Weisheng Liu

    2011-01-01

    Full Text Available In the title compound, C36H40N5O6+·NO3−·2C2H5OH, the nitrate anion is disordered over the two orientations of equal occupancy while the solvent molecule reveals large displacement parameters. The cation is formed by protonation of the N atom of a secondary amine in the middle of the flexible chain and the whole compound has crystallographically imposed C-2 symmetry with the crystallographic b axis. An O atom of the nitrate anion links the acidic H atoms of the cation via N—H...O hydrogen bonding. In addition, neighbouring cations are connected by intermolecular N—H...O hydrogen bonds and π–π interactions between the benzamide groups of the cations [centroid–centroid distance = 4.000 (3 Å], forming a chain along [001]. The ethanol solvent molecules are arranged on the side of the chain through O—H...O hydrogen bonds.

  20. Evaluation of DEET and eight essential oils for repellency against nymphs of the lone star tick, Amblyomma americanum (Acari: Ixodidae).

    Science.gov (United States)

    Meng, Hao; Li, Andrew Y; Costa Junior, Livio M; Castro-Arellano, Ivan; Liu, Jingze

    2016-02-01

    DEET and Eight commercially available essential oils (oregano, clove, thyme, vetiver, sandalwood, cinnamon, cedarwood, and peppermint) were evaluated for repellency against host-seeking nymphs of the lone star tick, Amblyomma americanum. Concentration-repellency response was established using the vertical paper bioassay technique for each essential oil and compared with that of N,N-diethyl-3-methyl benzamide (DEET), a standard repellent compound present in many commercial repellent formulations. The effective concentration of DEET that repels 50% of ticks (EC50) was estimated at 0.02 mg/cm(2), while EC50s of the essential oils fall between 0.113 and 0.297 mg/cm(2). Based on EC50 estimates, oregano essential oil was the most effective among all essential oils tested, followed by clove, thyme, vetiver, sandalwood, cinnamon, cedarwood, and peppermint oils. None of the tested essential oils demonstrated a level of tick repellency found with DEET. Results from this study illustrated the challenge in search for more effective natural tick repellents. PMID:26590930

  1. The contribution of delta subunit-containing GABAA receptors to phasic and tonic conductance changes in cerebellum, thalamus and neocortex.

    Directory of Open Access Journals (Sweden)

    Stephen G Brickley

    2013-12-01

    Full Text Available We have made use of the delta subunit-selective allosteric modulator DS2 (4-chloro-N-[2-(2-thienylimidazo[1,2-a]pyridine-3-yl benzamide to assay the contribution of delta-GABAARs to tonic and phasic conductance changes in the cerebellum, thalamus and neocortex. In cerebellar granule cells, an enhancement of the tonic conductance was observed for DS2 and the orthosteric agonist THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol. As expected, DS2 did not alter the properties of GABAA receptor-mediated inhibitory postsynaptic synaptic currents (IPSCs supporting a purely extrasynaptic role for delta-GABAARs in cerebellar granule cells. DS2 also enhanced the tonic conductance recorded from thalamic relay neurons of the visual thalamus with no alteration in IPSC properties. However, in addition to enhancing the tonic conductance DS2 also slowed the decay of IPSCs recorded from layer II/III neocortical neurons. A slowing of the IPSC decay also occurred in the presence of the voltage-gated sodium channel blocker TTX. Moreover, under conditions of reduced GABA release the ability of DS2 to enhance the tonic conductance was attenuated. These results indicate that delta-GABAARs can be activated following vesicular GABA release onto neocortical neurons and that the actions of DS2 on the tonic conductance may be influenced by the ambient GABA levels present in particular brain regions.

  2. Biomimetic anchors applied to the host-guest antifouling functionalization of titanium substrates.

    Science.gov (United States)

    Cai, Xiao Yan; Li, Ning Ning; Chen, Jiu Cun; Kang, En-Tang; Xu, Li Qun

    2016-08-01

    A biomimetic strategy was developed for the construction of antifouling titanium oxide (Ti(oxide)) surfaces based on host-guest interactions. Two catecholic derivatives, dopamine 4-(phenylazo)benzamide (AZODopa) and dopamine 1-adamantanecarboxamide (AdaDopa) were synthesized and immobilized onto the Ti(oxide) surfaces. The guest molecules-anchored Ti(oxide) surfaces were further functionalized with zwitterionic heptakis[6-deoxy-6-(N-3-sulfopropyl-N,N-dimethylammonium ethyl sulfanyl)]-β-cyclodextrin (SBCD) and hydrophilic β-CD polymer (CDP). The surface elemental compositions and hydrophobic/hydrophilic properties of the Ti(oxide) surfaces before and after modification were characterized by X-ray photoelectron spectroscopy (XPS) and static water contact angle measurements, respectively. The antifouling properties of the modified Ti(oxide) surfaces were evaluated by the protein adsorption and bacterial adhesion assays. The zwitterionic SBCD- and hydrophilic CDP-functionalized Ti(oxide) surfaces can reduce the adsorption of bovine plasma fibrinogen and adhesion of Escherichia coli, as compared to the pristine and guest molecules-anchored Ti(oxide) surfaces. PMID:27135943

  3. Bio-Inspired Nitrile Hydration by Peptidic Ligands Based on L-Cysteine, L-Methionine or L-Penicillamine and Pyridine-2,6-dicarboxylic Acid

    Directory of Open Access Journals (Sweden)

    Cillian Byrne

    2014-12-01

    Full Text Available Nitrile hydratase (NHase, EC 4.2.1.84 is a metalloenzyme which catalyses the conversion of nitriles to amides. The high efficiency and broad substrate range of NHase have led to the successful application of this enzyme as a biocatalyst in the industrial syntheses of acrylamide and nicotinamide and in the bioremediation of nitrile waste. Crystal structures of both cobalt(III- and iron(III-dependent NHases reveal an unusual metal binding motif made up from six sequential amino acids and comprising two amide nitrogens from the peptide backbone and three cysteine-derived sulfur ligands, each at a different oxidation state (thiolate, sulfenate and sulfinate. Based on the active site geometry revealed by these crystal structures, we have designed a series of small-molecule ligands which integrate essential features of the NHase metal binding motif into a readily accessible peptide environment. We report the synthesis of ligands based on a pyridine-2,6-dicarboxylic acid scaffold and L-cysteine, L-S-methylcysteine, L-methionine or L-penicillamine. These ligands have been combined with cobalt(III and iron(III and tested as catalysts for biomimetic nitrile hydration. The highest levels of activity are observed with the L-penicillamine ligand which, in combination with cobalt(III, converts acetonitrile to acetamide at 1.25 turnovers and benzonitrile to benzamide at 1.20 turnovers.

  4. Autoradiographic localization of extrastriatal D2-dopamine receptors in the human brain using [125I]epidepride.

    Science.gov (United States)

    Hall, H; Farde, L; Halldin, C; Hurd, Y L; Pauli, S; Sedvall, G

    1996-06-01

    Epidepride is a benzamide with high affinity for central D2- and D3-dopamine receptors. The anatomical distribution of [125I]epidepride binding was examined by autoradiography, using postmortem human whole-hemisphere cryosections. The density of [125I]epidepride binding sites was high in caudate nucleus and putamen. [125I]epidepride also labeled receptors in extrastriatal region such as in the pallidum, some thalamic nuclei, the neocortex, and the substantia nigra. The neocortical binding was heterogeneously distributed. In most cortical regions, binding sites were located in superficial layers (I-II). However, in basal levels of the occipital cortex, [125I]epidepride binding was located in a deeper layer, probably corresponding to layer V. Competition studies indicated that most of the [125I]epidepride binding represented predominantly D2-dopamine receptors, in striatal as well as in extrastriatal regions. The presence of extrastriatal D2-dopamine receptor populations is of particular interest for research on schizophrenia and antipsychotic drug action. PMID:8723716

  5. Striatal and extrastriatal imaging of dopamine D{sub 2}receptors in the living human brain with [ {sup 123}I]epidepride single-photon emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Kuikka, J.T. [Department of Clinical Physiology, Kuopio University Hospital, Kuopio (Finland); Aakerman, K.K. [Department of Clinical Physiology, Kuopio University Hospital, Kuopio (Finland); Hiltunen, J. [MAP Medical Technologies Inc., Tikkakoski (Finland); Bergstroem, K.A. [Department of Clinical Physiology, Kuopio University Hospital, Kuopio (Finland); Raesaenen, P. [Department of Forensic Psychiatry, University of Kuopio and Niuvanniemi Hospital, Kuopio (Finland); Vanninen, E. [Department of Clinical Physiology, Kuopio University Hospital, Kuopio (Finland); Halldin, C. [Karolinska Institutet, Department of Clinical Neuroscience, Karolinska Hospital, Stockholm (Sweden); Tiihonen, J. [Department of Forensic Psychiatry, University of Kuopio and Niuvanniemi Hospital, Kuopio (Finland)

    1997-05-01

    The iodine-123 labelled ligand benzamide epidepride was evaluated as a probe for in vivo imaging of striatal and extrastriatal dopamine D{sub 2}receptor sites in the human brain. Four healthy males were imaged with a high-resolution single-photon emission tomography scanner. Striatal radioactivity peaked at 3 h after injection. The specific binding in the striatum was 0.91 {+-}0.03 at 3 h and this ratio steadily increased with time. Extrastriatal radioactivity was highest in the thalamus, in the midbrain and in the temporal cortex, and peaked at 45-60 min after injection of tracer. A smaller amount of radioactivity was found in the parietal, frontal and occipital cortices. Two radioactive metabolites were observed, of which one was more lipophilic than the parent compound. The radiation burden to the patient was 0.035 mSv/MBq (effective dose equivalent). The preliminary results showed that [ {sup 123}I]epidepride can be used for imaging striatal and extrastriatal dopamine D {sub 2}receptor sites in the living human brain. (orig.). With 5 figs., 1 tab.

  6. Striatal and extrastriatal imaging of dopamine D2 receptors in the living human brain with [123I]epidepride single-photon emission tomography.

    Science.gov (United States)

    Kuikka, J T; Akerman, K K; Hiltunen, J; Bergström, K A; Räsänen, P; Vanninen, E; Halldin, C; Tiihonen, J

    1997-05-01

    The iodine-123 labelled ligand benzamide epidepride was evaluated as a probe for in vivo imaging of striatal and extrastriatal dopamine D2 receptor sites in the human brain. Four healthy males were imaged with a high-resolution single-photon emission tomography scanner. Striatal radioactivity peaked at 3 h after injection. The specific binding in the striatum was 0.91+/-0.03 at 3 h and this ratio steadily increased with time. Extrastriatal radioactivity was highest in the thalamus, in the midbrain and in the temporal cortex, and peaked at 45-60 min after injection of tracer. A smaller amount of radioactivity was found in the parietal, frontal and occipital cortices. Two radioactive metabolites were observed, of which one was more lipophilic than the parent compound. The radiation burden to the patient was 0.035 mSv/MBq (effective dose equivalent). The preliminary results showed that [123I]epidepride can be used for imaging striatal and extrastriatal dopamine D2 receptor sites in the living human brain. PMID:9142727

  7. Striatal and extrastriatal imaging of dopamine D2receptors in the living human brain with [ 123I[epidepride single-photon emission tomography

    International Nuclear Information System (INIS)

    The iodine-123 labelled ligand benzamide epidepride was evaluated as a probe for in vivo imaging of striatal and extrastriatal dopamine D2receptor sites in the human brain. Four healthy males were imaged with a high-resolution single-photon emission tomography scanner. Striatal radioactivity peaked at 3 h after injection. The specific binding in the striatum was 0.91 ±0.03 at 3 h and this ratio steadily increased with time. Extrastriatal radioactivity was highest in the thalamus, in the midbrain and in the temporal cortex, and peaked at 45-60 min after injection of tracer. A smaller amount of radioactivity was found in the parietal, frontal and occipital cortices. Two radioactive metabolites were observed, of which one was more lipophilic than the parent compound. The radiation burden to the patient was 0.035 mSv/MBq (effective dose equivalent). The preliminary results showed that [ 123I[epidepride can be used for imaging striatal and extrastriatal dopamine D 2receptor sites in the living human brain. (orig.). With 5 figs., 1 tab

  8. Fluorine-18 radiofluorination of (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(3-fluoropropyl)-2,3-dimethoxybenzamide

    International Nuclear Information System (INIS)

    Substituted benzamides are selective ligands for the dopamine D2 receptors in the mammalian brain. The 5-(3-fluoropropyl) analogue of the very potent SPECT agent [123I]epidepride was shown to have the properties of a potential PET agent. Cyclotron produced H18F was delivered in 400 μL H218O into a vessel containing 1 mL of K2CO3/Kryptofix [222] in 96:4 acetonitrile/water. The H218O was removed by azeotropic distillations with acetonitrile to give K+/[K222]18F as an oil. [18F]Fluoropropylepidepride 2 was prepared by adding 5 mg of the corresponding tosylate 1 in 1 mL of acetonitrile. The reaction was allowed to proceed at 88 degree C for 24 min. Unreacted 18F was removed by eluting the reaction mixture through a silica Sep-Pak with ether. The ether was evaporated and the crude product was dissolved in 100 μL of 50:50 acetonitrile/ethanol. HPLC purification gave radiochemically pure 2

  9. The novel NF-κB inhibitor IMD-0354 induces apoptosis in chronic lymphocytic leukemia

    International Nuclear Information System (INIS)

    Nuclear factor-κB (NF-κB) is an important regulator of cell survival and has been shown to be constitutively active in chronic lymphocytic leukemia (CLL) cells. Recently, a novel NF-κB inhibitor, IMD-0354 (N-(3, 5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide), was shown to specifically inhibit the phosphorylation of IκBα by IkB kinases, thus preventing NF-κB release. In this study, we investigated if IMD-0354 can inhibit NF-κB activation and induce apoptosis in CLL cells in vitro. The rate of increase in apoptosis, drug sensitivity and DNA-binding activity of NF-κB were studied using Annexin V stainings, the fluorometric microculture cytotoxicity assay and electrophoretic mobility shift assay, respectively. Finally, the impact of IMD-0354 treatment on the expression of a set of apoptosis-related genes was investigated. The results clearly show that IMD-0354 induced apoptosis (mean 26%, range 8–48%) in CLL cells, independent of immunoglobulin heavy variable (IGHV) gene mutational status, and showed a dose-dependent cytotoxic effect. IMD-0354 treatment also significantly lowered the DNA-binding activity of NF-κB in CLL cells. In addition, we identified differences in expression levels of pro- and antiapoptotic genes following IMD-0354 treatment. In summary, our novel findings show that IMD-0354 can induce apoptosis in CLL cells, and thus merits further investigation as an anticancer agent in vivo

  10. Synthesis, radiolabeling, and preliminary evaluation in mice of some (N-diethylaminoethyl)-4-iodobenzamide derivatives as melanoma imaging agents

    International Nuclear Information System (INIS)

    N-(2-Diethylaminoethyl)-4-iodobenzamide (BZA) is a radiopharmaceutical recently developed in our laboratory for the scintigraphic detection of melanoma and metastases. Optimal time for imaging was between 18-24 h p.i. of [123I] BZA. With a view to selecting compounds able to provide quality images shortly after the injection, synthesis of an initial series of BZA derivatives and their evaluation in B16 melanoma bearing mice have been carried out. The [125I] radiolabeled products were obtained by a simple isotopic exchange procedure with high radiochemical yields (85-95%). After i.v. administration of the compounds we observed a good tumoral targeting ability. Tumoral activity peaked at 2.6 to 7.7% injected dose per g within 1 h post-injection. One of the benzamides with a blood clearance faster than that of BZA--0.06 vs. 0.2% I D/g--6 h p.i. gave the same tumor to blood and to organ ratios as BZA at 12-18 h p.i. Based on these preclinical data we hope to obtain good tumoral images 6 h p.i. in scintigraphic studies in man

  11. Effect of heparin addition on expansion of cord blood hematopoietic progenitor cells in three-dimensional coculture with stromal cells in nonwoven fabrics.

    Science.gov (United States)

    Okamoto, Toru; Takagi, Mutsumi; Soma, Toshihiro; Ogawa, Hiroyasu; Kawakami, Manabu; Mukubo, Masaaki; Kubo, Kazusuke; Sato, Reiko; Toma, Kazunori; Yoshida, Toshiomi

    2004-01-01

    Primary human cord blood mononuclear cells (CB MNCs) were inoculated into layers of primary human bone marrow stromal cells prepared in a nonwoven fabric porous carrier [three dimensional (3-D)] or on a dish [two dimensional (2-D)] using a cytokine-free medium and were cultured for 7 days with or without the addition of heparin. The number of progenitor cells increased threefold during the 3-D coculture, whereas it decreased in the 2-D culture. Heparin addition to the 3-D coculture further increased the number of progenitors twofold, whereas the addition of desulfated heparin had no effect. The heparin effect was also observed in a 3-D culture of CB MNCs without stromal cells when conditioned medium was employed. The coating of the carrier with N-(O-beta-(6-O-sulfogalactopyranosyl)-6-oxyhexyl)-3,5-bis (dodecyloxy)-benzamide instead of heparin addition also increased the number of progenitor cells in the 3-D culture of CB MNCs without stromal cells when the conditioned medium was employed. The 3-D coculture constructed with nonwoven fabrics and stromal cells was clearly superior to the 2-D culture because of the expansion of CB hematopoietic progenitor cells without cytokine addition. Heparin addition to the 3-D coculture further increased the number of progenitor cells, which may result from a synergistic effect of soluble cytokines produced by stromal cells with the sulfur group of heparin. PMID:15739052

  12. Raman and surface enhanced Raman spectroscopic studies of specific, small molecule activator of histone acetyltransferase p300

    Science.gov (United States)

    Kundu, Partha P.; Pavan Kumar, G. V.; Mantelingu, Kempegowda; Kundu, Tapas K.; Narayana, Chandrabhas

    2011-07-01

    We report for the first time, the Raman and surface enhanced Raman scattering (SERS) studies of N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-benzamide (CTB). This molecule is specific activator of human histone acetyltransferase (HAT), p300, and serves as lead molecule to design anti-neoplastic therapeutics. A detailed Raman and SERS band assignments have been performed for CTB, which are compared with the density functional theory calculations. The observed red shift of N sbnd H stretching frequency from the computed wavenumber indicates the weakening of N sbnd H bond resulting from proton transfer to the neighboring oxygen atom. We observe Ag sbnd N vibrational mode at 234 cm -1 in SERS of CTB. This indicates there is a metal-molecule bond leading to chemical enhancement in SERS. We also observe, enhancement in the modes pertaining to substituted benzene rings and methyl groups. Based on SERS analysis we propose the adsorption sites and the orientation of CTB on silver surface.

  13. Synthesis of New Congeners of 1-methyl-3-aminoisoquinolines, Evaluation of Their Cytotoxic Activity, In Silico and In Vitro Study of Their Molecular Targets as PDE4B.

    Science.gov (United States)

    Lapa, Gennady B; Tsunoda, Toshiyuki; Shirasawa, Senji; Baryshnikova, Maria A; Evseev, Gregory G; Afanasyeva, Daria A; Chigorina, Elena A

    2016-04-01

    To examine the cytotoxic activity of congeners of 3-amino-isoquinoline, we performed the phenotypic screening using panel of 60 cell lines and found that (N-(6,7-dimethoxy-1-methyl-isoquinolin-3-yl)-4-{[(1-ethyl-4-methyl-1H-pyrazol-3-yl)methyl]amino}benzamide (4d)) exhibited the significant effect against different tumor cell lines while showing the high activity toward human colorectal cancer HCT-116 cells (IC50 = 18 μm) and human breast cancer T-47D cells (GI50 = 1.9 μm). Virtual screening indicated that these compounds target protein kinases and phosphodiesterases (PDE). However, wet screening among panel of protein kinases did not show any significant activity. By contrast, 50 μm of 4c and 4d inhibited the growth of HKe3-mtKRAS spheroids in the 3D floating (3DF) culture suggesting that 4c and 4d target PDE4B which is selectively upregulated by mtKRAS in 3DF culture. PMID:26613238

  14. Disposable microcolumns with welded metal frits.

    Science.gov (United States)

    Hong, Sung Hoon; Cheong, Won Jo

    2016-01-01

    This study reports the preparation of disposable microcolumns with welded metal frits for the first time. First, the bottom of glass-lined stainless-steel tubing of 30 cm length, 1.6 mm od, and 0.5 mm id was welded with a stainless-steel screen frit of 1.6 mm diameter. A micro-welding machine was used for this. Next, the column was connected to a slurry packer and packed with porous silica particles. Then, the inlet of the column was carefully welded with another frit. The column was tested for separation of a test mix composed of phenol, 2-nitrophenol, acetophenone, aceanilide, and benzamide. Another column of the same physical dimension was also prepared with frits that were not welded to the column. The chromatographic performances of the two groups of columns (welded frits versus non-welded frits) were examined. The columns of welded frits showed ca. 18% better separation efficiency (number of theoretical plates) than those of non-welded frits. PMID:26614222

  15. Synthesis of novel nanostructured chiral poly(amide-imide)s containing dopamine and natural amino acids

    Indian Academy of Sciences (India)

    Shadpour Mallakpour; Amin Zadehnazari

    2013-01-01

    Four new thermally stable and optically active poly(amide-imide)s (PAI)s with good inherent viscosities were synthesized from the direct polycondensation reaction of N,N'-(pyromellitoyl)-bis-L--amino acids with 3,5-diamino-N-(3,4-dihydroxy-phen-ethyl)benzamide in a medium consisting of a molten salt, tetrabutylammonium bromide, and triphenyl phosphite as the activator. The polymerization reactions produced a series of novel PAIs containing dopamine segment in the side chain in high yield with inherent viscosities between 0.33 and 0.49 dL/g. The obtained polymers were typically characterized by means of FT-IR, 1HNMR spectroscopy, elemental analyses, powder X-ray diffraction, field emission scanning electronmicroscopy, inherent viscosity, and solubility tests. Thermal properties and flame retardant behaviour of the PAIs were also investigated using thermal gravimetric analysis (TGA and DTG) and limiting oxygen index (LOI). Data obtained by thermal analysis revealed that these polymers showed good thermal stability. Furthermore, high char yield in TGA and good LOI values indicated that the obtained polymers were capable of exhibiting good flame retardant properties.

  16. Cinitapride protects against ethanol-induced gastric mucosal injury in rats: role of 5-hydroxytryptamine, prostaglandins and sulfhydryl compounds.

    Science.gov (United States)

    Alarcón-de-la-Lastra Romero, C; López, A; Martín, M J; la Casa, C; Motilva, V

    1997-04-01

    This study was designed to determine the gastroprotective properties of cinitapride (CNT), a novel prokinetic benzamide derivative agonist of 5-HT4 and 5-HT1 receptors and 5-HT2 antagonist, on mucosal injury produced by 50% (v/v) ethanol. Results were compared with those for 5-hydroxytryptamine (5-HT: 10 mg kg-1). The possible involvements of gastric mucus secretion, endogenous prostaglandins (PGs) and sulfhydryl compounds (SH) in the protection mediated by CNT were also examined. Intraperitoneal administration of CNT (0.50 and 1 mg kg-1), 30 min before ethanol, significantly prevented gastric ulceration and increased the hexosamine content of gastric mucus. CNT (1 mg kg-1) also produced a significant increase in gastric mucosal levels of PGE2, but did not induce any significant changes in SH values. On the contrary, pretreatment with 5-HT worsened ethanol-induced erosions, however, did not affect gastric mucus secretion, glycoprotein content or PGE2 levels, although the non-protein SH fraction was significantly decreased. The present results demonstrate that the gastroprotective effects of CNT could be partly explained by a complex PG dependent mechanism. We suggest that 5-HT dependent mechanisms through 5-HT2 receptor blockade and 5-HT1 receptor activation could be also involved. PMID:9211565

  17. Research Perspective: Potential Role of Nitazoxanide in Ovarian Cancer Treatment. Old Drug, New Purpose?

    Energy Technology Data Exchange (ETDEWEB)

    Di Santo, Nicola, E-mail: nico.disanto@duke.edu; Ehrisman, Jessie [Division of Gynecologic Oncology, Duke University Medical Center, Durham, NC 27710 (United States)

    2013-09-10

    Among gynecological malignancies epithelial ovarian cancer (EOC) is the leading cause of death. Despite improvements in conventional chemotherapy combinations, the overall cure rate has remained mostly stable over the years, and only 10%–15% of patients maintain a complete response following first-line therapy. To improve the efficacy of ovarian cancer chemotherapy it is essential to develop drugs with new mechanisms of action. Compared to normal tissues, protein disulfide isomerase (PDI) is overexpressed in ovarian tumors. PDI is a cellular enzyme in the lumen of the endoplasmic reticulum (ER) of eukaryotes or the periplasmic region of prokaryotes. This protein catalyzes the formation and breakage of disulphide bonds between cysteine residues in proteins, which affects protein folding. Selective inhibition of PDI activity has been exhibited both in vitro and in vivo anticancer activity in human ovarian cancer models. PDI inhibition caused accumulation of unfolded or misfolded proteins, which led to ER stress and the unfolded protein response (UPR), and in turn resulted in cell death. Nitazoxanide [NTZ: 2-acetyloxy-N-(5-nitro-2-thiazolyl)benzamide] is a thiazolide antiparasitic agent with excellent activity against a wide variety of protozoa and helminths. In this article, we propose that NTZ, acting as PDI inhibitor, may be a new and potent addition to the chemotherapeutic strategy against ovarian cancer.

  18. 6,7-Dimethoxy-2-{2-[4-(1H-1,2,3-triazol-1-yl)phenyl]ethyl}-1,2,3,4-tetrahydroisoquinolines as superior reversal agents for P-glycoprotein-mediated multidrug resistance.

    Science.gov (United States)

    Liu, Baomin; Qiu, Qianqian; Zhao, Tianxiao; Jiao, Lei; Li, Yunman; Huang, Wenlong; Qian, Hai

    2015-02-01

    P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a major obstacle for successful cancer chemotherapy. Based on our previous study, 17 novel compounds with the 6,7-dimethoxy-2-{2-[4-(1H-1,2,3-triazol-1-yl)phenyl]ethyl}-1,2,3,4-tetrahydroisoquinoline scaffold were designed and synthesized. Among them, 2-[(1-{4-[2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl]phenyl}-1H-1,2,3-triazol-4-yl)methoxy]-N-(p-tolyl)benzamide (compound 7 h) was identified as a potent modulator of P-gp-mediated MDR, with high potency (EC50 =127.5 ± 9.1 nM), low cytotoxicity (TI>784.3), and long duration (>24 h) in reversing doxorubicin (DOX) resistance in K562/A02 cells. Compound 7 h also enhanced the effects of other MDR-related cytotoxic agents (paclitaxel, vinblastine, and daunorubicin), increased the accumulation of DOX and blocked P-gp-mediated rhodamine 123 efflux function in K562/A02 MDR cells. Moreover, 7 h did not have any effect on cytochrome (CYP3A4) activity. These results indicate that 7 h is a relatively safe modulator of P-gp-mediated MDR that has good potential for further development. PMID:25470220

  19. Human sterol 14α-demethylase as a target for anticancer chemotherapy: towards structure-aided drug design.

    Science.gov (United States)

    Hargrove, Tatiana Y; Friggeri, Laura; Wawrzak, Zdzislaw; Sivakumaran, Suneethi; Yazlovitskaya, Eugenia M; Hiebert, Scott W; Guengerich, F Peter; Waterman, Michael R; Lepesheva, Galina I

    2016-08-01

    Rapidly multiplying cancer cells synthesize greater amounts of cholesterol to build their membranes. Cholesterol-lowering drugs (statins) are currently in clinical trials for anticancer chemotherapy. However, given at higher doses, statins cause serious side effects by inhibiting the formation of other biologically important molecules derived from mevalonate. Sterol 14α-demethylase (CYP51), which acts 10 steps downstream, is potentially a more specific drug target because this portion of the pathway is fully committed to cholesterol production. However, screening a variety of commercial and experimental inhibitors of microbial CYP51 orthologs revealed that most of them (including all clinical antifungals) weakly inhibit human CYP51 activity, even if they display high apparent spectral binding affinity. Only one relatively potent compound, (R)-N-(1-(3,4'-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide (VFV), was identified. VFV has been further tested in cellular experiments and found to decrease proliferation of different cancer cell types. The crystal structures of human CYP51-VFV complexes (2.0 and 2.5 Å) both display a 2:1 inhibitor/enzyme stoichiometry, provide molecular insights regarding a broader substrate profile, faster catalysis, and weaker susceptibility of human CYP51 to inhibition, and outline directions for the development of more potent inhibitors. PMID:27313059

  20. VFV as a New Effective CYP51 Structure-Derived Drug Candidate for Chagas Disease and Visceral Leishmaniasis.

    Science.gov (United States)

    Lepesheva, Galina I; Hargrove, Tatiana Y; Rachakonda, Girish; Wawrzak, Zdzislaw; Pomel, Sébastien; Cojean, Sandrine; Nde, Pius N; Nes, W David; Locuson, Charles W; Calcutt, M Wade; Waterman, Michael R; Daniels, J Scott; Loiseau, Philippe M; Villalta, Fernando

    2015-11-01

    Sterol 14α-demethylases (CYP51) are the enzymes essential for sterol biosynthesis. They serve as clinical targets for antifungal azoles and are considered as targets for treatment of human Trypanosomatidae infections. Recently, we have shown that VNI, a potent and selective inhibitor of trypanosomal CYP51 that we identified and structurally characterized in complex with the enzyme, can cure the acute and chronic forms of Chagas disease. The purpose of this work was to apply the CYP51 structure/function for further development of the VNI scaffold. As anticipated, VFV (R)-N-(1-(3,4'-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide, the derivative designed to fill the deepest portion of the CYP51 substrate-binding cavity, reveals a broader antiprotozoan spectrum of action. It has stronger antiparasitic activity in cellular experiments, cures the experimental Chagas disease with 100% efficacy, and suppresses visceral leishmaniasis by 89% (vs 60% for VNI). Oral bioavailability, low off-target activity, favorable pharmacokinetics and tissue distribution characterize VFV as a promising new drug candidate. PMID:25883390

  1. Radiopharmaceuticals for SPECT exploration of dopaminergic systems. Diagnosis and surveillance of neuro-degenerative diseases; Les radiopharmaceutiques pour l`exploration des system dopaminergique en TEMP. Interet pour le diagnostic et le suivi des maladies neurodegeneratives

    Energy Technology Data Exchange (ETDEWEB)

    Gouilloteau, D.; Prunier-Levallon, C.; Zimmer, L.; Autret, A.; Besnard, J-Cl.; Baulieu, J-L. [CHU TOURS (France)

    1997-12-31

    New radiopharmaceuticals were developed to explore the pre- or post-synaptic slopes of the dopaminergic terminations. At present, their interest is recognized for the differential diagnosis of the extra-pyramidal syndromes. Other various applications in neurology and psychiatry are in view. On the pre-synaptic slope, implied in the Parkinson`s disease, the dopamine carrier, able to be visualized due to its iodine derivatives of cocaine, is localized. The {beta}CIT, which is presently the best known specificity-free derivative, has actually an equivalent affinity for the dopamine carrier and the serotonin carrier. Besides, its kinetic does not allow its imaging in the day of injection. We have developed and validated another derivative, the PE2I: N-(3-Iodoprop-(2E)-enyl) -2{beta}-carbometoxy -3{beta}-(4`-methyl-phenyl) nortropane which displays the properties required by kinetic and specificity. On the post-synaptic slope the type-D2 dopaminergic receptors were localized, which can be explored by means of (iodolisuride) ergolenes and benzamide derivatives (IBZM). These ligands have not an AMM yet, therefore their utilization may be approached by magistral preparation. The scintigraphy of the D2 receptors and dopamine carrier could be useful for the earlier diagnosis and the therapeutic surveillance of the neuro-degenerative decease. The coupling of the pre- and post-synaptic scintigraphies may be taken into consideration to augment diagnosis potentiality

  2. Research Perspective: Potential Role of Nitazoxanide in Ovarian Cancer Treatment. Old Drug, New Purpose?

    International Nuclear Information System (INIS)

    Among gynecological malignancies epithelial ovarian cancer (EOC) is the leading cause of death. Despite improvements in conventional chemotherapy combinations, the overall cure rate has remained mostly stable over the years, and only 10%–15% of patients maintain a complete response following first-line therapy. To improve the efficacy of ovarian cancer chemotherapy it is essential to develop drugs with new mechanisms of action. Compared to normal tissues, protein disulfide isomerase (PDI) is overexpressed in ovarian tumors. PDI is a cellular enzyme in the lumen of the endoplasmic reticulum (ER) of eukaryotes or the periplasmic region of prokaryotes. This protein catalyzes the formation and breakage of disulphide bonds between cysteine residues in proteins, which affects protein folding. Selective inhibition of PDI activity has been exhibited both in vitro and in vivo anticancer activity in human ovarian cancer models. PDI inhibition caused accumulation of unfolded or misfolded proteins, which led to ER stress and the unfolded protein response (UPR), and in turn resulted in cell death. Nitazoxanide [NTZ: 2-acetyloxy-N-(5-nitro-2-thiazolyl)benzamide] is a thiazolide antiparasitic agent with excellent activity against a wide variety of protozoa and helminths. In this article, we propose that NTZ, acting as PDI inhibitor, may be a new and potent addition to the chemotherapeutic strategy against ovarian cancer

  3. Rational prescription of drugs within similar therapeutic or structural class for gastrointestinal disease treatment: Drug metabolism and its related interactions

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To review and summarize drug metabolism and its related interactions in prescribing drugs within the similar therapeutic or structural class for gastrointestinal disease treatment so as to promote rational use of medicines in clinical practice.METHODS: Relevant literature was identified by performing MEDLINE/Pubmed searches covering the period from 1988 to 2006. RESULTS: Seven classes of drugs were chosen, including gastric proton pump inhibitors, histamine H2-receptor antagonists, benzamide-type gastroprokinetic agents, selective 5-HT3 receptor antagonists, fluoroquinolones, macrolide antibiotics and azole antifungals. They showed significant differences in metabolic profile (I.e., the fraction of drug metabolized by cytochrome P450 (CYP), CYP reaction phenotype, impact of CYP genotype on interindividual pharmacokinetics variability and CYP-mediated drug-drug interaction potential). Many events of severe adverse drug reactions and treatment failures were closely related to the ignorance of the above issues. CONCLUSION: Clinicians should acquaint themselves with what kind of drug has less interpatient variability in clearance and whether to perform CYP genotyping prior to initiation of therapy. The relevant CYP knowledge helps clinicians to enhance the management of patients with gastrointestinal disease who may require treatment with polytherapeutic regimens.

  4. Effects of Side Chains with Similar Lengths and Different Structures of Polyimides on Liquid Crystal Alignment Behavior

    Institute of Scientific and Technical Information of China (English)

    Jia-hao Xia; Ying Jiang; Shi-ming Gong; Zhen Sun; Ying-han Wang

    2014-01-01

    Polyimides (PI) with different side chains in structure were synthesized by copolycondensation of pyromelliticmdianhydride (PMDA) with 3,5-diamino-(4'-methane acid hexyl ester) phenyl-benzamide (C6-PDA),(4-butoxybiphenol)-3',5'-diaminobenzoate (C4-BBDA) and 3,5-diamino-benzoic acid decyl ester (C 10-DA) named PI-PDA,PI-C4,PI-DA,respectively.The lengths of side chains of PI-PDA and PI-DA are as similar as that of PI-C4.Through the pretilt angle tests it is demonstrated that neither the structure of side chains nor the rubbing process could make an obvious difference on vertical alignment property when the lengths of the side chains are similar,standing at around 1.6 nm.The measurement of surface energy of PI surfaces further proved this result.The result of the X-ray photo-electron spectroscope measurement indicated that the side chains of PIs stretched out from the polymer bulk phase and accumulated on the surface.

  5. In vitro efficacy of nitro- and halogeno-thiazolide/thiadiazolide derivatives against Sarcocystis neurona.

    Science.gov (United States)

    Gargala, G; Le Goff, L; Ballet, J J; Favennec, L; Stachulski, A V; Rossignol, J F

    2009-06-10

    Sarcocystis neurona is an obligate intracellular parasite that causes equine protozoal myeloencephalitis (EPM). The aim of this work was to document inhibitory activities of nitazoxanide (NTZ, [2-acetolyloxy-N-(5-nitro 2-thiazolyl) benzamide]) and new thiazolides/thiadiazolides on S. neurona in vitro development, and investigate their structure-activity relationships. S. neurona was grown in bovine turbinate cell cultures. At concentrations varying from 1.0 to 5.0mg/L, nitazoxanide and 21 of 32 second generation thiazolide/thiadiazolide agents exerted a > or =95% maximum inhibition on S. neurona development. Most active agents were either NO(2) or halogen substituted in position 5 of their thiazole moiety. In contrast, other 5-substitutions such as hydrogen, methyl, SO(2)CH(3), and CH(3) negatively impacted activity. Compared with derivatives with an acetylated benzene moiety, deacetylated compounds which most probably represent primary metabolites exhibited similar inhibitory activities. Present data provide the first evidence of in vitro inhibitory activities of nitazoxanide and new thiazolides/thiadiazolides on S. neurona development. Active halogeno-thiazolide/thiadiazolides may provide a valuable nitro-free alternative to nitazoxanide for EPM treatment depending on further evaluation of their in vivo activities. PMID:19369006

  6. Minireview: Mode of action of meta-diamide insecticides.

    Science.gov (United States)

    Nakao, Toshifumi; Banba, Shinichi

    2015-06-01

    Meta-diamides [3-benzamido-N-(4-(perfluoropropan-2-yl)phenyl)benzamides] are a distinct class of RDL GABA receptor noncompetitive antagonists showing high insecticidal activity against Spodoptera litura. The mode of action of the meta-diamides was demonstrated to be distinct from that of conventional noncompetitive antagonists (NCAs) such as fipronil, picrotoxin, lindane, dieldrin, and α-endosulfan. It was suggested that meta-diamides act at or near G336 in the M3 region of the Drosophila RDL GABA receptor. Although the site of action of the meta-diamides appears to overlap with that of macrocyclic lactones including avermectins and milbemycins, differential effects of mutations on the actions of the meta-diamides and the macrocyclic lactones were observed. Molecular modeling studies revealed that the meta-diamides may bind to an inter-subunit pocket near G336 in the Drosophila RDL GABA receptor better when in the closed state, which is distinct from the NCA-binding site, which is in a channel formed by M2s. In contrast, the macrocyclic lactones were suggested to bind to an inter-subunit pocket near G336 in the Drosophila RDL GABA receptor when in the open state. Furthermore, mechanisms underlying the high selectivity of meta-diamides are discussed. This minireview highlights the unique features of novel meta-diamide insecticides and demonstrates why meta-diamides are anticipated to become prominent insecticides that are effective against pests resistant to cyclodienes and fipronil. PMID:26047110

  7. Broflanilide: A meta-diamide insecticide with a novel mode of action.

    Science.gov (United States)

    Nakao, Toshifumi; Banba, Shinichi

    2016-02-01

    Broflanilide is a meta-diamide [3-benzamido-N-(4-(perfluoropropan-2-yl)phenyl)benzamide] that exhibits high larvicidal activity against Spodoptera litura. It has been suggested that broflanilide is metabolized to desmethyl-broflanilide and that it acts as a noncompetitive resistant-to-dieldrin (RDL) γ-aminobutyric acid (GABA) receptor antagonist. The binding site of desmethyl-broflanilide was demonstrated to be distinct from that of conventional noncompetitive antagonists such as fipronil. It has been proposed that the site of action for desmethyl-broflanilide is close to G336 in the M3 region of the Drosophila RDL GABA receptor. However, although the site of action for desmethyl-broflanilide appears to overlap with that of macrocyclic lactones, different modes of actions have been demonstrated for desmethyl-broflanilide and the macrocyclic lactones. The mechanisms underlying the high selectivity of meta-diamides are also discussed in this review. Broflanilide is expected to become a prominent insecticide because it is effective against pests with resistance to cyclodienes and fipronil. PMID:26361738

  8. Physicochemical properties of new amide-based protic ionic liquids and their use as materials for anhydrous proton conductors

    Energy Technology Data Exchange (ETDEWEB)

    Xiang Jin [School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing Key Laboratory of Environmental Science and Engineering, Beijing 100081 (China); Chen Renjie, E-mail: chenrj@bit.edu.cn [School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing Key Laboratory of Environmental Science and Engineering, Beijing 100081 (China); National Development Center of High Technology Green Materials, Beijing 100081 (China); Wu Feng, E-mail: wufeng863@vip.sina.com [School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing Key Laboratory of Environmental Science and Engineering, Beijing 100081 (China); National Development Center of High Technology Green Materials, Beijing 100081 (China); Li Li; Chen Shi [School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing Key Laboratory of Environmental Science and Engineering, Beijing 100081 (China); National Development Center of High Technology Green Materials, Beijing 100081 (China); Zou Qinqin [School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing Key Laboratory of Environmental Science and Engineering, Beijing 100081 (China)

    2011-09-01

    We prepared 3 protic ionic liquids based on trifluoromethanesulfonic acid and an amide, namely isobutyramide (ITSA), n-butyramide(NTSA), and benzamide(BTSA). All of the protic ionic liquids exhibit excellent thermal stability (above 200 deg. C). ITSA has the highest ionic conductivity, which is 32.6 mS/cm at 150 deg. C. ITSA was used to prepare anhydrous, conducting composite membranes based on polymers of polyvinylidene-fluoride (PVDF) to serve as intermediate temperature proton exchange membrane fuel cells. This type of composite membrane possesses good thermal stability, high ionic conductivity and good mechanical properties. Increasing the polymer content leads to the improvement of mechanical properties, but is accompanied by a reduction in ionic conductivity. We made efforts to eliminate the trade-off between strength and conductivity of the ITSA/PVDF composite membrane by adding polyamide imide, which resulted in a simultaneous increase in strength and conductivity. A conductivity of 7.5 mS/cm is achieved in a membrane containing 60 wt.% ITSA and 5 wt.% PAI in PVDF at 150 deg. C.

  9. Antifungal compounds produced by Colletotrichum gloeosporioides, an endophytic fungus from Michelia champaca.

    Science.gov (United States)

    Chapla, Vanessa Mara; Zeraik, Maria Luiza; Leptokarydis, Ioanis Hcristos; Silva, Geraldo Humberto; Bolzani, Vanderlan Silva; Young, Maria Claudia M; Pfenning, Ludwig Heinrich; Araújo, Angela Regina

    2014-01-01

    In this study, eight endophytic fungi were isolated from the leaves, stems and roots of Michelia champaca. The isolates were screened and evaluated for their antifungal, anticancer and acetylcholinesterase (AChE) inhibitory activities. All of the extracts exhibited potent activity against two evaluated phytopathogenic fungi. Chemical investigation of EtOAc extracts of the endophytic fungus Colletotrichum gloeosporioides resulted in the isolation of one new compound, 2-phenylethyl 1H-indol-3-yl-acetate (1), and seven known compounds: uracil (2), cyclo-(S*-Pro-S*-Tyr) (3), cyclo-(S*-Pro-S*-Val) (4), 2(2-aminophenyl)acetic acid (5), 2(4-hydroxyphenyl)acetic acid (6), 4-hydroxy- benzamide (7) and 2(2-hydroxyphenyl)acetic acid (8). All of the compound structures were elucidated using 1D and 2D NMR and MS analyses. The antifungal and AChE inhibitory activities of compounds 1-8 were evaluated in vitro. Compound 1 exhibited promising activity against Cladosporium cladosporioides and C. sphaerospermum that was comparable to that of the positive control nystatin. PMID:25421415

  10. First synthesis and anticancer activity of novel naphthoquinone amides.

    Science.gov (United States)

    Pradidphol, Narathip; Kongkathip, Ngampong; Sittikul, Pichamon; Boonyalai, Nonlawat; Kongkathip, Boonsong

    2012-03-01

    Sixteen novel naphthoquinone aromatic amides were synthesized by a new route starting from 1-hydroxy-2-naphthoic acid in nine or ten steps with good to excellent yield. Amide formation reaction was carried out by using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) as an efficient condensing agent leading to carboxamides in high yield. The key step for converting naphthol to 3-hydroxynaphthoquinone was the Fremy's salt oxidation followed by hydroxylation with tert-butyl hydroperoxide and triton B. Anticancer activity of these new naphthoquinone amides were evaluated and benzamide 22 showed potent inhibition against NCI-H187 cell lines while naphthamides 23 and 43 were the most potent inhibition against KB cells. The decatenation assay revealed that compounds 24 and 43 at 20 μM can inhibit hTopoIIα activity while three other compounds, namely compounds 22, 23, and 45, exhibited hTopoIIα inhibitory activity at final concentration of 50 μM. Docking experiment revealed the same trend as the cytotoxicity and decatenation assay. Therefore, naphthamides 24 and 43 can be promising target molecules for anticancer drug development. PMID:22280818

  11. AMPA Receptors as Therapeutic Targets for Neurological Disorders.

    Science.gov (United States)

    Lee, Kevin; Goodman, Lucy; Fourie, Chantelle; Schenk, Susan; Leitch, Beulah; Montgomery, Johanna M

    2016-01-01

    Almost every neurological disease directly or indirectly affects synapse function in the brain. However, these diseases alter synapses through different mechanisms, ultimately resulting in altered synaptic transmission and/or plasticity. Glutamate is the major neurotransmitter that mediates excitatory synaptic transmission in the brain through activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors. These receptors have therefore been identified as a target for the development of therapeutic treatments for neurological disorders including epilepsy, neurodegenerative diseases, autism, and drug addiction. The fact that AMPA receptors play a dominant role throughout the brain raises the significant challenge of selectively targeting only those regions affected by disease, and clinical trials have raised doubt regarding the feasibility of specifically targeting AMPA receptors for new therapeutic options. Benzamide compounds that act as positive allosteric AMPA receptor modulators, known as AMPAkines, can act on specific brain regions and were initially proposed to revolutionize the treatment of cognitive deficits associated with neurological disorders. Their therapeutic potential has since declined due to inconsistent results in clinical trials. However, recent advances in basic biomedical research are significantly increasing our knowledge of AMPA receptor structure, binding sites, and interactions with auxiliary proteins. In particular, the large complex of postsynaptic proteins that interact with AMPA receptor subunits have been shown to control AMPA receptor insertion, location, pharmacology, synaptic transmission, and plasticity. These proteins are now being considered as alternative therapeutic target sites for modulating AMPA receptors in neurological disorders. PMID:26920691

  12. Electrochemical Sensor for the Selective Determination of Prindopril Based on Phosphotungestic Acid Plastic Membrane

    International Nuclear Information System (INIS)

    A novel PVC membrane sensor for perindopril based on perindopril-phosphotungstate ion pair complex was prepared. The influence of membrane composition (i.e. percent of PVC, plasticizer, ion-pair complex, and kind of plasticizer), inner solution, pH of test solution and foreign cations on the electrode performance was investigated. The optimized membrane demonstrates Nernstian response (30.9 ± 1.0 mV per decade) for perindopril cations over a wide linear range from 9.0 Χ 10-7 to 1 Χ 10-2 M at 25 .deg. C. The potentiometric response is independent of the pH in the range of 4.0-9.5. The proposed sensor has the advantages of easy preparation, fast response time. The selectivity coefficients indicate excellent selectivity for perindopril over many common cations (e. g., Na+, K+, Mg2+, Cu2+, Ni2+, rhamnose, maltose, glycine and benzamide). The practical applications of this electrode was demonstrated by measuring the concentrations of perindopril in pure solutions and pharmaceutical preparations with satisfactory results

  13. Borneol Is a TRPM8 Agonist that Increases Ocular Surface Wetness

    Science.gov (United States)

    Chen, Gui-Lan; Lei, Ming; Zhou, Lu-Ping; Zou, Fangdong

    2016-01-01

    Borneol is a compound widely used in ophthalmic preparations in China. Little is known about its exact role in treating eye diseases. Here we report that transient receptor potential melastatin 8 (TRPM8) channel is a pharmacological target of borneol and mediates its therapeutic effect in the eyes. Ca2+ measurement and electrophysiological recordings revealed that borneol activated TRPM8 channel in a temperature- and dose-dependent manner, which was similar to but less effective than the action of menthol, an established TRPM8 agonist. Borneol significantly increased tear production in guinea pigs without evoking nociceptive responses at 25°C, but failed to induce tear secretion at 35°C. In contrast, menthol evoked tearing response at both 25 and 35°C. TRPM8 channel blockers N-(3-Aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)benzamide hydrochloride (AMTB) and N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)piperazine-1-carboxamide (BCTC) abolished borneol- and menthol-induced tear secretion. Borneol at micromolar concentrations did not affect the viability of human corneal epithelial cells. We conclude that borneol can activate the cold-sensing TRPM8 channel and modestly increase ocular surface wetness, which suggests it is an active compound in ophthalmic preparations and particularly useful in treating dry eye syndrome. PMID:27448228

  14. Biology and control of swamp dodder (Cuscuta gronovii)

    International Nuclear Information System (INIS)

    A simple model predicting swamp dodder (Cuscuta gronovii Willd.) emergence was developed. The model states that 0.1% of the cranberry seedlings will emerge after 150 to 170 GDD have accumulated after the winter ice has melted on the cranberry beds, using 0 C as the low temperature threshold. Experiments in cranberry showed that pronamide [3,5-dichloro-(N-1,1-dimethyl-2-propynyl)benzamide] was effective in controlling swamp dodder when applied preemergence. Rates below 2.4 kg ai/ha appeared to be safe for cranberry plants and fruit. Experiments with 14C glyphosate showed that the herbicide moved out of carrot leaves to the physiological sinks in the plant. In carrots parasitized by swamp dodder the dodder acted as one of the strongest sinks for photosynthates from the host. In cranberry glyphosate moved out of the leaves, but most remained in the stem to which the treated leaves were attached. The only physiological sinks that accumulated significant amounts of label were the stem apices. The concentration of the herbicide in this sink decreased with time. Swamp dodder stems were able to absorb glyphosate directly from solution

  15. Electrochemical Sensor for the Selective Determination of Prindopril Based on Phosphotungestic Acid Plastic Membrane

    Energy Technology Data Exchange (ETDEWEB)

    Zareh, Mohsen M. [Univ. of Tabuk, Tabuk (Saudi Arabia); Wasel, Anower M. [Association of Drug Agency, Cairo (Egypt); Abd Alkreem, Yasser M. [Zagazig Univ., Zagazig (Egypt)

    2013-10-15

    A novel PVC membrane sensor for perindopril based on perindopril-phosphotungstate ion pair complex was prepared. The influence of membrane composition (i.e. percent of PVC, plasticizer, ion-pair complex, and kind of plasticizer), inner solution, pH of test solution and foreign cations on the electrode performance was investigated. The optimized membrane demonstrates Nernstian response (30.9 ± 1.0 mV per decade) for perindopril cations over a wide linear range from 9.0 Χ 10{sup -7} to 1 Χ 10{sup -2} M at 25 .deg. C. The potentiometric response is independent of the pH in the range of 4.0-9.5. The proposed sensor has the advantages of easy preparation, fast response time. The selectivity coefficients indicate excellent selectivity for perindopril over many common cations (e. g., Na{sup +}, K{sup +}, Mg{sup 2+}, Cu{sup 2+}, Ni{sup 2+}, rhamnose, maltose, glycine and benzamide). The practical applications of this electrode was demonstrated by measuring the concentrations of perindopril in pure solutions and pharmaceutical preparations with satisfactory results.

  16. Coordination behavior of tetraaza [N₄] ligand towards Co(II), Ni(II), Cu(II), Cu(I) and Pd(II) complexes: synthesis, spectroscopic characterization and anticancer activity.

    Science.gov (United States)

    El-Boraey, Hanaa A

    2012-11-01

    Novel eight Co(II), Ni(II), Cu(II), Cu(I) and Pd(II) complexes with [N(4)] ligand (L) i.e. 2-amino-N-{2-[(2-aminobenzoyl)amino]ethyl}benzamide have been synthesized and structurally characterized by elemental analysis, spectral, thermal (TG/DTG), magnetic, and molar conductivity measurements. On the basis of IR, mass, electronic and EPR spectral studies an octahedral geometry has been proposed for Co(II), Ni(II) complexes and Cu(II) chloride complex, square-pyramidal for Cu(I) bromide complex. For Cu(II) nitrate complex (6), Pd(II) complex (8) square planar geometry was proposed. The EPR data of Cu(II) complexes in powdered form indicate d(x2-y2) ground state of Cu(II) ion. The antitumor activity of the synthesized ligand and some selected metal complexes has been studied. The palladium(II) complex (8) was found to display cytotoxicity (IC(50)=25.6 and 41 μM) against human breast cancer cell line MCF-7 and human hepatocarcinoma HEPG2 cell line. PMID:22765944

  17. Coordination behavior of tetraaza [N4] ligand towards Co(II), Ni(II), Cu(II), Cu(I) and Pd(II) complexes: Synthesis, spectroscopic characterization and anticancer activity

    Science.gov (United States)

    El-Boraey, Hanaa A.

    2012-11-01

    Novel eight Co(II), Ni(II), Cu(II), Cu(I) and Pd(II) complexes with [N4] ligand (L) i.e. 2-amino-N-{2-[(2-aminobenzoyl)amino]ethyl}benzamide have been synthesized and structurally characterized by elemental analysis, spectral, thermal (TG/DTG), magnetic, and molar conductivity measurements. On the basis of IR, mass, electronic and EPR spectral studies an octahedral geometry has been proposed for Co(II), Ni(II) complexes and Cu(II) chloride complex, square-pyramidal for Cu(I) bromide complex. For Cu(II) nitrate complex (6), Pd(II) complex (8) square planar geometry was proposed. The EPR data of Cu(II) complexes in powdered form indicate dx2-y2 ground state of Cu(II) ion. The antitumor activity of the synthesized ligand and some selected metal complexes has been studied. The palladium(II) complex (8) was found to display cytotoxicity (IC50 = 25.6 and 41 μM) against human breast cancer cell line MCF-7 and human hepatocarcinoma HEPG2 cell line.

  18. Synthesis and characterization of dopamine substitue tripodal trinuclear [(salen/salophen/salpropen)M] (Mdbnd Cr(III), Mn(III), Fe(III) ions) capped s-triazine complexes: Investigation of their thermal and magnetic properties

    Science.gov (United States)

    Uysal, Şaban; Koç, Ziya Erdem

    2016-04-01

    In this work, we aimed to synthesize and characterize a novel tridirectional ligand including three catechol groups and its novel tridirectional-trinuclear triazine core complexes. For this purpose, we used melamine (2,4,6-triamino-1,3,5-triazine) (MA) as starting material. 2,4,6-tris(4-carboxybenzimino)-1,3,5-triazine (II) was synthesized by the reaction of an equivalent melamine (I) and three equivalent 4-carboxybenzaldehyde. 4,4‧,4″-((1E,1‧E,1″E)-((1,3,5-triazine-2,4,6-triyl)tris(azanylylidene))tris(methanylylidene))tris(N-(3,4-dihydroxyphenethyl)benzamide) L (IV) was synthesized by the reaction of one equivalent (II) and three equivalent dopamine (3,4-dihydroxyphenethylamine) (DA) by using two different methods. (II, III, IV) and nine novel trinuclear Cr(III), Mn(III) and Fe(III) complexes of (IV) were characterized by means of elemental analyses, 1H NMR, FT-IR spectrometry, LC-MS (ESI+) and thermal analyses. The metal ratios of the prepared complexes were performed using Atomic Absorption Spectrophotometry (AAS). We also synthesized novel tridirectional-trinuclear systems and investigated their effects on magnetic behaviors of [salen, salophen, salpropen Cr(III)/Mn(III)/Fe(III)] capped complexes. The complexes were determined to be low-spin distorted octahedral Mn(III) and Fe(III), and distorted octahedral Cr(III) all bridged by catechol group.

  19. Association of downregulated HDAC 2 with the impaired mitochondrial function and cytokine secretion in the monocytes/macrophages from gestational diabetes mellitus patients.

    Science.gov (United States)

    Qu, Xin; Yu, Hongna; Jia, Bei; Yu, Xiaoyan; Cui, Qing; Liu, Zhifen; Sun, Chengming; Chu, Yongli

    2016-06-01

    Gestational diabetes mellitus (GDM) is associated with an increased risk of type 2 diabetes (T2DM) and cardiovascular diseases in later life, yet with underlying mechanisms unclear. The present study was to explore the association of upregulated histone deacetylase 2 (HDAC 2) with the impaired mitochondrial function and the cytokine secretion in the monocytes/macrophages from GDM patients. In this study, we examined the mitochondrial function, proinflamatory cytokine secretion and the HDAC 2 level in the serum or in the monocytes/macrophages from GDM patients, investigated the influence by HDAC 2 inhibitor, AR-42 (N-hydroxy-4-[[(2S)-3-methyl-2-phenylbutanoyl]amino]benzamide), on the mitochondrial function and cytokine secretion in the isolated GDM monocytes/macrophages. Results demonstrated an increased mitochondria size, mitochondrial superoxide and reactive oxygen species (ROS) production, and an undermined mitochondria membrane potential (MMP) in the GDM monocytes/macrophages. And the serum levels of interleukin (IL)-1β, tumor necrosis factor (TNF)-α and IL-6 were also markedly higher in the GDM pregnancies, while the expression and activity of HDAC 2 was downregulated. Moreover, AR-42-mediated HDAC 2 inhibition in vitro contributed to the impaired mitochondrial function and the proinflamatory cytokine secretion. In conclusion, this study suggests an association of the impaired mitochondrial function and the promoted proinflamatory cytokine secretion with the reduced HDAC 2 activity in GDM. These findings may present HDAC 2 as a target for GDM treatment. PMID:26936353

  20. Pharmacotherapy of gastroparesis.

    LENUS (Irish Health Repository)

    Quigley, E M

    2012-02-03

    The evaluation and management of gastric motor dysfunction continues to represent a significant clinical challenge. The very definition of what constitutes a clinically relevant disturbance of gastric motility remains unclear. The spectrum of gastroparesis extends from those with classical symptoms and severe delay of gastric emptying to those with dyspepsia and a mild delay in emptying rate. Indeed, for many patients with dyspepsia, the role of gastric emptying delay in the pathogenesis of symptoms, remains unclear. Any assessment of the efficacy of any therapeutic class in gastroparesis must be mindful, therefore, of these variations in definition. For those individuals with severe established gastroparesis, therapeutic success often remains elusive and i.v. erythromycin and oral dopamine antagonists, or substituted benzamides, remain the best options for acute severe exacerbations and chronic maintenance therapy, respectively. Alternatives, currently under investigation, include a number of 5-HT4 agonists, macrolides devoid of antibiotic activity, CCK antagonists and gastric electrical stimulation. Other novel approaches include strategies to address some of the regional abnormalities in gastric motor function that have been identified in some patients with dyspepsia.

  1. A soluble and fluorescent new type thienylpyrrole based conjugated polymer: optical, electrical and electrochemical properties.

    Science.gov (United States)

    Soganci, Tugba; Soyleyici, Hakan Can; Ak, Metin

    2016-06-01

    Recently, increased attention has been focused on the synthesis of soluble and processable conducting polymers due to interest in their potential application. For this purpose a new type electroactive 2,5-di(2-thienyl)pyrrole derivative was synthesized and its novel solution-processable and fluorescent polymer, namely poly(N-(2,5-di(thiophen-2-yl)-1H-pyrrol-1-yl)-3,4,5-tris(dodecyloxy)benzamide) (P(TPDOB)), was electrochemically synthesized. Characterization of the monomer and the polymer was performed by (1)H-NMR, (13)C-NMR, cyclic voltammetry, and UV-vis and fluorescence spectroscopy. This soluble polymer has very well-defined and reversible redox processes in the acetonitrile-lithium perchlorate (ACN/LiClO4) couple. Moreover, P(TPDOB) shows multielectrochromic behavior: blue in the oxidized state, caesious in the intermediate state and greenish in the neutral state. Also the copolymer consists of EDOT and TPDOB was synthesized by cyclic voltammetry. A copolymer film has superior electrochromic and electrical properties when compared with a homopolymer. Furthermore, the fluorescence features of the monomer and the polymer were investigated. Although the monomer is a violet light emitter, its polymer is a yellow light emitter. Synthesis of this new type solution-processable and fluorescent conducting polymer is an alternative to the conventional synthesis of soluble conducting polymers which allows the direct application of the conductive polymer to any desired surface for potential technological applications. PMID:27171850

  2. Radiosynthesis, evaluation and preclinical studies of a new 5HT2A radioligand

    International Nuclear Information System (INIS)

    123I-5-I-R91150, a radioiodinated analogue of R91150 (a ligand (antagonist) of Janssen Research Foundation), showing high affinity and selectivity for 5HT2A receptors, was developed as a potential in vivo 5HT2A receptor tracer for SPECT. The applied radiochemistry, whereby the radioiodine was substituted on the 5 - position of the benzamide ring, allowed to obtain the tracer with high specific activity and high purity. In vitro and in vivo rat studies revealed that the new tracer bound reversibly with the required high affinity (Kd=0.1 nM) and high selectivity (a factor ranging from 10000 to at least 50 vis a vis other receptors) to 5HT2A receptors. In young normal subjects the major part of the 123I-5-I-R91150 radioactivity in the brain is present in cortical areas. Cortical area to cerebellum activity ratio reaches an equilibrium value of about 1.8 around 90 min. till 4 hours p.i.. This binding was specific and reversible. The cortical activity reflects a distribution in the brain similar to that of the mapping of 5HT2A receptors from post mortem studies. These findings suggested that 123I-5-I-R91150 allows imaging and quantitative estimation with SPECT and could be used for further clinical studies. The radiobromine analogue was synthetised as a potential PET tracer. (author)

  3. Single photon emission tomography (SPET) imaging of dopamine D2 receptors in the course of dopamine replacement therapy in patients with nocturnal myoclonus syndrome (NMS)

    International Nuclear Information System (INIS)

    Single photon emission tomography (SPET) permits the in vivo measurements of regional cerebral radioactivity in the human brain following the administration of compounds labeled with photon-emitting isotopes. According to our SPET findings of a reduced binding of [123I]labeled (S)-2-hydroxy-3-iodo-6-methoxy-([1-ethyl-2-pyrrolidinyl]methyl) benzamide (IBZM) (a highly selective CNS D2 dopamine receptor ligand) to D2 dopamine receptors in striatal structures in untreated patients with nocturnal myoclonus syndrome (NMS) it seemed to be of interest to investigate whether there are changes in D2 receptor binding under dopamine replacement therapy or not. We studied the uptake and distribution of [123I]IBZM before and in the course of dopamine replacement therapy in four patients with severe insomnia caused by nocturnal myoclonus syndrome (NMS). We found an increase of the IBZM binding to D2 receptors in the course of treatment, which was associated with an improvement of sleep quality. Reasons for this are discussed. The [123I]IBZM SPET technique in conclusion offers an interesting tool for in vivo investigations of functional changes in the dopaminergic neurotransmitter system in longitudinal studies. (author)

  4. The discovery of epidepride and its analogs as high-affinity radioligands for imaging extrastriatal dopamine D(2) receptors in human brain.

    Science.gov (United States)

    de Paulis, Tomas

    2003-01-01

    [(123)I]Epidepride, [(18)F]fallypride, and [(76)Br]isoremoxipride (FLB-457) and their corresponding [(11)C]labeled derivatives belong to a class of high-affinity radioligands for SPECT or PET imaging of dopamine D(2) receptors in the human brain. In contrast to previously used imaging agents, these ligands are capable of identifying extrastriatal dopamine D(2) receptors. The design of these substituted benzamides derive its origin from the atypical antipsychotic agent, remoxipride. Starting in the late 1970's, halogenated analogs of (S)-sulpiride were evaluated in binding assays and behavioral studies, leading to the discovery of remoxipride. Remoxipride was 10 times weaker than sulpiride in vitro but 50 times more potent in vivo. Search for a putative active metabolite of remoxipride led to the discovery of raclopride and eticlopride, the former becoming a useful radioligand as tritium or carbon-11 labeled form for receptor binding and PET studies, respectively. In the US, the mono-iodine analog of raclopride, [(123)I]iodobenzamide (IBZM), was found to have moderate putamen-to-cerebellum ratio in rat and human brain. Continued search for metabolites of remoxipride led to the discovery of its 3,6-dihydroxy derivative, NCQ-344, with an extremely potent in vivo activity in the rat. SAR studies of the metabolites of remoxipride led to the discovery of the 3-methoxy isomer, isoremoxipride (FLB-457) and its corresponding 6-hydroxy analog, FLB-463, both having affinities for the dopamine D(2) receptor in the 20-30 pM range. Later, the 5-[(123)I]iodo analog of FLB-463, [(123)I]ioxipride ([(123)I]NCQ-298), became a potential SPECT imaging agent. In the mean time, the deshydroxy analog of IBZM, [(125)I]iodopride, showed binding potential in the rat similar to [(125)I]IBZM. Epidepride was designed by combining the structure of isoremoxipride with that of iodopride. In 1988, epidepride was independently prepared and radiolabeled in three separate laboratories in Stockholm

  5. 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

  6. Food restriction alters N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride (pramipexole)-induced yawning, hypothermia, and locomotor activity in rats: evidence for sensitization of dopamine D2 receptor-mediated effects.

    Science.gov (United States)

    Collins, Gregory T; Calinski, Diane M; Newman, Amy Hauck; Grundt, Peter; Woods, James H

    2008-05-01

    Food restriction enhances sensitivity to the reinforcing effects of a variety of drugs of abuse including opiates, nicotine, and psychostimulants. Food restriction has also been shown to alter a variety of behavioral and pharmacological responses to dopaminergic agonists, including an increased sensitivity to the locomotor stimulatory effects of direct- and indirect-dopamine agonists, elevated extracellular dopamine levels in responses to psychostimulants, as well as suppression of agonist-induced yawning. Behavioral and molecular studies suggest that augmented dopaminergic responses observed in food-restricted animals result from a sensitization of the dopamine D2 receptor; however, little is known about how food restriction affects dopamine D3 receptor function. The current studies were aimed at better defining the effects of food restriction on D2 and D3 receptor function by assessing the capacity of N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride (pramipexole) to induce yawning, penile erection (PE), hypothermia, and locomotor activity in free-fed and food-restricted rats. Food restriction resulted in a suppression of pramipexole-induced yawning, a sensitized hypothermic response, and an enhanced locomotor response to pramipexole, effects that are suggestive of an enhanced D2 receptor activity; no effect on pramipexole-induced PE was observed. Antagonist studies further supported a food restriction-induced enhancement of the D2 receptor activity because the D2 antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole (L741,626) recovered pramipexole-induced yawning to free-fed levels, whereas yawning and PE were suppressed following pretreatment with the D3 antagonist N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide hydrochloride (PG01037). The results of the current studies suggest that food restriction sensitized rats to the D2-mediated effects of pramipexole while having no effect

  7. International Union of Basic and Clinical Pharmacology. XCV. Recent Advances in the Understanding of the Pharmacology and Biological Roles of Relaxin Family Peptide Receptors 1–4, the Receptors for Relaxin Family Peptides

    Science.gov (United States)

    Halls, Michelle L.; Bathgate, Ross A. D.; Sutton, Steve W.; Dschietzig, Thomas B.

    2015-01-01

    Relaxin, insulin-like peptide 3 (INSL3), relaxin-3, and INSL5 are the cognate ligands for the relaxin family peptide (RXFP) receptors 1–4, respectively. RXFP1 activates pleiotropic signaling pathways including the signalosome protein complex that facilitates high-sensitivity signaling; coupling to Gαs, Gαi, and Gαo proteins; interaction with glucocorticoid receptors; and the formation of hetero-oligomers with distinctive pharmacological properties. In addition to relaxin-related ligands, RXFP1 is activated by Clq-tumor necrosis factor-related protein 8 and by small-molecular-weight agonists, such as ML290 [2-isopropoxy-N-(2-(3-(trifluoromethylsulfonyl)phenylcarbamoyl)phenyl)benzamide], that act allosterically. RXFP2 activates only the Gαs- and Gαo-coupled pathways. Relaxin-3 is primarily a neuropeptide, and its cognate receptor RXFP3 is a target for the treatment of depression, anxiety, and autism. A variety of peptide agonists, antagonists, biased agonists, and an allosteric modulator target RXFP3. Both RXFP3 and the related RXFP4 couple to Gαi/Gαo proteins. INSL5 has the properties of an incretin; it is secreted from the gut and is orexigenic. The expression of RXFP4 in gut, adipose tissue, and β-islets together with compromised glucose tolerance in INSL5 or RXFP4 knockout mice suggests a metabolic role. This review focuses on the many advances in our understanding of RXFP receptors in the last 5 years, their signal transduction mechanisms, the development of novel compounds that target RXFP1–4, the challenges facing the field, and current prospects for new therapeutics. PMID:25761609

  8. International Union of Basic and Clinical Pharmacology. XCV. Recent advances in the understanding of the pharmacology and biological roles of relaxin family peptide receptors 1-4, the receptors for relaxin family peptides.

    Science.gov (United States)

    Halls, Michelle L; Bathgate, Ross A D; Sutton, Steve W; Dschietzig, Thomas B; Summers, Roger J

    2015-01-01

    Relaxin, insulin-like peptide 3 (INSL3), relaxin-3, and INSL5 are the cognate ligands for the relaxin family peptide (RXFP) receptors 1-4, respectively. RXFP1 activates pleiotropic signaling pathways including the signalosome protein complex that facilitates high-sensitivity signaling; coupling to Gα(s), Gα(i), and Gα(o) proteins; interaction with glucocorticoid receptors; and the formation of hetero-oligomers with distinctive pharmacological properties. In addition to relaxin-related ligands, RXFP1 is activated by Clq-tumor necrosis factor-related protein 8 and by small-molecular-weight agonists, such as ML290 [2-isopropoxy-N-(2-(3-(trifluoromethylsulfonyl)phenylcarbamoyl)phenyl)benzamide], that act allosterically. RXFP2 activates only the Gα(s)- and Gα(o)-coupled pathways. Relaxin-3 is primarily a neuropeptide, and its cognate receptor RXFP3 is a target for the treatment of depression, anxiety, and autism. A variety of peptide agonists, antagonists, biased agonists, and an allosteric modulator target RXFP3. Both RXFP3 and the related RXFP4 couple to Gα(i)/Gα(o) proteins. INSL5 has the properties of an incretin; it is secreted from the gut and is orexigenic. The expression of RXFP4 in gut, adipose tissue, and β-islets together with compromised glucose tolerance in INSL5 or RXFP4 knockout mice suggests a metabolic role. This review focuses on the many advances in our understanding of RXFP receptors in the last 5 years, their signal transduction mechanisms, the development of novel compounds that target RXFP1-4, the challenges facing the field, and current prospects for new therapeutics. PMID:25761609

  9. Effect of a novel synthesized sulfonamido-based gallate-SZNTC on chondrocytes metabolism in vitro.

    Science.gov (United States)

    Liu, Qin; Li, Mu-Yan; Lin, Xiao; Lin, Cui-Wu; Liu, Bu-Ming; Zheng, Li; Zhao, Jin-Min

    2014-09-25

    The ideal therapeutic agent for treatment of osteoarthritis (OA) should have not only potent anti-inflammatory effect but also favorable biological properties to restore cartilage function. Gallic acid (GA) and its derivatives are anti-inflammatory agents reported to have an effect on OA (Singh et al., 2003) [1]. However, GA has much weaker antioxidant effects and inferior bioactivity compared with its derivatives. We modified GA with the introduction of sulfonamide to synthesize a novel sulfonamido-based gallate named sodium salt of 3,4,5-trihydroxy-N-[4-(thiazol-2-ylsulfamoyl)-phenyl]-benzamide (SZNTC) and analyzed its chondro-protective and pharmacological effects. Comparison of SZNTC with GA and sulfathiazole sodium (ST-Na) was also performed. Results showed that SZNTC could effectively inhibit the Interleukin-1 (IL-1)-mediated induction of metalloproteinase-1 (MMP-1) and MMP-3 and could induce the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), which demonstrated ability to reduce the progression of OA. SZNTC can also exert chondro-protective effects by promoting cell proliferation and maintaining the phenotype of articular chondrocytes, as evidenced by improved cell growth, enhanced synthesis of cartilage specific markers such as aggrecan, collagen II and Sox9. Expression of the collagen I gene was effectively down-regulated, revealing the inhibition of chondrocytes dedifferentiation by SZNTC. Hypertrophy that may lead to chondrocyte ossification was also undetectable in SZNTC groups. The recommended dose of SZNTC ranges from 3.91μg/ml to 15.64μg/ml, among which the most profound response was observed with 7.82μg/ml. In contrast, its source products of GA and ST-Na have a weak effect in the bioactivity of chondrocytes, which indicated the significance of this modification. This study revealed SZNTC as a promising novel agent in the treatment of chondral and osteochondral lesions. PMID:25130855

  10. Imaging dopamine transmission in schizophrenia

    Energy Technology Data Exchange (ETDEWEB)

    Laruelle, M. [New York, Columbia Univ. College of Physicians and Surgeons, NY (United States). New York State Psychiatric Insitute. Brain Imaging Division

    1998-09-01

    Over the last ten years, several positron emission tomography (PET) and single photon computerized tomography (SPECT) studies of the dopamine (DA) system in patients with schizophrenia were performed to test the hypothesis that DA hyperactivity is associated with this illness. In this paper are reviewed the results of fifteen brain imaging studies comparing indices of DA function in drug naive or drug free patients with schizophrenia and healthy controls: thirteen studies included measurements of Da D{sub 2} receptor density, two studies compared amphetamine-induced DA release, and two studies measured DOPA decarboxylase activity, an enzyme involved in DA synthesis. It was conducted a meta-analysis of the studies measuring D{sub 2} receptor density parameters, under the assumption that all tracers labeled the same population of D{sub 2} receptors. This analysis revealed that, compared to healthy controls, patients with schizophrenia present a significant but mild elevation of D{sub 2} receptor density parameters and a significant larger variability of these indices. It was found no statistical evidence that studies performed with radiolabeled butyrophenones detected a larger increase in D{sub 2} receptor density parameters than studies performed with other radioligands, such as benzamides. Studies of presynaptic activity revealed an increase in DA transmission response to amphetamine challenge, and an increase in DOPA decarboxylase activity. Together, these data are compatible with both pre- and post-synaptic alterations of DA transmission in schizophrenia. Future studies should aim at a better characterization of these alterations, and at defining their role in the pathophysiology of the illness.

  11. The Effects of Pharmacological Inhibition of Histone Deacetylase 3 (HDAC3 in Huntington's Disease Mice.

    Directory of Open Access Journals (Sweden)

    Haiqun Jia

    Full Text Available An important epigenetic modification in Huntington's disease (HD research is histone acetylation, which is regulated by histone acetyltransferase and histone deacetylase (HDAC enzymes. HDAC inhibitors have proven effective in HD model systems, and recent work is now focused on functional dissection of the individual HDAC enzymes in these effects. Histone deacetylase 3 (HDAC3, a member of the class I subfamily of HDACs, has previously been implicated in neuronal toxicity and huntingtin-induced cell death. Hence, we tested the effects of RGFP966 ((E-N-(2-amino-4-fluorophenyl-3-(1-cinnamyl-1H-pyrazol-4-ylacrylamide, a benzamide-type HDAC inhibitor that selectively targets HDAC3, in the N171-82Q transgenic mouse model of HD. We found that RGFP966 at doses of 10 and 25 mg/kg improves motor deficits on rotarod and in open field exploration, accompanied by neuroprotective effects on striatal volume. In light of previous studies implicating HDAC3 in immune function, we measured gene expression changes for 84 immune-related genes elicited by RGFP966 using quantitative PCR arrays. RGFP966 treatment did not cause widespread changes in cytokine/chemokine gene expression patterns, but did significantly alter the striatal expression of macrophage migration inhibitory factor (Mif, a hormone immune modulator associated with glial cell activation, in N171-82Q transgenic mice, but not WT mice. Accordingly, RGFP966-treated mice showed decreased glial fibrillary acidic protein (GFAP immunoreactivity, a marker of astrocyte activation, in the striatum of N171-82Q transgenic mice compared to vehicle-treated mice. These findings suggest that the beneficial actions of HDAC3 inhibition could be related, in part, with lowered Mif levels and its associated downstream effects.

  12. Loss of dysbindin-1, a risk gene for schizophrenia, leads to impaired group 1 metabotropic glutamate receptor function in mice.

    Directory of Open Access Journals (Sweden)

    Sanjeev K Bhardwaj

    2015-03-01

    Full Text Available The expression of dysbindin-1, a protein coded by the risk gene dtnbp1, is reduced in the brains of schizophrenia patients. Evidence indicates a role of dysbindin-1 in dopaminergic and glutamatergic transmission. Glutamatergic transmission and plasticity at excitatory synapses is critically regulated by G-protein coupled metabotropic glutamate receptor (mGluR family members, that have been implicated in schizophrenia. Here, we report a role of dysbindin-1 in hippocampal group 1 mGluR (mGluRI function in mice. In hippocampal synaptoneurosomal preparations from sandy (sdy mice, that have a loss of function mutation in dysbindin-1 gene, we observed a striking reduction in mGluRI agonist [(S-3,5-dihydroxyphenylglycine] (DHPG-induced phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2. This mGluR-ERK1/2 deficit occurred in the absence of significant changes in protein levels of the two members of the mGluRI family (i.e., mGluR1 and mGluR5 or in another mGluRI signaling pathway, i.e., protein kinase C (PKC. Aberrant mGluRI-ERK1/2 signaling affected hippocampal synaptic plasticity in the sdy mutants as DHPG-induced long-term depression (LTD at CA1 excitatory synapses was significantly reduced. Behavioral data suggest that the mGluRI hypofunction may underlie some of the cognitive abnormalities described in sdy mice as the administration of CDPPB (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl benzamide, a positive allosteric modulator of mGluR5, rescued short-term object recognition and spatial learning and memory deficits in these mice. Taken together, our data suggest a novel role of dysbindin-1 in regulating mGluRI functions.

  13. Clinical study of dopamine transporter imaging with 131I-epidepride for Parkinson's disease

    International Nuclear Information System (INIS)

    Objective: Epidepride is a novel benzamide derivative with high affinity for dopaminergic D2 receptors. It has been used to study striatal and extrastriatal D2 receptor abnormalities in humans. The aim of this study was to evaluate the level of D2 receptors in dopaminergic nitrostriatal pathway and its correlation with clinical severity in Parkinson's disease (PD). Methods: Thirty-eight patients with idiopathic PD [graded according to Hoehn and Yahr (H/Y) stage: n(I)=13, n(II)=11, n(III)=8, n (IV)=6] and 12 healthy volunteers as control were included in this study. SPECT brain imaging was performed 3 h after 18.5 MBq 131I-epidepride administration. Regions of interest (ROIs) were drawn over the striatum (ST) and occipital cortex (OC). The ratios of ST to OC ROI counts (ST/OC) were calculated and correlated with clinical severity H/Y stage. SPSS 10.0 was used for data analysis, the t test and Spearman correlation analysis were used. Results: ST showed intense uptake of 131I-eplaepnde, whereas frontal, parietal, temporal, occipital lobes and cerebellum showed low uptake in control group. Increased 131I-epidepride uptake was observed in PD patients when compared with normal control group but without statistically significant difference. Early stage patients (hemi-PD with H/Y I) showed increased 131I-epidepride uptake intensity and size in contralateral ST (especially caudate nucleus) significantly more than unilateral ST (t= 7.89, P0.05). Conclusions: This study suggested that 131I-epidepride SPECT was useful in qualitative and quantitative evaluation of D2 receptor status in dopaminergic nigrostriatal neurons, which were over-expressed in PD patients. However, no statistically significant correlation was found between ST 131I-epidepride binding ratios and disease severity. (authors)

  14. Characterization and distribution of [125I]epidepride binding to dopamine D2 receptors in basal ganglia and cortex of human brain

    International Nuclear Information System (INIS)

    The distribution and pharmacology of the binding of 125I-epidepride, a substituted benzamide with high affinity and selectivity for dopamine (DA) D2 receptors in rat brain is described in human brain. Saturation analysis of the binding of 125I-epidepride to membranes derived from striatum and regions of cortex demonstrated similar Kd values (34 and 28-33 pM, respectively) but differing maximum density of binding site values (152 and 3-8 fmol/mg of protein, respectively). The pharmacological profile of binding in cortex was also similar to striatum (epidepride greater than spiperone greater than butaclamol = flupenthixol greater than clozapine) except that an additional low-affinity site, blocked by the alpha-2 adrenergic antagonist idazoxan, was present in cortex. Quantification by autoradiography also demonstrated the greatest binding in the basal ganglia, with the striatum exhibiting greater binding than the pallidal complex or midbrain regions. For the pallidum, binding in the external segment was higher than the internal segment. Within the midbrain the binding of 125I-epidepride correlated well with the known distribution of DA-containing cell bodies, with the substantia nigra (pars compacta and pars lateralis) and ventral tegmental area (A10) higher than area A8 and central gray. Binding in frontal and parietal cortex was highest in the internal layers (layers V and VI). Temporal cortex showed a 2-fold higher density of binding than other cortical regions and a trilaminar pattern; binding was greater in the external (layers I and II) and internal layers than in the middle layers (III and IV). This pattern changed in the parahippocampal complex. Within the lateral occipitotemporal cortex, binding was densest in layers I to III and very low in layers IV to VI, but binding was almost nonexistent in the adjacent entorhinal cortex

  15. Characterization and distribution of (125I)epidepride binding to dopamine D2 receptors in basal ganglia and cortex of human brain

    Energy Technology Data Exchange (ETDEWEB)

    Joyce, J.N.; Janowsky, A.; Neve, K.A. (Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia (USA))

    1991-06-01

    The distribution and pharmacology of the binding of {sup 125}I-epidepride, a substituted benzamide with high affinity and selectivity for dopamine (DA) D2 receptors in rat brain is described in human brain. Saturation analysis of the binding of {sup 125}I-epidepride to membranes derived from striatum and regions of cortex demonstrated similar Kd values (34 and 28-33 pM, respectively) but differing maximum density of binding site values (152 and 3-8 fmol/mg of protein, respectively). The pharmacological profile of binding in cortex was also similar to striatum (epidepride greater than spiperone greater than butaclamol = flupenthixol greater than clozapine) except that an additional low-affinity site, blocked by the alpha-2 adrenergic antagonist idazoxan, was present in cortex. Quantification by autoradiography also demonstrated the greatest binding in the basal ganglia, with the striatum exhibiting greater binding than the pallidal complex or midbrain regions. For the pallidum, binding in the external segment was higher than the internal segment. Within the midbrain the binding of {sup 125}I-epidepride correlated well with the known distribution of DA-containing cell bodies, with the substantia nigra (pars compacta and pars lateralis) and ventral tegmental area (A10) higher than area A8 and central gray. Binding in frontal and parietal cortex was highest in the internal layers (layers V and VI). Temporal cortex showed a 2-fold higher density of binding than other cortical regions and a trilaminar pattern; binding was greater in the external (layers I and II) and internal layers than in the middle layers (III and IV). This pattern changed in the parahippocampal complex. Within the lateral occipitotemporal cortex, binding was densest in layers I to III and very low in layers IV to VI, but binding was almost nonexistent in the adjacent entorhinal cortex.

  16. Dopamine D(2) receptor quantification in extrastriatal brain regions using [(123)I]epidepride with bolus/infusion.

    Science.gov (United States)

    Pinborg, L H; Videbaek, C; Knudsen, G M; Swahn, C G; Halldin, C; Friberg, L; Paulson, O B; Lassen, N A

    2000-06-15

    The iodinated benzamide epidepride, which shows a picomolar affinity binding to dopamine D(2) receptors, has been designed for in vivo studies using SPECT. The aim of the present study was to apply a steady-state condition by the bolus/infusion approach with [(123)I]epidepride for the quantification of striatal and extrastriatal dopamine D(2) receptors in humans. In this way the distribution volume of the tracer can be determined from a single SPECT image and one blood sample. Based on bolus experiments, an algorithm using conventional convolution arguments for prediction of the outcome of a bolus/infusion (B/I) experiment was applied. It was predicted that a B/I protocol with infusion of one-third of the initial bolus per hour would be appropriate. Steady-state conditions were attained in extrastriatal regions within 3-4 h but the infusion continued up to 7 h in order to minimize the significance of individual differences in plasma clearance and binding parameters. A steady-state condition, however, could not be attained in striatal brain regions using a B/I protocol of 20 h, even after 11 h. Under near steady-state conditions a striatal:cerebellar ratio of 23 was demonstrated. Epidepride has a unique signal-to-noise ratio compared to [(123)I]IBZM but present difficulties for steady-state measurements of striatal regions. The bolus/infusion approach is particularly feasible for quantification of the binding potential in extrastriatal regions. PMID:10819910

  17. Influence of inhibitors of poly(ADP-ribose) polymerase on DNA repair, chromosomal alterations, and mutations

    Energy Technology Data Exchange (ETDEWEB)

    Natarajan, A.T.; van Zeeland, A.A.; Zwanenburg, T.S.

    1983-01-01

    The influence of inhibitors of poly(ADP-ribose) polymerase such as 3-aminobenzamide (3AB) and benzamide (B) on the spontaneously occurring as well as mutagen induced chromosomal aberrations, sister chromatid exchanges (SCEs) and point mutations has been studied. In addition, the influence of 3AB on DNA repair was measured following treatment with physical and chemical mutagens. Post treatment of X-irradiated mammalian cells with 3AB increases the frequencies of induced chromosomal aberrations by a factor of 2 to 3. 3AB, when present in the medium containing bromodeoxyuridine(BrdUrd) during two cell cycles, increases the frequencies of SCEs in Chinese hamster ovary cells (CHO) in a concentration dependent manner leading to about a 10-fold increase at 10 mM concentration. The extent of increase in the frequencies of SCEs due to 1 mM 3AB in several human cell lines has been studied, including those derived from patients suffering from genetic diseases such as ataxia telangiectasia (A-T), Fanconi's anemia (FA), and Huntington's chorea. None of these syndromes showed any increased response when compared to normal cells. 3AB, however, increased the frequencies of spontaneously occurring chromosomal aberrations in A-T and FA cells. 3AB does not influence the frequencies of SCEs induced by UV or mitomycin C (MMC) in CHO cells. However, it increases the frequencies of SCEs induced by ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS). Under the conditions in which 3AB increases the frequencies of spontaneously occurring as well as induced SCEs, it does not increase the frequencies of point mutations in hypoxanthine-guanine phosphoribosyltransferase (HGPRT) locus. 3AB does not influence the amount of repair replication following dimethylsulphate (DMS) treatment of human fibroblasts, or UV irradiated human lymphocytes.

  18. Slow DNA rejoining in ultraviolet-irradiated human diploid fibroblasts treated with the mitogens trypsin and insulin

    International Nuclear Information System (INIS)

    Normally in mammalian cells the postincision steps of UV-induced excision repair are much more rapid than the recognition of damage and incision. This means that at any one time the level of repair-generated single-stranded DNA breaks is very low. Here we report that detectable levels of DNA breaks accumulate in quiescent human fibroblasts which are UV irradiated a few hours after replating in conditions that stimulate progress through the cell cycle. Most DNA breaks accumulate in cultures trypsinized and seeded in medium supplemented with insulin, and irradiated in early G1. Because trypsin and insulin have no effect on UV-induced incision rates, as measured by DNA break accumulation in the presence of DNA synthesis inhibitors, we argue that our ability to detect incomplete repair-sites is due to a significant reduction in the rate of gap sealing indicative of a shift in the steady state of excision repair. Provision of DNA precursors prevents the enhancing effect of trypsin and insulin on the accumulation of DNA breaks, implying that these agents affect DNA precursor metabolism. Perturbation of the repair process, which leads to the accumulation of 1500-2000 DNA breaks/genome, is also associated with other effects including increased lethality, the appearance of double-strand breaks and the loss of NAD, the last effect presumably arising as a consequence of break-stimulated poly(ADPR) transferase activity. Addition of 3-amino-benzamide, an inhibitor of poly(ADPR) synthesis, completely blocks the decline in NAD levels, but does not change the rate of sealing of the accumulated DNA breaks. These results strongly suggest that ligation is largely, if not entirely, independent of ADP ribosylation in this system

  19. Novel Cholinesterase Inhibitors Based on O-Aromatic N,N-Disubstituted Carbamates and Thiocarbamates.

    Science.gov (United States)

    Krátký, Martin; Štěpánková, Šárka; Vorčáková, Katarína; Švarcová, Markéta; Vinšová, Jarmila

    2016-01-01

    Based on the presence of carbamoyl moiety, twenty salicylanilide N,N-disubstituted (thio)carbamates were investigated using Ellman's method for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). O-Aromatic (thio)carbamates exhibited weak to moderate inhibition of both cholinesterases with IC50 values within the range of 1.60 to 311.0 µM. IC50 values for BChE were mostly lower than those obtained for AChE; four derivatives showed distinct selectivity for BChE. All of the (thio)carbamates produced a stronger inhibition of AChE than rivastigmine, and five of them inhibited BChE more effectively than both established drugs rivastigmine and galantamine. In general, 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)-phenyl]benzamide, 2-hydroxy-N-phenylbenzamide as well as N-methyl-N-phenyl carbamate derivatives led to the more potent inhibition. O-{4-Chloro-2-[(4-chlorophenyl)carbamoyl]phenyl} dimethylcarbamothioate was identified as the most effective AChE inhibitor (IC50 = 38.98 µM), while 2-(phenylcarbamoyl)phenyl diphenylcarbamate produced the lowest IC50 value for BChE (1.60 µM). Results from molecular docking studies suggest that carbamate compounds, especially N,N-diphenyl substituted representatives with considerable portion of aromatic moieties may work as non-covalent inhibitors displaying many interactions at peripheral anionic sites of both enzymes. Mild cytotoxicity for HepG2 cells and consequent satisfactory calculated selectivity indexes qualify several derivatives for further optimization. PMID:26875979

  20. Dopamine D2 receptor SPECT imaging

    International Nuclear Information System (INIS)

    The purposes of this study were to evaluate the utility of kit formulation, the basic in vivo charactristics, and clinical usefulness of dopamine D2 receptor imaging with 123I-(S)-(-)-3-iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2-pyrrodinyl)methyl]-benzamide (123I-IBZM). We studied 22 normal controls, 3 early symptomatic Huntington's disease patients, and 1 patient with visual hallucination on and off neuroleptics. 123I-IBZM could be conveniently prepared with a high degree of purity from a kit, but with relatively low radiochemical yield. We demonstrated 123I-IBZM receptor binding equilibrium by performing serial SPECT scanning in a normal volunteer. The basal ganglia/frontal cortex (BG/FC) ratios plateaued after the specific binding reached equilibrium approximately 60 minutes after injection. The BG/FC ratio declined significantly with age. The ratios for the Huntington's disease patients were significantly lower than those for normal controls. The images of the patient off neuroleptic therapy showed dramatically increased BG activity compared with those obtained while on therapy. The BG/FC ratio provides an estimate of Bmax/Kd and hence the receptor density. It appears important to perform SPECT early in the equilibrium phase and at a fixed time after injection to obtain significantly high signal to noise ratios. 123I-IBZM is an ideal tracer for SPECT including a rotating gamma camera type which can provide estimates of the receptor density objectively by calculating the BG/FC ratio, and is a promising agent for the investigation of dopamine D2 receptors in clinical conditions. (author)

  1. The Effects of Pharmacological Inhibition of Histone Deacetylase 3 (HDAC3) in Huntington’s Disease Mice

    Science.gov (United States)

    Jia, Haiqun; Wang, Ying; Morris, Charles D.; Jacques, Vincent; Gottesfeld, Joel M.; Rusche, James R.; Thomas, Elizabeth A.

    2016-01-01

    An important epigenetic modification in Huntington’s disease (HD) research is histone acetylation, which is regulated by histone acetyltransferase and histone deacetylase (HDAC) enzymes. HDAC inhibitors have proven effective in HD model systems, and recent work is now focused on functional dissection of the individual HDAC enzymes in these effects. Histone deacetylase 3 (HDAC3), a member of the class I subfamily of HDACs, has previously been implicated in neuronal toxicity and huntingtin-induced cell death. Hence, we tested the effects of RGFP966 ((E)-N-(2-amino-4-fluorophenyl)-3-(1-cinnamyl-1H-pyrazol-4-yl)acrylamide), a benzamide-type HDAC inhibitor that selectively targets HDAC3, in the N171-82Q transgenic mouse model of HD. We found that RGFP966 at doses of 10 and 25 mg/kg improves motor deficits on rotarod and in open field exploration, accompanied by neuroprotective effects on striatal volume. In light of previous studies implicating HDAC3 in immune function, we measured gene expression changes for 84 immune-related genes elicited by RGFP966 using quantitative PCR arrays. RGFP966 treatment did not cause widespread changes in cytokine/chemokine gene expression patterns, but did significantly alter the striatal expression of macrophage migration inhibitory factor (Mif), a hormone immune modulator associated with glial cell activation, in N171-82Q transgenic mice, but not WT mice. Accordingly, RGFP966-treated mice showed decreased glial fibrillary acidic protein (GFAP) immunoreactivity, a marker of astrocyte activation, in the striatum of N171-82Q transgenic mice compared to vehicle-treated mice. These findings suggest that the beneficial actions of HDAC3 inhibition could be related, in part, with lowered Mif levels and its associated downstream effects. PMID:27031333

  2. Oral administration of the pimelic diphenylamide HDAC inhibitor HDACi 4b is unsuitable for chronic inhibition of HDAC activity in the CNS in vivo.

    Directory of Open Access Journals (Sweden)

    Maria Beconi

    Full Text Available Histone deacetylase (HDAC inhibitors have received considerable attention as potential therapeutics for a variety of cancers and neurological disorders. Recent publications on a class of pimelic diphenylamide HDAC inhibitors have highlighted their promise in the treatment of the neurodegenerative diseases Friedreich's ataxia and Huntington's disease, based on efficacy in cell and mouse models. These studies' authors have proposed that the unique action of these compounds compared to hydroxamic acid-based HDAC inhibitors results from their unusual slow-on/slow-off kinetics of binding, preferentially to HDAC3, resulting in a distinctive pharmacological profile and reduced toxicity. Here, we evaluate the HDAC subtype selectivity, cellular activity, absorption, distribution, metabolism and excretion (ADME properties, as well as the central pharmacodynamic profile of one such compound, HDACi 4b, previously described to show efficacy in vivo in the R6/2 mouse model of Huntington's disease. Based on our data reported here, we conclude that while the in vitro selectivity and binding mode are largely in agreement with previous reports, the physicochemical properties, metabolic and p-glycoprotein (Pgp substrate liability of HDACi 4b render this compound suboptimal to investigate central Class I HDAC inhibition in vivo in mouse per oral administration. A drug administration regimen using HDACi 4b dissolved in drinking water was used in the previous proof of concept study, casting doubt on the validation of CNS HDAC3 inhibition as a target for the treatment of Huntington's disease. We highlight physicochemical stability and metabolic issues with 4b that are likely intrinsic liabilities of the benzamide chemotype in general.

  3. Pharmacological Characterization of the Edema Caused by Vitalius dubius (Theraphosidae, Mygalomorphae) Spider Venom in Rats.

    Science.gov (United States)

    Rocha-E-Silva, Thomaz A A; Linardi, Alessandra; Antunes, Edson; Hyslop, Stephen

    2016-01-01

    Bites by tarantulas (Theraphosidae, Mygalomorphae) in humans can result in mild clinical manifestations such as local pain, erythema, and edema. Vitalius dubius is a medium-sized, nonaggressive theraphosid found in southeastern Brazil. In this work, we investigated the mediators involved in the plasma extravasation caused by V. dubius venom in rats. The venom caused dose-dependent (0.1-100 μg/site) edema in rat dorsal skin. This edema was significantly inhibited by ((S)1-{2-[3(3-4-dichlorophenyl)-1-(3-iso-propoxyphenylacetyl)piperidine-3-yl]ethyl}-4-phenyl-1-azoniabicyclo[2.2.2]octone, chloride) (SR140333, a neurokinin NK1 receptor antagonist), indomethacin [a nonselective cyclooxygenase (COX) inhibitor], cyproheptadine (a serotonin 5-hydroxytryptamine1/2 and histamine H1 receptor antagonist), and N(ω)-nitro-L-arginine methyl ester (a nitric oxide synthase inhibitor). In contrast, mepyramine (a histamine H1 receptor antagonist), D-Arg-[Hyp(3),Thi(5),D-Tic(7),Oic(8)-]-BK (JE 049, a bradykinin B2 receptor antagonist), and ((S)-N-methyl-N-[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-di-chlorophenyl)butyl]benzamide) (SR48968, a neurokinin NK2 receptor antagonist) had no effect on the venom-induced increase in vascular permeability. In rat hind paws, the venom-induced edema was attenuated by ketoprofen (a nonselective COX inhibitor) administered 15 minutes postvenom. Preincubation of venom with commercial antiarachnid antivenom attenuated the venom-induced edema. These results suggest that the enhanced vascular permeability evoked by V. dubius venom involves serotonin, COX products, neurokinin NK1 receptors, and nitric oxide formation. The attenuation of hind paw edema by ketoprofen suggests that COX inhibitors could be useful in treating the local inflammatory response to bites by these spiders. PMID:26607257

  4. Virucidal agents in the eve of manorapid synergy

    Directory of Open Access Journals (Sweden)

    Galabov, Angel S.

    2007-09-01

    Full Text Available Virucidal agents are chemical substances that attack and inactivate viral particles outside the cell (virions. In general this is accomplished by damaging their protein shells (capsid or the substance penetrates the core itself, where it destroys the genetic material. Damage to the virion structure is also possible. These agents are used not only for traditional surface disinfection or sterilization of blood, blood products, and other medicinal products as well as in antiviral chemotherapy. They have also been used in recent times for inactivation of viruses in foodstuffs, detergents or cosmetics. Below is given an overview of the data currently available on the performance of these substances when used for the latter applications (cleaning and cosmetics. These include: * hydrogen peroxide, hypochlorites, cupric and ferric ions, per-acids * ethanol, parachlorometaxylenol in a sodium C14-16 olefin sulfonate, glutaraldehyde, quaternary ammonium salts, chlorhexidine and chlorhexidine gluconate, curdline sulphate, glycerol, lipids, azodicarbonamide, cicloxolone sodium, dichlorisocyanuric acid (sodium salt, benzalkonium salts, disulfate benzamides and benzisothiazolones, congo red, ascorbic acid, nonoxynol-9, para-aminobenzoic acid, bis(monosuccinamide derivative of p,p’-bis(2-aminoethyl diphenlyi-C60 (fullerene. * merocyanine, benzoporphyrin derivative monoacid ring A, rose bengal, hypericin, hypocrellin A, anthraquinones extracted from plants, sulfonated anthraquinones and other anthraquinone derivatives * gramicidine, gossypol, garlic (Allium sativum extract and its components: ajoene, diallyl thiosulfinate (allicin, allyl methyl thioulfinate, methyl allyl thiosulfinate, extracts of ledium, motherworth, celandine, black currant, coaberry and bilberry, extract of Cordia salicifolia, steam distillate from Houttuynia cordata (Saururaceae and its component, 5,6,7-trimethoxyflavone from Calicarpa japonica, isoscullarein (5,7,8,4

  5. Metabolic consequences of DNA damage: The role of poly (ADP-ribose) polymerase as mediator of the suicide response

    International Nuclear Information System (INIS)

    Recent studies show that DNA damage can produce rapid alterations in steady state levels of deoxynucleoside triphosphate pools, for example, MNNG or uv-irradiation cause rapid increases in dATP and dTTP pools without significant changes in dGTP or dCTP pools. In vitro, studies with purified eukaryotic DNA polymerases show that the frequency of nucleotide misincorporation was affected by alterations in relative concentrations of the deoxynucleoside triphosphates. Thus the alterations in dNTP pool sizes that occur consequent to DNA damage may contribute to an increased mutagenic frequency. Poly(ADP-ribose) polymerase mediated suicide mechanism may participate in the toxicity of adenosine deaminase deficiency and severe combined immune deficiency disease in humans. Individuals with this disease suffer severe lymphopenia due to the toxic effects of deoxyadenosine. The lymphocytotoxic effect of adenosine deaminase deficiency can be simulated in lymphocyte cell lines from normal individuals by incubating them with the adenosine deaminase inhibitor, deoxycoformycin. Incubation of such leukocytes with deoxycoformycin and deoxyadenosine results in the gradual accumulation of DNA strand breaks and the depletion of NAD+ leading to cell death over a period of several days. This depletion of NAD and loss of cell viability were effectively blocked by nicotinamide or 3-amino benzamide. Thus, persistent activation of poly(ADP-ribose) polymerase by unrepaired or recurrent DNA strand breaks may activate the suicide mechanism of cell death. This study provides a basis for the interesting suggestion that treatment with nicotinamide could block the persistent activity of poly(ADP-ribose) polymerase and may help preserve lymphocyte function in patients with adenosine deaminase deficiency. 16 refs., 3 figs., 2 tabs

  6. Structure-Functional Characterization of Cytochrome P450 Sterol 14α-Demethylase (CYP51B) from Aspergillus fumigatus and Molecular Basis for the Development of Antifungal Drugs.

    Science.gov (United States)

    Hargrove, Tatiana Y; Wawrzak, Zdzislaw; Lamb, David C; Guengerich, F Peter; Lepesheva, Galina I

    2015-09-25

    Aspergillus fumigatus is the opportunistic fungal pathogen that predominantly affects the immunocompromised population and causes 600,000 deaths/year. The cytochrome P450 51 (CYP51) inhibitor voriconazole is currently the drug of choice, yet the treatment efficiency remains low, calling for rational development of more efficient agents. A. fumigatus has two CYP51 genes, CYP51A and CYP51B, which share 59% amino acid sequence identity. CYP51B is expressed constitutively, whereas gene CYP51A is reported to be inducible. We expressed, purified, and characterized A. fumigatus CYP51B, including determination of its substrate preferences, catalytic parameters, inhibition, and x-ray structure in complexes with voriconazole and the experimental inhibitor (R)-N-(1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide (VNI). The enzyme demethylated its natural substrate eburicol and the plant CYP51 substrate obtusifoliol at steady-state rates of 17 and 16 min(-1), respectively, but did not metabolize lanosterol, and the topical antifungal drug miconazole was the strongest inhibitor that we identified. The x-ray crystal structures displayed high overall similarity of A. fumigatus CYP51B to CYP51 orthologs from other biological kingdoms but revealed phylum-specific differences relevant to enzyme catalysis and inhibition. The complex with voriconazole provides an explanation for the potency of this relatively small molecule, whereas the complex with VNI outlines a direction for further enhancement of the efficiency of this new inhibitory scaffold to treat humans afflicted with filamentous fungal infections. PMID:26269599

  7. Crystal Structures of Trypanosoma brucei Sterol 14[alpha]-Demethylase and Implications for Selective Treatment of Human Infections

    Energy Technology Data Exchange (ETDEWEB)

    Lepesheva, Galina I.; Park, Hee-Won; Hargrove, Tatiana Y.; Vanhollebeke, Benoit; Wawrzak, Zdzislaw; Harp, Joel M.; Sundaramoorthy, Munirathinam; Nes, W. David; Pays, Etienne; Chaudhuri, Minu; Villalta, Fernando; Waterman, Michael R. (ULdB); (Vanderbilt); (TTU); (Toronto); (NWU); (Meharry)

    2010-01-25

    Sterol 14{alpha}-demethylase (14DM, the CYP51 family of cytochrome P450) is an essential enzyme in sterol biosynthesis in eukaryotes. It serves as a major drug target for fungal diseases and can potentially become a target for treatment of human infections with protozoa. Here we present 1.9 {angstrom} resolution crystal structures of 14DM from the protozoan pathogen Trypanosoma brucei, ligand-free and complexed with a strong chemically selected inhibitor N-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl-4-(5-phenyl-1,3,4-oxadi-azol-2-yl)benzamide that we previously found to produce potent antiparasitic effects in Trypanosomatidae. This is the first structure of a eukaryotic microsomal 14DM that acts on sterol biosynthesis, and it differs profoundly from that of the water-soluble CYP51 family member from Mycobacterium tuberculosis, both in organization of the active site cavity and in the substrate access channel location. Inhibitor binding does not cause large scale conformational rearrangements, yet induces unanticipated local alterations in the active site, including formation of a hydrogen bond network that connects, via the inhibitor amide group fragment, two remote functionally essential protein segments and alters the heme environment. The inhibitor binding mode provides a possible explanation for both its functionally irreversible effect on the enzyme activity and its selectivity toward the 14DM from human pathogens versus the human 14DM ortholog. The structures shed new light on 14DM functional conservation and open an excellent opportunity for directed design of novel antiparasitic drugs.

  8. Effects of zacopride and BMY25801 (batanopride) on radiation-induced emesis and locomotor behavior in the ferret

    Energy Technology Data Exchange (ETDEWEB)

    King, G.L.; Landauer, M.R. (Armed Forces Radiobiology Research Institute, Bethesda, MD (USA))

    1990-06-01

    The antiemetic and locomotor effects of two substituted benzamides, zacopride and batanopride (BMY25801), were compared in ferrets after bilateral 60Co irradiation at 2, 4 or 6 Gy. Both zacopride and BMY25801 were effective against emesis and related signs. Zacopride, tested at several doses (0.003, 0.03 and 0.3 mg/kg), appeared to be more potent because it abolished emesis at 100-fold lower doses than did BMY25801 (3 mg/kg). The ED50 value for the antiemetic effect of zacopride was 0.026 mg/kg (confidence levels = 0.0095, 0.072 mg/kg). However, analysis of emetic parameters recorded from vomiting animals (e.g., latency to first emesis) demonstrated that BMY25801 provided greater antiemetic protection in this population than zacopride without any apparent side effects. Locomotor activity was significantly depressed by both radiation (all doses) and zacopride alone (0.03 mg/kg and 0.3 mg/kg). BMY25801 alone did not affect locomotor activity, and protected against the radiation-induced locomotor decrement. Although zacopride potentiated the locomotor decrement to radiation, no clear dose-response relationship was evident. Bilateral abdominal vagotomy significantly increased the latency to the first emetic episode and significantly reduced the number of retches, but did not alter the duration of the prodromal response to 4-Gy irradiation. Unilateral vagotomies had no effect. Zacopride (at 0.03 mg/kg and 0.3 mg/kg) remained an effective antiemetic in animals that received a bilateral vagotomy, abolishing emesis in four of eight and two of eight ferrets, respectively. These data suggest that the antiemetic action of zacopride does not fully depend on intact vagal innervation and also acts via other pathways.

  9. Inhibition of hepatitis B virus replication by targeting ribonucleotide reductase M2 protein.

    Science.gov (United States)

    Liu, Xia; Xu, Zhijian; Hou, Chuanwei; Wang, Meng; Chen, Xinhuan; Lin, Qinghui; Song, Rui; Lou, Meng; Zhu, Lijun; Qiu, Yunqing; Chen, Zhi; Yang, Chunhao; Zhu, Weiliang; Shao, Jimin

    2016-03-01

    Chronic hepatitis B virus (HBV) infection is a key factor for hepatocellular carcinoma worldwide. Ribonucleotide reductase (RR) regulates the deoxyribonucleoside triphosphates biosynthesis and serves as a target for anti-cancer therapy. Here, we demonstrate that RR is essential for HBV replication and the viral covalently-closed-circular DNA (cccDNA) synthesis in host liver cells. By performing computer-assisted virtual screening against the crystal structure of RR small subunit M2 (RRM2), osalmid, was identified as a potential RRM2-targeting compound. Osalmid was shown to be 10-fold more active in inhibiting RR activity than hydroxyurea, and significantly inhibited HBV DNA and cccDNA synthesis in HepG2.2.15 cells. In contrast, hydroxyurea and the RR large subunit (RRM1)-inhibitory drug gemcitabine showed little selective activity against HBV replication. In addition, osalmid also was shown to possess potent activity against a 3TC-resistant HBV strain, suggesting utility in treating drug-resistant HBV infections. Interestingly, osalmid showed synergistic effects with lamivudine (3TC) in vitro and in vivo without significant toxicity, and was shown to inhibit RR activity in vivo, thus verifying its in vivo function. Furthermore, 4-cyclopropyl-2-fluoro-N-(4-hydroxyphenyl) benzamide (YZ51), a novel derivative of osalmid, showed higher efficacy than osalmid with more potent RR inhibitory activity. These results suggest that RRM2 might be targeted for HBV inhibition, and the RRM2-targeting compound osalmid and its derivative YZ51 could be a novel class of anti-HBV candidates with potential use for hepatitis B and HBV-related HCC treatment. PMID:26774458

  10. Meta-diamide insecticides acting on distinct sites of RDL GABA receptor from those for conventional noncompetitive antagonists.

    Science.gov (United States)

    Nakao, Toshifumi; Banba, Shinich; Nomura, Michikazu; Hirase, Kangetsu

    2013-04-01

    The RDL GABA receptor is an attractive target of insecticides. Here we demonstrate that meta-diamides [3-benzamido-N-(4-(perfluoropropan-2-yl)phenyl)benzamides] are a distinct class of RDL GABA receptor antagonists showing high insecticidal activity against Spodoptera litura. We also suggest that the mode of action of the meta-diamides is distinct from that of conventional noncompetitive antagonists (NCAs), such as fipronil, picrotoxin, lindane, dieldrin, and α-endosulfan. Using a membrane potential assay, we examined the effects of the meta-diamide 3-benzamido-N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-2-fluorobenzamide (meta-diamide 7) and NCAs on mutant Drosophila RDL GABA receptors expressed in Drosophila Mel-2 cells. NCAs had little or no inhibitory activity against at least one of the three mutant receptors (A2'S, A2'G, and A2'N), which were reported to confer resistance to NCAs. In contrast, meta-diamide 7 inhibited all three A2' mutant receptors, at levels comparable to its activity with the wild-type receptor. Furthermore, the A2'S·T6'V mutation almost abolished the inhibitory effects of all NCAs. However, meta-diamide 7 inhibited the A2'S・T6'S mutant receptor at the same level as its activity with the wild-type receptor. In contrast, a G336M mutation in the third transmembrane domain of the RDL GABA receptor abolished the inhibitory activities of meta-diamide 7, although the G336M mutation had little effect on the inhibitory activities of conventional NCAs. Molecular modeling studies also suggested that the binding site of meta-diamides was different from those of NCAs. Meta-diamide insecticides are expected to be prominent insecticides effective against A2' mutant RDL GABA receptors with a different mode of action. PMID:23416568

  11. Identification of tetraphenylborate radiolysis products in a simulated feedstock for radioactive waste processing

    International Nuclear Information System (INIS)

    The first step towards immobilization of the soluble radioactive species in borosilicate glass is the addition of sodium tetraphenylborate (TPB) and sodium titanate to the radioactive aqueous solution. Initial studies of the TPB hydrolysis process have found that some component of the radiolysis mixture inactivates the Cu catalyst. The interaction of organic materials with the catalyst, and the subsequent interference with the hydrolysis process, would have presented problems with the use of the vitrification process. Prevention of the catalyst deactivation is obtained by washing the irradiated TPB precipitate in the Late Wash Facility prior to hydrolysis to remove the soluble radiolysis products. Identification of the organic radiolysis products, their distribution in the Late Wash Facility, and their interactions with the Cu catalyst has become an important analytical issue. To further investigate the reaction products of the TPB precipitation process, a simulated feedstock was created from compounds known to be present in the starting materials. This simulated feedstock was precipitated with sodium TPB and then exposed to Co-60 gamma radiation to simulate two years of additional storage time prior to the hydrolysis process. The irradiated product was divided into two parts, the filtered supernatant liquid and the precipitate slurry, which contains the TPB and the solid sodium titanate. Using gas chromatography/mass spectrometry, liquid secondary ion mass spectrometry, inductively coupled plasma/mass spectrometry, ion chromatography, and high performance liquid chromatography, over 50 organic and inorganic species have been identified in the aqueous portion of a simulated feedstock for TPB hydrolysis. The major organic species present are benzene, phenol, benzamide and a variety of substituted phenylphenols. The major inorganic species present are sodium, nitrite, and oxalate ions

  12. Study of polymorphism in imatinib mesylate: A quantum chemical approach using electronic and vibrational spectra

    Science.gov (United States)

    Srivastava, Anubha; Joshi, B. D.; Tandon, Poonam; Ayala, A. P.; Bansal, A. K.; Grillo, Damián

    2013-02-01

    Imatinib mesylate, 4-(4-methyl-piperazin-1-ylmethyl)-N-u[4-methyl-3-(4-pyridin-3-yl)pyrimidine-2-ylamino)phenyl]benzamide methanesulfonate is a therapeutic drug that is approved for the treatment of chronic myelogeneous leukemia (CML) and gastrointestinal stromal tumors (GIST). It is known that imatinib mesylate exists in two polymorphic forms α and β. However, β-form is more stable than the α-form. In this work, we present a detailed vibrational spectroscopic investigation of β-form by using FT-IR and FT-Raman spectra. These data are supported by quantum mechanical calculations using DFT employing 6-311G(d,p) basis set, which allow us to characterize completely the vibrational spectra of this compound. The FT-IR spectrum of α-form has also been discussed. The importance of hydrogen-bond formation in the molecular packing arrangements of both forms has been examined with the vibrational shifts observed due to polymorphic changes. The red shift of the NH stretching bands in the infrared spectrum from the computed wavenumber indicates the weakening of the NH bond. The UV-vis spectroscopic studies along with the HOMO-LUMO analysis of both polymorphs (α and β) were performed and their chemical activity has been discussed. The TD-DFT method was used to calculate the electronic absorption spectra in the gas phase as well as in the solvent environment using IEF-PCM model and 6-31G basis set. Finally, the results obtained complements to the experimental findings.

  13. CX717 as a positive allosteric modulator of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid receptor: research advances%AMPA受体正向变构调节剂CX717研究进展

    Institute of Scientific and Technical Information of China (English)

    贺艺超; 肖典; 齐倩倩; 赵国明; 周辛波

    2013-01-01

    α-氨基-3-羟基-5-甲基-4-异噁唑丙酸(AMPA)受体是离子型谷氨酸受体的一种亚型,分布于中枢神经系统的突触后膜,介导大多数快速兴奋性神经传递.CX717是由美国Cortex制药公司研制的苯甲酰胺类AMPA受体正向调节剂,能够降低AMPA受体失活或降敏的速度从而提高突触的活性,与阿尔茨海默病、帕金森病、抑郁症和注意力缺陷多动症等疾病的治疗密切相关.本文主要综述CX717在化学结构、药代动力学、毒理学和药效学方面的研究进展.%α-Amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA) receptor,a subtype of ionotropic glutamate receptors in the postsynaptic membrane of the central nervous system (CNS),mediates most of the fast excitatory neurotransmission.CX717 developed by Cortex Pharmaceuticals Company of the USA belongs to the benzamide series of AMPA receptor positive modulators.It can reduce the speed of AMPA receptor inactivation or desensitization,thereby enhancing synaptic activity,and is closely related to the treatment of Alzheimer's disease,Parkinson's disease,depression and attention deficit hyperactivity disorder(ADHD).This article reviews the latest research of CX717 regarding its structure,pharmacokinetics,toxicology and pharmacodynamics.

  14. Laboratory and field trial of developing medicinal local Thai plant products against four species of mosquito vectors.

    Science.gov (United States)

    Trongtokit, Yuwadee; Rongsriyam, Yupha; Komalamisra, Narumon; Krisadaphong, Panvipa; Apiwathnasorn, Chamnarn

    2004-06-01

    Oils of Syzygium aromaticum (clove) and Zanthoxylum limonella (makaen), widely used essential oils for dental caries or flavoring of food in Thailand, were prepared as 10 experimental repellent products in gel or cream form against Aedes aegypti, Culex quinquefasciatus, and Anopheles dirus under laboratory conditions, using the human-arm-in-cage method. Two products that gave the longest-lasting complete protection were selected to examine their repellency against a variety of mosquito species under field conditions. In laboratory tests, 0.1 g of each product was applied to 3x10 cm of exposed area on a volunteer's forearm, while in field trials, 1.0 g was applied to each volunteer's leg (from knee to ankle). In the laboratory, the gel dosage form contained 20% clove oil (Gel B) or 10% clove plus 10% makaen oil mixture (Gel E) were promising plant-based repellents against three mosquito species and gave significantly longer complete protection times of 4-5 hours than all other developing products. Therefore, their efficacy in the field was evaluated. Under field conditions, Gel E showed complete protection for 4 hours and gave 95.7% repellency after 5 hours application, whereas Gel B and 20% deet (di-methyl benzamide) provided only 86.8 and 82.7% repellency after treatment, respectively against Ae. aegypti, daytime-biting mosquitos. For nighttime-biting, the 3 repellents under development yielded equally excellent (average 97.1%) repellency for 5 hours against the predominant Cx. quinquefasciatus and Mansonia uniformis, but they gave 89.0% repellency against Cx. tritaeniorhynchus and Cx. gelidus. This finding demonstrated the effectiveness of Gel B and Gel E products for possible use by low-income rural communities against various mosquito species. PMID:15691131

  15. Evaluation of new iodinated acridine derivatives for targeted radionuclide therapy of melanoma using 125I, an Auger electron emitter

    International Nuclear Information System (INIS)

    The full text of the publication follows. The increasing incidence of melanoma and the lack of effective therapy on the disseminated form have led to an urgent need for new specific therapies. Several iodo-benzamides or analogs are known to possess specific affinity for melanoma tissue. New hetero-aromatic derivatives have been designed with a cytotoxic moiety and termed DNA intercalating agents. These compounds could be applied in targeted radionuclide therapy using 125I, Auger electrons emitter which gives high-energetic localized irradiation. Two iodinated acridine derivatives have been reported to present an in vivo kinetic profile conducive to application in targeted radionuclide therapy. The aim of the present study was to perform a preclinical evaluation of these compounds. The DNA intercalating property was confirmed for both compounds. After radiolabeling with 125I, the two compounds induced in vitro a significant radiotoxicity on B16F0 melanoma cells. The acridine compound, ICF01040, appeared more radio toxic than the acridone compound, ICF01035. While cellular uptake was similar for both compounds, SIMS analysis and in vitro protocol showed a stronger affinity for melanin with ICF01035, which was able to induce a predominant scavenging process in the melanosome and restrict access to the nucleus. Nevertheless, an important radiotoxicity was measured for the two compounds while the nuclear accumulation was low. Indeed, even if nuclear localization remains the main target sensitive to Auger electrons, the cell membrane remains sensitive to 125I decays. So, these compounds may induce secondary toxic effects of irradiation, such as membrane lipid damage. Conducted to current experiments are evaluate such hypothesis. Taken together, these results suggest that ICF01040 is a better candidate for application in targeted radionuclide therapy using 125I. The next step will be in vivo evaluation, where high tumoral vectorization gives promising perspectives

  16. Characterization and structural analysis of the potent antiparasitic and antiviral agent tizoxanide

    Science.gov (United States)

    Bruno, Flavia P.; Caira, Mino R.; Martin, Eliseo Ceballos; Monti, Gustavo A.; Sperandeo, Norma R.

    2013-03-01

    Tizoxanide [2-(hydroxy)-N-(5-nitro-2-thiazolyl)benzamide, TIZ] is a new potent anti-infective agent which may enhance current therapies for leishmaniasis, Chagas disease and viral hepatitis. The aim of this study was to identify the conformational preferences that may be related to the biological activity of TIZ by resolving its crystal structure and characterizing various physicochemical properties, including its experimental vibrational and 13C nuclear magnetic resonance properties, behavior on heating and solubility in several solvents at 25 °C. TIZ crystallizes from dimethylformamide as the carboxamide tautomer in the triclinic system, space group P(-1) (No. 2) with the following unit cell parameters at 173(2) K: a = 5.4110(3) Å, b = 7.3315(6) Å, c = 13.5293(9) Å, α = 97.528(3), β = 95.390(4), γ = 97.316(5), V = 524.41(6) Å3, Z = 2, Dc = 1.680 g/cm3, R1 = 0.0482 and wR2 = 0.0911 for 2374 reflections. This modification of TIZ has a 'graphitic' structure and is composed of tightly packed layers of extensively hydrogen-bonded molecules. The various spectroscopic data [Diffuse Fourier transform infrared (DRIFT) and FT-Raman, recorded in the range 3600-500 and 4000-200 cm-1 respectively, and solid-state 13C NMR] were consistent with the structure determined by X-ray crystallography. From DSC, TG and thermomicroscopy, it was concluded that TIZ is thermally stable as a solid and that melting is not an isolated event from the one-step thermal decomposition that it undergoes above 270 °C. This modification of TIZ is practically insoluble in water and slightly soluble in polar aprotic solvents such as dimethylsulfoxide, dimethylformamide and dioxane.

  17. On-line solid phase extraction-high performance liquid chromatography-isotope dilution-tandem mass spectrometry approach to quantify N,N-diethyl-m-toluamide and oxidative metabolites in urine.

    Science.gov (United States)

    Kuklenyik, Peter; Baker, Samuel E; Bishop, Amanda M; Morales-A, Pilar; Calafat, Antonia M

    2013-07-17

    Human exposure to N,N-diethyl-m-toluamide (DEET) occurs because of the widespread use of DEET as an active ingredient in insect repellents. However, information on the extent of such exposure is rather limited. Therefore, we developed a fast on-line solid phase extraction-high performance liquid chromatography-isotope dilution tandem mass spectrometry (HPLC-MS/MS) method to measure in urine the concentrations of DEET and two of its oxidative metabolites: N,N-diethyl-3-(hydroxymethyl)benzamide and 3-(diethylcarbamoyl)benzoic acid (DCBA). To the best of our knowledge, this is the first HPLC-MS/MS method for the simultaneous quantification of DEET and its select metabolites in human urine. After enzymatic hydrolysis of the conjugated species in 0.1 mL of urine, the target analytes were retained and pre-concentrated on a monolithic column, separated from each other and from other urinary biomolecules on a reversed-phase analytical column, and detected by atmospheric pressure chemical ionization in positive ion mode. The limits of detection ranged from 0.1 ng mL(-1) to 1.0 ng mL(-1), depending on the analyte. Accuracy ranged between 90.4 and 104.9%, and precision ranged between 5.5 and 13.1% RSD, depending on the analyte and the concentration. We tested the usefulness of this method by analyzing 75 urine samples collected anonymously in the Southeastern United States in June 2012 from adults with no known exposure to DEET. Thirty eight samples (51%) tested positive for at least one of the analytes. We detected DCBA most frequently and at the highest concentrations. Our results suggest that this method can be used for the analysis of a large number of samples for epidemiological studies to assess human exposure to DEET. PMID:23830449

  18. Novel Cholinesterase Inhibitors Based on O-Aromatic N,N-Disubstituted Carbamates and Thiocarbamates

    Directory of Open Access Journals (Sweden)

    Martin Krátký

    2016-02-01

    Full Text Available Based on the presence of carbamoyl moiety, twenty salicylanilide N,N-disubstituted (thiocarbamates were investigated using Ellman’s method for their ability to inhibit acetylcholinesterase (AChE and butyrylcholinesterase (BChE. O-Aromatic (thiocarbamates exhibited weak to moderate inhibition of both cholinesterases with IC50 values within the range of 1.60 to 311.0 µM. IC50 values for BChE were mostly lower than those obtained for AChE; four derivatives showed distinct selectivity for BChE. All of the (thiocarbamates produced a stronger inhibition of AChE than rivastigmine, and five of them inhibited BChE more effectively than both established drugs rivastigmine and galantamine. In general, 5-chloro-2-hydroxy-N-[4-(trifluoromethyl-phenyl]benzamide, 2-hydroxy-N-phenylbenzamide as well as N-methyl-N-phenyl carbamate derivatives led to the more potent inhibition. O-{4-Chloro-2-[(4-chlorophenylcarbamoyl]phenyl} dimethylcarbamothioate was identified as the most effective AChE inhibitor (IC50 = 38.98 µM, while 2-(phenylcarbamoylphenyl diphenylcarbamate produced the lowest IC50 value for BChE (1.60 µM. Results from molecular docking studies suggest that carbamate compounds, especially N,N-diphenyl substituted representatives with considerable portion of aromatic moieties may work as non-covalent inhibitors displaying many interactions at peripheral anionic sites of both enzymes. Mild cytotoxicity for HepG2 cells and consequent satisfactory calculated selectivity indexes qualify several derivatives for further optimization.

  19. On-line solid phase extraction-high performance liquid chromatography–isotope dilution–tandem mass spectrometry approach to quantify N,N-diethyl-m-toluamide and oxidative metabolites in urine

    Energy Technology Data Exchange (ETDEWEB)

    Kuklenyik, Peter; Baker, Samuel E.; Bishop, Amanda M.; Morales-A, Pilar; Calafat, Antonia M., E-mail: aic7@cdc.gov

    2013-07-17

    Graphical abstract: -- Highlights: •A fast assay to quantify the concentrations of N,N-Diethyl-m-Toluamide and two urinary metabolites was developed •It uses online SPE, reversed phase HPLC and tandem mass spectrometry •The method is precise and accurate with limits of detection ≤1 ng mL{sup −1} -- Abstract: Human exposure to N,N-diethyl-m-toluamide (DEET) occurs because of the widespread use of DEET as an active ingredient in insect repellents. However, information on the extent of such exposure is rather limited. Therefore, we developed a fast on-line solid phase extraction–high performance liquid chromatography–isotope dilution tandem mass spectrometry (HPLC-MS/MS) method to measure in urine the concentrations of DEET and two of its oxidative metabolites: N,N-diethyl-3-(hydroxymethyl)benzamide and 3-(diethylcarbamoyl)benzoic acid (DCBA). To the best of our knowledge, this is the first HPLC-MS/MS method for the simultaneous quantification of DEET and its select metabolites in human urine. After enzymatic hydrolysis of the conjugated species in 0.1 mL of urine, the target analytes were retained and pre-concentrated on a monolithic column, separated from each other and from other urinary biomolecules on a reversed-phase analytical column, and detected by atmospheric pressure chemical ionization in positive ion mode. The limits of detection ranged from 0.1 ng mL{sup −1} to 1.0 ng mL{sup −1}, depending on the analyte. Accuracy ranged between 90.4 and 104.9%, and precision ranged between 5.5 and 13.1% RSD, depending on the analyte and the concentration. We tested the usefulness of this method by analyzing 75 urine samples collected anonymously in the Southeastern United States in June 2012 from adults with no known exposure to DEET. Thirty eight samples (51%) tested positive for at least one of the analytes. We detected DCBA most frequently and at the highest concentrations. Our results suggest that this method can be used for the analysis of a large

  20. Proerectile effects of dopamine D2-like agonists are mediated by the D3 receptor in rats and mice.

    Science.gov (United States)

    Collins, Gregory T; Truccone, Andrew; Haji-Abdi, Faiza; Newman, Amy Hauck; Grundt, Peter; Rice, Kenner C; Husbands, Stephen M; Greedy, Benjamin M; Enguehard-Gueiffier, Cecile; Gueiffier, Alain; Chen, Jianyong; Wang, Shaomeng; Katz, Jonathan L; Grandy, David K; Sunahara, Roger K; Woods, James H

    2009-04-01

    Dopamine D(2)-like agonists induce penile erection (PE) and yawning in a variety of species, effects that have been suggested recently to be specifically mediated by the D(4) and D(3) receptors, respectively. The current studies were aimed at characterizing a series of D(2), D(3), and D(4) agonists with respect to their capacity to induce PE and yawning in the rat and the proerectile effects of apomorphine [(R)-(-)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo-[de,g]quinoline-10,11-diol hydrochloride] in wild-type and D(4) receptor (R) knockout (KO) mice. All D(3) agonists induced dose-dependent increases in PE and yawning over a similar range of doses, whereas significant increases in PE or yawning were not observed with any of the D(4) agonists. Likewise, D(2), D(3), and D(4) antagonists were assessed for their capacity to alter apomorphine- and pramipexole (N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride)-induced PE and yawning. The D(3) antagonist, PG01037 [N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide hydrochloride], inhibited the induction of PE and yawning, whereas the D(2) antagonist, L-741,626 [3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole], reversed the inhibition of PE and yawning observed at higher doses. The D(4) antagonist, L-745,870 [3-(4-[4-chlorophenyl]piperazin-1-yl)-methyl-1H-pyrrolo[2,3-b]pyridine trihydrochloride], did not alter apomorphine- or pramipexole-induced PE or yawning. A role for the D(3) receptor was further supported because apomorphine was equipotent at inducing PE in wild-type and D(4)RKO mice, effects that were inhibited by the D(3) antagonist, PG01037, in both wild-type and D(4)R KO mice. Together, these studies provide strong support that D(2)-like agonist-induced PE and yawning are differentially mediated by the D(3) (induction) and D(2) (inhibition) receptors. These studies fail to support a role for the D(4) receptor in the regulation of PE or

  1. Targeting Lysine Deacetylases (KDACs in Parasites.

    Directory of Open Access Journals (Sweden)

    Qi Wang

    Full Text Available Due to an increasing problem of drug resistance among almost all parasites species ranging from protists to worms, there is an urgent need to explore new drug targets and their inhibitors to provide new and effective parasitic therapeutics. In this regard, there is growing interest in exploring known drug leads of human epigenetic enzymes as potential starting points to develop novel treatments for parasitic diseases. This approach of repurposing (starting with validated targets and inhibitors is quite attractive since it has the potential to reduce the expense of drug development and accelerate the process of developing novel drug candidates for parasite control. Lysine deacetylases (KDACs are among the most studied epigenetic drug targets of humans, and a broad range of small-molecule inhibitors for these enzymes have been reported. In this work, we identify the KDAC protein families in representative species across important classes of parasites, screen a compound library of 23 hydroxamate- or benzamide-based small molecules KDAC inhibitors, and report their activities against a range of parasitic species, including the pathogen of malaria (Plasmodium falciparum, kinetoplastids (Trypanosoma brucei and Leishmania donovani, and nematodes (Brugia malayi, Dirofilaria immitis and Haemonchus contortus. Compound activity against parasites is compared to that observed against the mammalian cell line (L929 mouse fibroblast in order to determine potential parasite-versus-host selectivity. The compounds showed nanomolar to sub-nanomolar potency against various parasites, and some selectivity was observed within the small panel of compounds tested. The possible binding modes of the active compounds at the different protein target sites within different species were explored by docking to homology models to help guide the discovery of more selective, parasite-specific inhibitors. This current work supports previous studies that explored the use of KDAC

  2. Effect of scopolamine on central DAT and D2 receptor in morphine dependent rats

    International Nuclear Information System (INIS)

    Objective: To investigate the effect of scopolamine (Sco) on central dopamine transporter (DAT) and D2 receptor in morphine (Mor) dependent rats. Methods: Chronic Mor exposure was induced by repeated Mor (20 mg·kg-1·d-1, i.p.) treatment for 8 d. Conditioned place preference test was used to evaluate the drug seeking behavior. Biodistribution of the imaging agents 125I-2β-carbomethoxy-3β-(4-iodophenyl) tropane (β-CIT) and 125I-3-iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl] benzamide (IBZM) were used to evaluate the central DAT and D2 receptor during chronic Mor exposure. Results: For the Mor plus pretreating with Sco (Mor+Sco) rats, the time for the rats entering C2 from C1 was (1.72 ± 0.69) min in the first day, with little difference from the control and Mor group (P>0.05), and (1.12 ± 0.33) min for the 8th day, still longer than that of the Mor group (t=5.171, P125I-β- CIT %ID/g in striatum (ST) and nucleus accumbens (NAC) for Mor + Sco group were 3.307 ± 0.189 and 1.577 ± 0.401 respectively, higher than those of the control group (2.431 ± 0.104, 1.441 ± 0.043, t was 4.151 and 5.416 respectively, P125I-IBZM %ID/g in ST, NAC, hippocampus (HIP) and frontal cortex (FC) for Mor + Sco group were 0.589 ± 0.081, 0.683 ± 0.046, 0.175 ± 0.039 and 0.257 ± 0.034 lower than that of the control rats (0.735 ± 0.096, 0.709 ± 0.098, 0.281 ± 0.038, 0.289 ± 0.020, t was 7.841, 6.170, 5.446 and 4.337 respectively, P2 receptor induced by Mor to some extent

  3. Influence of inhibitors of poly(ADP-ribose) polymerase on DNA repair, chromosomal alterations, and mutations.

    Science.gov (United States)

    Natarajan, A T; van Zeeland, A A; Zwanenburg, T S

    1983-01-01

    The influence of inhibitors of poly(ADP-ribose) polymerase such as 3-aminobenzamide (3AB) and benzamide (B) on the spontaneously occurring as well as mutagen induced chromosomal aberrations, sister chromatid exchanges (SCEs) and point mutations has been studied. In addition, we have measured the influence of 3AB on DNA repair following treatment with physical and chemical mutagens. Post treatment of X-irradiated mammalian cells with 3AB increases the frequencies of induced chromosomal aberrations by a factor of 2 to 3. Both acentric fragments and exchanges increase indicating that the presence of 3AB slows down the repair of DNA strand breaks (probably DNA double strand breaks), thus making breaks available for interaction with each other to give rise to exchanges. 3AB, when present in the medium containing bromodeoxyuridine(BrdUrd) during two cell cycles, increases the frequencies of SCEs in Chinese hamster ovary cells (CHO) in a concentration dependent manner leading to about a 10-fold increase at 10 mM concentration. Most 3AB induced SCEs occur during the second cell cycle, in which DNA containing bromouridine (BU) is used as template for replication. BU containing DNA appears to be prone to errors during replication. The extent of increase in the frequencies of SCEs by 3AB is correlated with the amount of BU incorporated in the DNA of the cells. The frequencies of spontaneously occurring DNA single strand breaks in cells grown in BrdUrd containing medium are higher than in the cells grown in normal medium and this increase depends on the amount of BU incorporated in the DNA of these cells. We have studied the extent of increase in the frequencies of SCEs due to 1 mM 3AB in several human cell lines, including those derived from patients suffering from genetic diseases such as ataxia telangiectasia (A-T), Fanconi's anemia (FA), and Huntington's chorea. None of these syndromes showed any increased response when compared to normal cells. 3AB, however, increased the

  4. Transient Receptor Potential Channel Opening Releases Endogenous Acetylcholine, which Contributes to Endothelium-Dependent Relaxation Induced by Mild Hypothermia in Spontaneously Hypertensive Rat but Not Wistar-Kyoto Rat Arteries.

    Science.gov (United States)

    Zou, Q; Leung, S W S; Vanhoutte, P M

    2015-08-01

    Mild hypothermia causes endothelium-dependent relaxations, which are reduced by the muscarinic receptor antagonist atropine. The present study investigated whether endothelial endogenous acetylcholine contributes to these relaxations. Aortic rings of spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats were contracted with prostaglandin F2 α and exposed to progressive mild hypothermia (from 37 to 31°C). Hypothermia induced endothelium-dependent, Nω-nitro-l-arginine methyl ester-sensitive relaxations, which were reduced by atropine, but not by mecamylamine, in SHR but not in WKY rat aortae. The responses in SHR aortae were also reduced by acetylcholinesterase (the enzyme responsible for acetylcholine degradation), bromoacetylcholine (inhibitor of acetylcholine synthesis), hemicholinium-3 (inhibitor of choline uptake), and vesamicol (inhibitor of acetylcholine release). The mild hypothermia-induced relaxations in both SHR and WKY rat aortae were inhibited by AMTB [N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide; the transient receptor potential (TRP) M8 inhibitor]; only those in SHR aortae were inhibited by HC-067047 [2-methyl-1-[3-(4-morpholinyl)propyl]-5-phenyl-N-[3-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide; TRPV4 antagonist] while those in WKY rat aortae were reduced by HC-030031 [2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; TRPA1 antagonist]. The endothelial uptake of extracellular choline and release of cyclic guanosine monophosphate was enhanced by mild hypothermia and inhibited by HC-067047 in SHR but not in WKY rat aortae. Compared with WKY rats, the SHR preparations expressed similar levels of acetylcholinesterase and choline acetyltransferase, but a lesser amount of vesicular acetylcholine transporter, located mainly in the endothelium. Thus, mild hypothermia causes nitric oxide-dependent relaxations by opening TRPA1 channels in WKY rat aortae

  5. SIRT1 inactivation induces inflammation through the dysregulation of autophagy in human THP-1 cells

    International Nuclear Information System (INIS)

    Highlights: ► SIRT1 inactivation decreases autophagy in THP-1 cell. ► Inhibition of autophagy induces inflammation. ► SIRT1 inactivation induces inflammation through NF-κB activation. ► The p62/Sqstm1 accumulation by impairment of autophagy is related to NF-κB activation. ► SIRT1 inactivation is involved in the activation of mTOR and decreased AMPK activation. -- Abstract: Inflammation plays a crucial role in atherosclerosis. Monocytes/macrophages are some of the cells involved in the inflammatory process in atherogenesis. Autophagy exerts a protective effect against cellular stresses like inflammation, and it is regulated by nutrient-sensing pathways. The nutrient-sensing pathway includes SIRT1, a NAD+-dependent histone deacetylase, which is implicated in the regulation of a variety of cellular processes including inflammation and autophagy. The mechanism through which the dysfunction of SIRT1 contributes to the regulation of inflammation in relation to autophagy in monocytes/macrophages is unclear. In the present study, we demonstrate that treatment with 2-[(2-Hydroxynaphthalen-1-ylmethylene)amino]-N-(1-phenethyl)benzamide (Sirtinol), a chemical inhibitor of SIRT1, induces the overexpression of inflammation-related genes such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 through nuclear factor (NF)-κB signaling activation, which is associated with autophagy dysfunction, as shown through p62/Sqstm1 accumulation and decreased expression of light chain (LC) 3 II in THP-1 cells. The autophagy inhibitor, 3-methyladenine, also induces inflammation-related NF-κB activation. In p62/Sqstm1 knockdown cells, Sirtinol-induced inflammation through NF-κB activation is blocked. In addition, inhibition of SIRT1 is involved in the activation of the mammalian target of rapamycin (mTOR) pathway and is implicated in decreased 5′-AMP activated kinase (AMPK) activation, leading to the impairment of autophagy. The mTOR inhibitor, rapamycin, abolishes

  6. Avaliação de xaropes contendo cloridrato de metoclopramida, pelo método de Bratton-Marshall Evaluation of metoclopramide syrups by Bratton-Marshall method

    Directory of Open Access Journals (Sweden)

    Beatriz Resende Freitas

    2005-06-01

    Full Text Available Atualmente, a maioria dos fármacos apresenta grupamento amínico. Estes quando associados a açúcares redutores ou a outros adjuvantes farmacêuticos contendo carbonila, freqüentemente produzem problemas de estabilidade, comprometendo a idoneidade do produto. A Reação de Maillard pode explicar tal ocorrência. Neste trabalho estudou-se o comportamento de xarope contendo amina aromática, tendo em vista a associação de açúcares e aminas, a Reação de Maillard e problemas de estabilidade. O protótipo escolhido foi o cloridrato de metoclopramida, benzamida com atividade farmacológica antiemética. Amostras dos xaropes de cloridrato de metoclopramida foram mantidas em estufa a 40 °C por seis meses. Em intervalos regulares de tempo alíquotas foram retiradas e submetidas à análise pelo método de Bratton-Marshall, seguida de leitura espectrofotométrica. Não houve grande variação no teor do cloridrato de metoclopramida em relação ao teor de açúcar, sendo que foram preparadas amostras padronizadas dos xaropes de cloridrato de metoclopramida em diferentes concentrações de açúcar. Houve diminuição do teor do cloridrato de metoclopramida, da ordem de 50%, tanto para amostras padronizadas como para amostra comercial.Nowadays, most of the drugs have amine group in their structure. These drugs, when associated to sugar reducers, or other carbonyl excipients frequently produce dark stains or fading. The Maillard reaction can explain such occurrence. In this work, we have studied the behavior of syrups containing aromatic amines. It is known that association of sugars and amines can generate problems of stability. The chosen prototype was the metoclopramide hydrochloride, a benzamide, with anti-emetic pharmacological activity. Samples of the metoclopramide syrups were maintained in stove at 40 °C for six months. In regular time intervals aliquots were removed and submitted to quantitative determination by the Bratton

  7. A comparison of the stimulatory effects of metoclopramide and cinitapride in the guinea-pig isolated ileum.

    Science.gov (United States)

    Massingham, R; Bou, J; Roberts, D J

    1985-03-01

    The pharmacological effects of a new benzamide derivative cinitapride, have been compared to those of metoclopramide in guinea-pig isolated ileum and longitudinal smooth muscle-myenteric plexus preparations treated with propranolol (3 microM). Cinitapride (EC50 = 0.74 microM) was 6 times more potent than metoclopramide (EC50 = 4.69 microM) in enhancing the twitch response of co-axially stimulated preparations and 11 times more potent in eliciting contractions in non-stimulated tissues, their respective EC50 values being 0.58 microM and 6.52 microM. These contractile effects of cinitapride and metoclopramide amounted to approximately 25% of the maximum response of the tissues to acetylcholine (1 microM). Neither cinitapride nor metoclopramide, in concentrations up to 10 microM, significantly affected concentration-response curves to exogenous acetylcholine or 5-hydroxytryptamine but both drugs elicited a concentration-dependent potentiation of the ileum responses to a fixed concentration (10 microM) of the ganglion stimulant dimethylphenylpiperazinium (DMPP). Analysis of the twitch-enhancing and contractile effects of cinitapride using a variety of drugs suggested that a common, prejunctional locus of action upon the cell bodies or axons of postganglionic, parasympathetic neurones of the myenteric plexus is involved in both of these responses. In hexamethonium (100 microM) and methysergide (0.1 microM)-treated longitudinal smooth muscle preparations desensitization or blockade of 5-hydroxytryptamine receptors using high concentrations of the same agonist (30 microM) or quipazine (10 microM) or the putative antagonists cocaine (30 microM) or tubocurarine (10 microM) produced small inhibitions (congruent to 20%) of the contractile responses to metoclopramide and cinitapride but did not affect twitch responses to these drugs. It is concluded that cinitapride is a more potent stimulant of guinea-pig intestinal smooth muscle than metoclopramide in vitro although the

  8. SIRT1 inactivation induces inflammation through the dysregulation of autophagy in human THP-1 cells

    Energy Technology Data Exchange (ETDEWEB)

    Takeda-Watanabe, Ai; Kitada, Munehiro; Kanasaki, Keizo [Diabetology and Endocrinology, Kanazawa Medical University, Kahoku-Gun, Ishikawa (Japan); Koya, Daisuke, E-mail: koya0516@kanazawa-med.ac.jp [Diabetology and Endocrinology, Kanazawa Medical University, Kahoku-Gun, Ishikawa (Japan)

    2012-10-12

    Highlights: Black-Right-Pointing-Pointer SIRT1 inactivation decreases autophagy in THP-1 cell. Black-Right-Pointing-Pointer Inhibition of autophagy induces inflammation. Black-Right-Pointing-Pointer SIRT1 inactivation induces inflammation through NF-{kappa}B activation. Black-Right-Pointing-Pointer The p62/Sqstm1 accumulation by impairment of autophagy is related to NF-{kappa}B activation. Black-Right-Pointing-Pointer SIRT1 inactivation is involved in the activation of mTOR and decreased AMPK activation. -- Abstract: Inflammation plays a crucial role in atherosclerosis. Monocytes/macrophages are some of the cells involved in the inflammatory process in atherogenesis. Autophagy exerts a protective effect against cellular stresses like inflammation, and it is regulated by nutrient-sensing pathways. The nutrient-sensing pathway includes SIRT1, a NAD{sup +}-dependent histone deacetylase, which is implicated in the regulation of a variety of cellular processes including inflammation and autophagy. The mechanism through which the dysfunction of SIRT1 contributes to the regulation of inflammation in relation to autophagy in monocytes/macrophages is unclear. In the present study, we demonstrate that treatment with 2-[(2-Hydroxynaphthalen-1-ylmethylene)amino]-N-(1-phenethyl)benzamide (Sirtinol), a chemical inhibitor of SIRT1, induces the overexpression of inflammation-related genes such as tumor necrosis factor (TNF)-{alpha} and interleukin (IL)-6 through nuclear factor (NF)-{kappa}B signaling activation, which is associated with autophagy dysfunction, as shown through p62/Sqstm1 accumulation and decreased expression of light chain (LC) 3 II in THP-1 cells. The autophagy inhibitor, 3-methyladenine, also induces inflammation-related NF-{kappa}B activation. In p62/Sqstm1 knockdown cells, Sirtinol-induced inflammation through NF-{kappa}B activation is blocked. In addition, inhibition of SIRT1 is involved in the activation of the mammalian target of rapamycin (mTOR) pathway and

  9. A Significant but Constrained Geometry Pt→Al Interaction: Fixation of CO2 and CS2, Activation of H2 and PhCONH2.

    Science.gov (United States)

    Devillard, Marc; Declercq, Richard; Nicolas, Emmanuel; Ehlers, Andreas W; Backs, Jana; Saffon-Merceron, Nathalie; Bouhadir, Ghenwa; Slootweg, J Chris; Uhl, Werner; Bourissou, Didier

    2016-04-13

    Reaction of the geminal PAl ligand [Mes2PC(═CHPh)AltBu2] (1) with [Pt(PPh3)2(ethylene)] affords the T-shape Pt complex [(1)Pt(PPh3)] (2). X-ray diffraction analysis and DFT calculations reveal the presence of a significant Pt→Al interaction in 2, despite the strain associated with the four-membered cyclic structure. The Pt···Al distance is short [2.561(1) Å], the Al center is in a pyramidal environment [Σ(C-Al-C) = 346.6°], and the PCAl framework is strongly bent (98.3°). Release of the ring strain and formation of X→Al interactions (X = O, S, H) impart rich reactivity. Complex 2 reacts with CO2 to give the T-shape adduct 3 stabilized by an O→Al interaction, which is a rare example of a CO2 adduct of a group 10 metal and actually the first with η(1)-CO2 coordination. Reaction of 2 with CS2 affords the crystalline complex 4, in which the PPtP framework is bent, the CS2 molecule is η(2)-coordinated to Pt, and one S atom interacts with Al. The Pt complex 2 also smoothly reacts with H2 and benzamide PhCONH2 via oxidative addition of H-H and H-N bonds, respectively. The ensuing complexes 5 and 7 are stabilized by Pt-H→Al and Pt-NH-C(Ph) = O→Al bridging interactions, resulting in 5- and 7-membered metallacycles, respectively. DFT calculations have been performed in parallel with the experimental work. In particular, the mechanism of reaction of 2 with H2 has been thoroughly analyzed, and the role of the Lewis acid moiety has been delineated. These results generalize the concept of constrained geometry TM→LA interactions and demonstrate the ability of Al-based ambiphilic ligands to participate in TM/LA cooperative reactivity. They extend the scope of small molecule substrates prone to such cooperative activation and contribute to improve our knowledge of the underlying factors. PMID:26977772

  10. Exploration of dopamine transporter and D2 receptors in morphine dependent rats through 125I-β-CTT, 125I-IBZM cerebral autoradiography and the biodistribution study

    International Nuclear Information System (INIS)

    Objective: To explore the variation of cerebral dopamine (DA) transmitting system in morphine dependent (MD) rats using dopamine transporter (DAT) and D2 receptors imaging agent. Methods: MD model rats were established by using a two-compartment (C1 and C2-morphine conditioned compartment) apparatus for assessing morphine conditioned place preferences in rats. 125I-2β-carbomethoxy-3β-(4-iodophenyl) tropane (125I-β-CIT) and 125I-3-iodo-2-hydroxy-6-methoxy-N[(1-ethyl-2-pyrrolidinyl) methyl] benzamide (125I-IBZM) cerebral DAT and D2 receptor autoradiography and biodistribution study were used to evaluate the variation of DAT and D2 receptors in morphine dependent rats. Results: The mean time of MD rats entering from C1 to C2 was (0.84 +- 0.50) min after 6 days' conditioned place preference training, shorter than that of the control group [(2.40 +- 1.10) min, P 125I-β-CIT uptake ratio of striatum (ST)/cerebellum (CB) and nucleus acumens (NAC)/CB in MD group were 4.76 +- 0.92 and 2.72 +- 0.96, significantly lower than that of control group (5.92 +- 0.67 and 4.16 +- 0.56, P 125I-IBZM uptake ratio in MD group were 4.11 +- 0.56 and 2.64 +- 0.25, lower than that in control group (5.43 +- 0.74 and 3.49 +- 0.65, P 125I-β-CIT, 125I-IBZM biodistribution study also showed that the DAT and D2 binding sites were reduced in ST of MD group by (21.68 +- 11.11)% and (18.69 +- 9.97)% comparing to the controls, respectively. Conclusions: The DAT and D2 receptors in both ST and NAC were all involved and reduced to some extent in morphine dependent model rats, the DAT and D2 receptor imaging agent could reflect the variation of DAT and D2receptors, this would afford the theoretical basis for D2 receptors and DAT imaging in study on preventing drug addiction and on its abstinence

  11. Searching for combinations of small-molecule correctors to restore f508del-cystic fibrosis transmembrane conductance regulator function and processing.

    Science.gov (United States)

    Boinot, Clément; Jollivet Souchet, Mathilde; Ferru-Clément, Romain; Becq, Frédéric

    2014-09-01

    The mutated protein F508del-cystic fibrosis transmembrane conductance regulator (CFTR) failed to traffic properly as a result of its retention in the endoplasmic reticulum and functions as a chloride (Cl(-)) channel with abnormal gating and endocytosis. Small chemicals (called correctors) individually restore F508del-CFTR trafficking and Cl(-) transport function, but recent findings indicate that synergistic pharmacology should be considered to address CFTR defects more clearly. We studied the function and maturation of F508del-CFTR expressed in HeLa cells using a combination of five correctors [miglustat, IsoLAB (1,4-dideoxy-2-hydroxymethyl-1,4-imino-l-threitol), Corr4a (N-[2-(5-chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]-benzamide), VX-809 [3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid], and suberoylamilide hydroxamic acid (SAHA)]. Using the whole-cell patch-clamp technique, the current density recorded in response to CFTR activators (forskolin + genistein) was significantly increased in the presence of the following combinations: VX-809 + IsoLAB; VX-809 + miglustat + SAHA; VX-809 + miglustat + IsoLAB; VX-809 + IsoLAB + SAHA; VX-809 + miglustat + IsoLAB + SAHA. These combinations restored the activity of F508del-CFTR but with a differential effect on the appearance of mature c-band of F508del-CFTR proteins. Focusing on the VX-809 + IsoLAB cocktail, we recorded a level of correction higher at 37°C versus room temperature, but without amelioration of the thermal instability of CFTR. The level of functional rescue with VX-809 + IsoLAB after 4 hours of incubation was maximal and similar to that obtained in optimal conditions of use for each compound (i.e., 24 hours for VX-809 + 4 hours for IsoLAB). Finally, we compared the stimulation of F508del-CFTR by forskolin or forskolin + VX-770 [N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide] with cells corrected by

  12. Ultra-structural cell distribution of the melanoma marker iodobenzamide: improved potentiality of SIMS imaging in life sciences

    Directory of Open Access Journals (Sweden)

    Papon Janine

    2004-04-01

    Full Text Available Abstract Background Analytical imaging by secondary ion mass spectrometry (SIMS provides images representative of the distribution of a specific ion within a sample surface. For the last fifteen years, concerted collaborative research to design a new ion microprobe with high technical standards in both mass and lateral resolution as well as in sensitivity has led to the CAMECA NanoSims 50, recently introduced onto the market. This instrument has decisive capabilities, which allow biological applications of SIMS microscopy at a level previously inaccessible. Its potential is illustrated here by the demonstration of the specific affinity of a melanoma marker for melanin. This finding is of great importance for the diagnosis and/or treatment of malignant melanoma, a tumour whose worldwide incidence is continuously growing. Methods The characteristics of the instrument are briefly described and an example of application is given. This example deals with the intracellular localization of an iodo-benzamide used as a diagnostic tool for the scintigraphic detection of melanic cells (e.g. metastasis of malignant melanoma. B16 melanoma cells were injected intravenously to C57BL6/J1/co mice. Multiple B16 melanoma colonies developed in the lungs of treated animals within three weeks. Iodobenzamide was injected intravenously in tumour bearing mice six hours before sacrifice. Small pieces of lung were prepared for SIMS analysis. Results Mouse lung B16 melanoma colonies were observed with high lateral resolution. Cyanide ions gave "histological" images of the cell, representative of the distribution of C and N containing molecules (e.g. proteins, nucleic acids, melanin, etc. while phosphorus ions are mainly produced by nucleic acids. Iodine was detected only in melanosomes, confirming the specific affinity of the drug for melanin. No drug was found in normal lung tissue. Conclusion This study demonstrates the potential of SIMS microscopy, which allows the

  13. Design and preclinical evaluation of melanoma targeting agents for internal radionuclide therapy

    Energy Technology Data Exchange (ETDEWEB)

    Chezal, J.M.; Papon, J.; Labarre, P.; Denoyer, D.; Bonnet-Duquennoy, M.; Miot-Noirault, E.; Bayle, M.; Chavignon, O.; Teulade, J.C.; Maublant, J.; Madelmont, J.C.; Moins, N. [Centre Jean Perrin, Inserm-Univ. d' Auvergne, UMR 484, 63 - Clermont Ferrand (France)

    2008-02-15

    Targeted internal radionuclide therapy would be an effective alternative to current therapies for disseminated melanoma treatment. N-(2-diethylaminoethyl)-4-iodo benzamide (B.Z.A.) and compounds of this series exhibit a specific affinity for melanoma tissue giving them a potent application for gamma imaging ({sup 123}I) or radionuclide therapy ({sup 131}I or {sup 125}I).With the aim of internal radionuclide therapy, a pharmaco-chemical study has been carried out in order to select new derivatives with a longer retention time in the tumor of melanoma bearing mice and suitable dosimetry. New molecules synthesized are B.Z.A. analogs differing by (1) the aliphatic side chain, (2) aromatic ring. After the design of compounds, the synthesis, and the labelling with {sup 125}I, a study of their biodistribution was performed in B 16 F0 melanoma bearing C.57 B.L.6 mice after i.v. injection. The radioactivity biodistribution was analysed using an A.M.B.I.S.4000 detector on whole body slices of mice obtained by cryo section. The radioactivity was quantified in different organs including tumor and expressed as percentage of injected dose/g of tissue (% I.D./g). Dosimetry parameters for a {sup 131}I utilization were extrapolated using the M.I.R.D. program. The first selected compound has been further evaluated on different models. S.I.M.S. imaging, metabolism and in vivo anti tumoral activity after {sup 131}I labelling were assessed. For number of the studied molecules, a tumor uptake was observed and at least four compounds exhibited an original pharmacokinetic profile: high, specific and durable tumour concentration with a rapid clearance from non-target organs. The tumour concentration after 72 h was increased up to 16- fold compared to B.Z.A. and in term of dosimetry, for a {sup 131}I labelling, the tumor absorbed dose was increased by more than 6-fold. Such profiles made these compounds promising for an application to internal radionuclide therapy. The first selected

  14. Presynaptic modulation of 5-HT release in the rat septal region.

    Science.gov (United States)

    Rutz, S; Riegert, C; Rothmaier, A K; Jackisch, R

    2007-05-11

    5-HT released from serotonergic axon terminals in the septal nuclei modulates the activity of septal output neurons (e.g. septohippocampal cholinergic neurons) bearing somatodendritic 5-HT receptors. Therefore, we studied the mechanisms involved in the presynaptic modulation of 5-HT release in the lateral (LS) and medial septum (MS), and the diagonal band of Broca (DB). HPLC analysis showed that tissue concentrations of noradrenaline, dopamine and 5-HT were highest in DB (DB>MS>LS). Slices prepared from LS, MS and DB regions were preincubated with [(3)H]5-HT, superfused in the presence of 6-nitro-2-(1-piperazinyl)-quinoline (6-nitroquipazine) and electrically stimulated up to three times (first electrical stimulation period (S(1)), S(2), S(3); 360 pulses, 3 Hz, 2 ms, 26-28 mA). In all septal regions the Ca(2+)-dependent and tetrodotoxin-sensitive electrically-evoked overflow of [(3)H] was inhibited by the 5-HT(1B) agonist CP-93,129 and the alpha(2)-adrenoceptor agonist 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline tartrate (UK-14,304). Also the mu- and kappa-opioid receptor agonists (d-Ala(2), N-Me-Phe(4), glycinol(5))-enkephalin (DAMGO) and [trans-(1S,2S(-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]-benzenacetamide hydro-chloride] (U-50,488H), respectively, acted inhibitory (although less potently), whereas the delta-opioid receptor agonist (d-Pen(2), d-Pen(5))-enkephalin (DPDPE), the dopamine D(2) receptor agonist quinpirole and the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine were all ineffective; the GABA(B) receptor agonist baclofen had weak effects. All inhibitory effects of the agonists were antagonized by the corresponding antagonists (3-[3-(dimethylamino)propyl]-4-hydroxy-N-[4-(4-pyridinyl)phenyl]benzamide dihydrochloride (GR-55,562), idazoxan, naloxone, nor-binaltorphimine), which also significantly enhanced the evoked release of 5-HT at S(1). It is concluded that 5-HT release in septal nuclei of the rat is modulated by

  15. Synthesis and positron emission tomography studies of carbon-11-labeled imatinib (Gleevec)

    Energy Technology Data Exchange (ETDEWEB)

    Kil, Kun-Eek [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400 (United States); Ding Yushin [Department of Radiology, Yale University School of Medicine, New Haven, CT 06520-8048 (United States); Lin Kuoshyan [Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15213 (United States); Alexoff, David [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Kim, Sung Won [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400 (United States); Shea, Colleen [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Xu Youwen [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Muench, Lisa [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Fowler, Joanna S. [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States) and Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400 (United States)]. E-mail: fowler@bnl.gov

    2007-02-15

    Introduction: Imatinib mesylate (Gleevec) is a well known drug for treating chronic myeloid leukemia and gastrointestinal stromal tumors. Its active ingredient, imatinib ([4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridyl) -2-pyrimidinyl]amino]phenyl]benzamide), blocks the activity of several tyrosine kinases. Here we labeled imatinib with carbon-11 as a tool for determining the drug distribution and pharmacokinetics of imatinib, and we carried out positron emission tomography (PET) studies in baboons. Methods: [N-{sup 11}C-methyl]imatinib was synthesized from [{sup 11}C]methyl iodide and norimatinib was synthesized by the demethylation of imatinib (isolated from Gleevec tablets) according to a patent procedure [Collins JM, Klecker RW Jr, Anderson LW. Imaging of drug accumulation as a guide to antitumor therapy. US Patent 20030198594A1, 2003]. Norimatinib was also synthesized from the corresponding amine and acid. PET studies were carried out in three baboons to measure pharmacokinetics in the brain and peripheral organs and to determine the effect of a therapeutic dose of imatinib. Log D and plasma protein binding were also measured. Results: [N-{sup 11}C-methyl]imatinib uptake in the brain is negligible (consistent with P-glycoprotein-mediated efflux); it peaks and clears rapidly from the heart, lungs and spleen. Peak uptake and clearance occur more slowly in the liver and kidneys, followed by accumulation in the gallbladder and urinary bladder. Pretreatment with imatinib did not change uptake in the heart, lungs, kidneys and spleen, and increased uptake in the liver and gallbladder. Conclusions: [N-{sup 11}C-methyl]imatinib has potential for assessing the regional distribution and kinetics of imatinib in the human body to determine whether the drug targets tumors and to identify other organs to which the drug or its labeled metabolites distribute. Paired with tracers such as 2'deoxy-2'-[{sup 18}F]fluoro-D-glucose ({sup 18}FDG) and 3&apos

  16. Induction of NO production from macrophages by γ-irradiation involves DNA damage and NF-κ B activation

    International Nuclear Information System (INIS)

    Full text: We have reported that γ-irradiation enhanced nitric oxide (NO) production from resident peritoneal macrophages, participating in augmentation of anti-tumor activity of the cells. The murine macrophage cell line RAW264.7 treated with interferon-γ(IFN- γ) also showed enhanced NO production by γ-irradiation in a dose-dependent manner. We investigated the mechanism of NO augmentation after γ-irradiation. The cells showed enhanced inducible nitric oxide synthase (iNOS) expression by γ-irradiation, the promoter of which gene contains binding sites for nuclear factor kappa B (NF-κB). The activation was also induced 1h after γ-irradiation, which was detected by the degradation of I-κB. Inhibitors of I-κB degradation, MG132 and N□ -p-tosyl-L-lysine chloromethyl ketone (TLCK), suppressed the increase in NO production, showing that γ-irradiation induced NO production via NF-κB activation. Although NF-κB is known to be a redox sensitive transcription factor, the antioxidant agents N-acetyl-cysteine and 6-hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylic acid (trolox) showed no suppression and treatment with H 2 O 2 showed only slight enhancement of NO production. The DNA damaging agents camptothecin and etoposide enhanced NO production and induced I-κB degradation. These results indicated that the increase in NO production was due to direct DNA damage, not to reactive oxygen species. Furthermore, 3-aminobenzamide and benzamide, inhibitors of poly (ADP-ribose) polymerase (PARP) that are activated upon recognition of DNA strand breaks, suppressed the increase in NO production and the I-κB degradation by γ-irradiation. We concluded that (1) the increase in NO production was due to direct DNA damage by γ- irradiation, and that (2) PARP activation through DNA damage induced NF-κB activation, leading to iNOS expression and NO production

  17. Quantitative determination of two polymorphic forms of imatinib mesylate in a drug substance and tablet formulation by X-ray powder diffraction, differential scanning calorimetry and attenuated total reflectance Fourier transform infrared spectroscopy.

    Science.gov (United States)

    Bellur Atici, Esen; Karlığa, Bekir

    2015-10-10

    Imatinib has been identified as a tyrosine kinase inhibitor that selectively inhibits the Abl tyrosine kinases, including Bcr-Abl. The active substance used in drug product is the mesylate salt form of imatinib, a phenylaminopyrimidine derivative and chemically named as N-(3-(4-(pyridin-3-yl) pyrimidin-2-ylamino)-4-methylphenyl)-4-((4-methylpiperazin-1-yl) methyl)-benzamide methanesulfonic acid salt. It exhibits many polymorphic forms and most stable and commercialized polymorphs are known as α and β forms. Molecules in α and β polymorphic forms exhibit significant conformational differences due to their different intra- and intermolecular interactions, which stabilize their molecular conformations and affect their physicochemical properties such as bulk density, melting point, solubility, stability, and processability. The manufacturing process of a drug tablet included granulation, compression, coating, and drying may cause polymorphic conversions. Therefore, polymorphic content of the drug substance should be controlled during quality control and stability testing. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD) methods were evaluated for determination of the polymorphic content of the drug substance and drug product; and PXRD was the most accurate technique and selected as preferred method and validated. Prior to development of a quantification method, pure α and β polymorphs were characterized and used throughout the method development and validation studies. Mixtures with different ratios of α and β forms were scanned using X-ray diffractometer with a scan rate of 0.250°/min over an angular range of 19.5-21.0° 2θ and the peak heights for characteristic peak of β form at 20.5 ± 0.2° 2θ diffraction angle were used to generate a calibration curve. The detection limit of β polymorph in α form imatinib mesylate tablets was found as 4% and

  18. On-line solid phase extraction-high performance liquid chromatography–isotope dilution–tandem mass spectrometry approach to quantify N,N-diethyl-m-toluamide and oxidative metabolites in urine

    International Nuclear Information System (INIS)

    Graphical abstract: -- Highlights: •A fast assay to quantify the concentrations of N,N-Diethyl-m-Toluamide and two urinary metabolites was developed •It uses online SPE, reversed phase HPLC and tandem mass spectrometry •The method is precise and accurate with limits of detection ≤1 ng mL−1 -- Abstract: Human exposure to N,N-diethyl-m-toluamide (DEET) occurs because of the widespread use of DEET as an active ingredient in insect repellents. However, information on the extent of such exposure is rather limited. Therefore, we developed a fast on-line solid phase extraction–high performance liquid chromatography–isotope dilution tandem mass spectrometry (HPLC-MS/MS) method to measure in urine the concentrations of DEET and two of its oxidative metabolites: N,N-diethyl-3-(hydroxymethyl)benzamide and 3-(diethylcarbamoyl)benzoic acid (DCBA). To the best of our knowledge, this is the first HPLC-MS/MS method for the simultaneous quantification of DEET and its select metabolites in human urine. After enzymatic hydrolysis of the conjugated species in 0.1 mL of urine, the target analytes were retained and pre-concentrated on a monolithic column, separated from each other and from other urinary biomolecules on a reversed-phase analytical column, and detected by atmospheric pressure chemical ionization in positive ion mode. The limits of detection ranged from 0.1 ng mL−1 to 1.0 ng mL−1, depending on the analyte. Accuracy ranged between 90.4 and 104.9%, and precision ranged between 5.5 and 13.1% RSD, depending on the analyte and the concentration. We tested the usefulness of this method by analyzing 75 urine samples collected anonymously in the Southeastern United States in June 2012 from adults with no known exposure to DEET. Thirty eight samples (51%) tested positive for at least one of the analytes. We detected DCBA most frequently and at the highest concentrations. Our results suggest that this method can be used for the analysis of a large number of samples

  19. Human umbilical cord blood mesenchymal stem cell transplantation for the treatment of hepatic cirrhosis in rats%人脐血间充质干细胞移植治疗大鼠肝硬化模型*

    Institute of Scientific and Technical Information of China (English)

    詹三华; 张鲁峰; 姚卫民; 杨明辉; 宋晓玲; 焦红亮

    2013-01-01

    BACKGROUND:Studies have shown that cord blood mesenchymal stem cel s can be induced into hepatocyte-like cel s in a specific environment, and the transplanted cel s can exercise the normal function of liver cel s. OBJECTIVE:To establish the rat model of hepatic cirrhosis induced with carbon tetrachloride, and to observe the therapeutic effect of umbilical cord blood mesenchymal stem cel transplantation on a rat model of hepatic cirrhosis. METHODS:Hepatic cirrhosis models were established through carbon tetrachloride inducing, then 20 rat models of hepatic cirrhosis were randomly divided into two groups. The control group was injected with 0.5 mL normal saline via the tail vein;the treatment group was injected with chloromethyl benzamide labeled umbilical cord blood mesenchymal stem cel suspension, and the number of the stem cel s was 1×106. After 2 weeks, al animals were sacrificed. Liver tissues were obtained for the histological observation and the venous blood was col ected to detected the liver function indicators. RESULTS AND CONCLUSION:The liver cel s of the hepatic cirrhosis models were loose and cloudy swel ing, part of the cel s were degenerated and necrosis, the structure of the hepatic lobule was vague, and several pseudolobules with different sizes were formed which meet the diagnostic criteria of hepatic cirrhosis. Compared with the control group, the level of serum albumin in the treatment group was significantly increased (P<0.05), while the levels of bilirubin and transaminases in the treatment group were significantly decreased (P<0.05). There were lots of red chloromethyl benzamide labeled umbilical cord blood mesenchymal stem cel s in the liver tissue of the treatment group. Human umbilical cord blood mesenchymal stem cel s can effectively improve the physiological function of hepatic cirrhosis through tail vein.%  背景:研究表明,脐血间充质干细胞可在特定环境下诱导为肝样细胞,移植入体内能行使正常肝

  20. On the clinical impact of cerebral dopamine D{sub 2} receptor scintigraphy; Zur klinischen Wertigkeit der zerebralen Dopamin-D{sub 2}-Rezeptorszintigraphie

    Energy Technology Data Exchange (ETDEWEB)

    Larisch, R. [Duesseldorf Univ. (Germany). Klinik fuer Nuklearmedizin; Klimke, A. [Duesseldorf Univ. (Germany). Psychiatrische Klinik

    1998-12-31

    The present review describes findings and clinical indications for the dopamine D{sub 2} receptor scintigraphy. Methods for the examination of D{sub 2} receptors are positron emission tomography (PET) using {sup 11}C- or {sup 18}F-labelled butyrophenones or benzamides or single photon emission tomography (SPECT) using {sup 123}I-iodobenzamide (IBZM) respectively. The most important indication in neurology is the differential diagnosis of Parkinsonism: Patients with early Parkinson`s disease show an increased D{sub 2} receptor binding (D{sub 2}-RB) compared to control subjects. However, patients suffering from Steele-Richardson-Olszewski-Syndrome or Multiple System Atrophy show a decreased D{sub 2}-RB and are generally non-responsive to treatment. Postsynaptic blockade of D{sub 2} receptors results in a drug induced Parkinsonian syndrome, which can be diagnosed by D{sub 2} scintigraphy. Further possible indications occur in psychiatry: The assessment of receptor occupancy is useful in schizophrenic patients treated with neuroleptics. Additionally, D{sub 2} receptor scintigraphy might help to clarify the differential diagnosis between neuroleptic malignant syndrome and lethal catatonia. The method might be useful for supervising neurobiochemical changes in drug dependency and during withdrawal. Assessment of dopamine D{sub 2} receptor binding can simplify the choice of therapy in depressive disorder: Patients showing a low D{sub 2} binding are likely to improve following an antidepressive drug treatment whereas sleep deprivation is promising in patients with high D{sub 2} binding. (orig.) [Deutsch] Die vorliegende Arbeit gibt eine Uebersicht ueber Befunde und klinische Indikationen zur Dopamin-D{sub 2}-Rezeptorszintigraphie. Methoden zur Untersuchung der D{sub 2}-Rezeptoren sind die Positronen-Emissions-Tomographie (PET) mit {sup 11}C- oder {sup 18}F-markierten Butyrophenonen oder Benzamiden oder die Einzelphotonen-Emissions-Tomographie (SPECT) mit {sup 123}I

  1. 查尔酮类似化合物的合成及其抑菌活性研究%Study on Synthesis and Antifungal Activity of Chalcone Analogues

    Institute of Scientific and Technical Information of China (English)

    田珈源; 罗青春; 梁华忠; 谌晓洪

    2011-01-01

    [目的]合成查尔酮类似化合物,并研究其抑菌活性,以寻找高效、安全的抑菌活性化合物.[方法]以苯甲酰氯类化合物和胺类化合物为原料,通过酰氯的胺解反应设计并合成了16种查尔酮类似化合物,对其分子结构经红外光谱(IR)和氢核磁共振波谱(1H NMR)进行确认.[结果]该类化合物具有一定的抑菌活性,当浓度为100 mg/L时,化合物A2(2-氯-N-苯基苯甲酰胺)对水稻纹枯病(Rhizoctonia solani)和油菜菌核病菌(Sclerotiua sclerotiorum的抑制率分别达90.27%和92.56%.[结论]产物A2为查尔酮的类似化合物,且属于天然产物,在自然界中能够自然降解,不会引起环境污染;而且其化学结构简单,人工合成也比较容易,可以以此为先导化合物对其结构进行优化和改造;研究其结构和活性之间的关系,开发出高效、低毒、对非靶标生物安全的新型抑菌剂.%[Objective] To synthesize chalcone analogues and study their antifungal activity so as to find high-efficient and safe compounds with antifungal activity. [Method] With benzoyl chloride compounds and amines as the materials, 16 chalcone analogues were designed and synthe sized through the aminolysis reaction of acyl chloride, and their molecular structures were determined by IR and ' H NMR. [ Result ] The chal cone analogues had certain antifungal activity. The antifungal rate of 100 mg/L compound A2 (2-chloro-N-phenyl benzamide) against Rhizoctonia solani and Sclerotiua sclerotiorum reached 90. 27% and 92.56% , respectively. [Conclusion] Product A2 was an analogue of the natural product chalcone that could naturally degrade without causing environmental pollution. What's more, its chemical structure was simple and easy to pre pare. Using A2 as a lead compound, new high-efficient and low-toxic antifungal agents which were safe to the non-target organisms could be de veloped through optimizing its chemical structure and studying the relationship

  2. Radiopharmaceuticals targeting melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Pham, T.Q.; Berghofer, P.; Liu, X.; Greguric, I.; Dikic, B.; Ballantyne, P.; Mattner, F.; Nguyen, V.; Loc' h, C.; Katsifis, A. [Radiopharmaceuticals Research Institute, Australian Nuclear Science and Technology Organisation, Menai, N.S.W., Sydney (Australia)

    2008-02-15

    Melanoma is one of the most aggressive cancers known with a high rate of mortality and increasing global incidence. So, the development of radiopharmaceuticals for either diagnostic or therapeutic purposes could make enormous contributions to melanoma patient health care. We have been studying melanoma tumours through several targeting mechanisms including melanin or specific receptor based radiopharmaceuticals Structure activity studies indicate that the substitution patterns on radioiodinated benzamides significantly influence the uptake mechanism from melanin to sigma-receptor binding. Furthermore, the position of the iodine as well as the presence of key functional groups and substituents has resulted in compounds with varying degrees of activity uptake and retention in tumours. From these results, a novel molecule 2-(2-(4-(4-iodo benzyl)piperazin-1-yl)-2-oxo-ethyl)isoindoline- 1,3-dione (M.E.L.037) was synthesized, labelled with iodine-123 and evaluated for application in melanoma tumour scintigraphy and radiotherapy. The tumour imaging potential of {sup 123}IM.E.L.037 was studied in vivo in C.57 B.L./ 6 J female mice bearing the B.16 F.0. murine melanoma tumour and in BALB/c nude mice bearing the A.375 human amelanotic melanoma tumour by biodistribution, competition studies and by SPECT imaging. {sup 123}I-M.E.L.037 exhibited high and rapid uptake in the B.16 F.0 melanoma tumour at 1 h (13 % I.D./g) increasing with time to reach 25 % I.D./g at 6 h. A significant uptake was also observed in the eyes (2% I.D., at 3-6 h p.i.) of black mice. No uptake was observed in the tumour or in the eyes of nude mice bearing the A.375 tumour. Due to high uptake and long retention in the tumour and rapid body clearance, standardized uptake values(S.U.V.) of {sup 123}I-M.E.L.037 were 30 and 60, at 24 and 48 h p.i.,respectively. SPECT imaging of mice bearing the B.16 melanoma indicated the radioactivity was predominately located in the tumour followed by the eyes, while no

  3. Clinical study of dopamine transporter imaging with 131I-epidepride for Parkinson's disease%多巴胺D2受体乃131I-epidepride显像对帕金森病的临床研究

    Institute of Scientific and Technical Information of China (English)

    武婕; 王峰; 杨敏; 王自正; 孟庆乐; 过燕萍

    2008-01-01

    Objective Epidepride is a novel benzamide derivative with high affinity for dopaminergic D2 receptors.It has been used to study striatal and extrastriatal D2 receptor abnormalities in humans.The aim of this study was to evaluate the level of D2 receptors in dopaminergic nitrostriatal pathway and its correlation with clinical severity in Parkinson's disease(PD).Methods Thirty-eight patients with idio-pathic PD[graded according to Hoehn and Yahr(H/Y)stage:n(Ⅰ)=13,n(Ⅱ)=11,n(Ⅲ)=8,n(Ⅳ)=6]and 12 healthy volunteers as control were included in this study.SPECT brain imaging was performed 3 h after 18.5 MBq 131I-epidepride administration.Regions of interest(ROIs)were drawn over the striatum(ST)and occipital cortex(OC).The ratios of ST to OC ROI counts(ST/OC)were calculated and correlated with clinical severity H/Y stage.SPSS 10.0 was used for data analysis,the t test and Spearman correlation analysis were used.Results ST showed intense uptake of 131I-epidepride,whereas frontal,parietal,temporal,occipital lobes and cerebellum showed low uptake in control group.Increased 131I-epide-pride uptake was observed in PD patients when compared with normal control group but without statistically significant difference.Early stage patients(hemi-PD with H/Y I)showed increased [131]I-epidepride uptake intensity and size in contralateral ST(especially caudate nucleus)significantly more than unilateral ST(t=7.89.P<0.05).ST/OC ratio was not found to be statistically significant when correlated with the clinical severity H/Y stage(r=0.1 2,P>0.05).Conclusions This study suggested that 131I-epidepride SPECT was useful in qualitative and quantitative evaluation of D2 receptor status in dopaminergic nigrostriatal neurons,which were over-expressed in PD patients.However,no statistically significant correlation was,found between ST 131I-epidepride binding ratios and disease severity.%目的 评价多巴胺D2受体显像剂131I-(s)-(-)-N-[(1-乙基-2-吡咯烷基)甲基]-5-碘-2,3-二

  4. Novel 99mTc labeled

    Institute of Scientific and Technical Information of China (English)

    FAN; Caiyun

    2006-01-01

    [1]Quirion,R.,Bowen,W.D.,Itzhak,Y.et al.,A proposal for the classification of sigma binding sites,Trends Pharmacol.Sci.,1992,13:85-86.[2]Su,T.P.,Sigma receptors:Putative links between nervous,endocrine and immune systems,Eur.J.Biochem.,1991,200:633-642.[3]Guitart,X.,Codony,X.,Monroy,X.,Sigma receptors:Biology and therapeutic potential,Psychopharmacology,2004,174:301-319.[4]Vilner,B.J.,John,C.S.,Bowen,W.D.,Sigma-1 and sigma-2 receptors are expressed in a wide variety of human and rodent tumor cell lines,Cancer Res.,1995,55:408-413.[5]Mach,R.H.,Smith,C.R.,al-Nabulsi,I.et al.,σ2 receptors as potential biomarkers of proliferation in breast cancer,Cancer Res.,1997,57:156-161.[6]Shiue,C.Y.,Shiue,G.G.,Zhang,S.X.et al.,N-(N-benzylpi-peridin-4-yl)-2-[18F]fluorobenzamide:A potential ligand for PET imaging of σ receptors,Nucl.Med.Biol.,1997,24:671-676.[7]Dence,C.S.,John,C.S.,Bowen,W.D.et al.,Synthesis and evaluation of [18F] labeled benzamides:High affinity sigma receptor ligands for PET imaging,Nucl.Med.Biol.,1997,24:333-340.[8]Shiue,C.Y.,Shiue,G.G.,Benard,F.et al.,N-(N-benzylpi-peridin-4-yl)-2-[18F]fluorobenzamide:A potential ligand for PET imaging of breast cancer,Nucl.Med.Biol.,2000,27:763-767.[9]Rowland,D.J.,Tu,Z.,Mach,R.H.et al.,Investigation of a new sigma-2 receptor ligand for detection of breast cancer,J.Labelled Cpd.Radiopharm.,2003,46:S6.[10]Everaert,H.,Flamen,P.,Franken,P.R.et al.,Sigma receptor imaging by means of 123-IDAB scintigraphy;clinical application in melanoma and non-small cell lung cancer,Anticancer Res.,1997,17:1577-1582.[11]John,C.S.,Gulden,M.E.,Li,J.et al.,Synthesis,in vitro binding,and tissue distribution of radioiodinated 2-[125I]N-(N-benzylpip-eridin-4-yl)-2-iodobenzamide,2-[125I]BP:A potential σ receptor marker for human prostate tumors,Nucl.Med.Biol.,1998,25:189-194.[12]Staelens,L.,Oltenfreiter,R.,Dumont,F.et al.,In vivo evaluation of [123I]-4-iodo-N-(4-(4-(2-me-thoxyphenyl)-piperazin-1-yl)butyl)-benzamide:A potential sigma receptor ligand