Design, Synthesis and Antitumor Activity of Novel 4-Methyl-(3'S,4'S-cis-khellactone Derivatives

Directory of Open Access Journals (Sweden)

Taigang Liang

2013-04-01

Full Text Available An asymmetric synthesis of a series of novel 4-methyl-(3'S,4'S-cis-khellactone derivatives 3a–o is reported for the first time. Their structures were confirmed by 1H-NMR, 13C-NMR and MS. Their cytotoxic activity was evaluated by the MTT assay against three selected human cancer cell lines: HEPG-2 (human liver carcinoma, SGC-7901 (human gastric carcinoma, LS174T (human colon carcinoma. Some compounds showed high inhibitory activity against these human cancer cell lines. Among them, compound 3a exhibited strong cytotoxicity, with IC50 values ranging from 8.51 to 29.65 μM. The results showed that 4-methyl-cis-khellactone derivatives with S,S configuration could be a potential antitumor agents.

Mitochondrial toxicity of selective COX-2 inhibitors via inhibition of oxidative phosphorylation (ATP synthesis) in rat liver mitochondria

DEFF Research Database (Denmark)

Syed, Muzeeb; Skonberg, Christian; Hansen, Steen Honoré

2016-01-01

Cyclooxygenase-2 (COX-2) inhibitors (coxibs) are non-steroidal anti-inflammatory drugs (NSAIDs) designed to selectively inhibit COX-2. However, drugs of this therapeutic class are associated with drug induced liver injury (DILI) and mitochondrial injury is likely to play a role. The effects...... of selective COX-2 inhibitors on inhibition of oxidative phosphorylation (ATP synthesis) in rat liver mitochondria were investigated. The order of potency of inhibition of ATP synthesis was: lumiracoxib (IC50: 6.48 ± 2.74 μM)>celecoxib (IC50: 14.92 ± 6.40 μM)>valdecoxib (IC50: 161.4 ± 28.6 μM)>rofecoxib (IC50...... correlation (with r(2)=0.921) was observed between the potency of inhibition of ATP synthesis and the log P values. The in vitro metabolism of coxibs in rat liver mitochondria yielded for each drug substance a major single metabolite and identified a hydroxy metabolite with each of the coxibs...

A new practical method for the preparation of [3H6]-leukotrienes C4 and D4

International Nuclear Information System (INIS)

Belley, M.L.; Gareau, Y.; Zamboni, R.J.; Ahern, D.G.; Yang Hong

1995-01-01

A new method for the synthesis of highly deuterated or tritiated leukotrienes was developed. The higher reactivity of a terminal alkene compared to a 1,2-disubstituted one permitted the selective deuteration or tritiation of the diyne 14,15,19,19,20,20-hexadehydro LTC 4 troester 1. After hydrolysis, LTC 4 was obtained in 36% overall yield. An average of seven deuterium or tritium atoms was incorporated and the specific activity of the tritiated LTC 4 was greater than 180Ci/mmol. 1 was obtained from the addition of glutathione to 14,15,19,19,20,20-hexadehydro LTA 4 ethyl ester which was the product of a Wittig reaction between (3,8-nonanediyn-1-yl) triphenylphosphonium iodide and 5(S), 6(S), 7(E), 9(E) ethyl 5,6-epoxy-11-oxo-7,9-undecadienoate. (Author)

Release of leukotriene C4 from human polymorphonuclear leucocytes as determined by radioimmunoassay

International Nuclear Information System (INIS)

Aehringhaus, U.; Woelbling, R.H.; Peskar, B.M.; Peskar, B.A.; Koenig, W.; Patrono, C.

1982-01-01

Rabbits were immunized with a conjugate of leukotriene (LT)C 4 and bovine serum albumin prepared by coupling the single free amino group of the hapten to the protein using gluteraldehyde. Binding of [ 3 H]LTC 4 to the antibodies obtained is inhibited by 50% with 1.5 ng LTC 4 . The relative cross-section of LTD 4 is 16% and of LTC 4 -methyl ester 3.6%. The validity of the radioimmunoassay was demonstrated by comparison with bioassay using the isolated guinea pig ileum. Using the radioimmunoassay it could be shown that endogenous LTC 4 is released in a dose-dependent manner by human polymorphonuclear leucocytes stimulated with the divalent cation ionophore A23187. (Auth.)

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

DEFF Research Database (Denmark)

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

2003-01-01

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

A novel application of t-statistics to objectively assess the quality of IC50 fits for P-glycoprotein and other transporters.

Science.gov (United States)

O'Connor, Michael; Lee, Caroline; Ellens, Harma; Bentz, Joe

2015-02-01

Current USFDA and EMA guidance for drug transporter interactions is dependent on IC50 measurements as these are utilized in determining whether a clinical interaction study is warranted. It is therefore important not only to standardize transport inhibition assay systems but also to develop uniform statistical criteria with associated probability statements for generation of robust IC50 values, which can be easily adopted across the industry. The current work provides a quantitative examination of critical factors affecting the quality of IC50 fits for P-gp inhibition through simulations of perfect data with randomly added error as commonly observed in the large data set collected by the P-gp IC50 initiative. The types of errors simulated were (1) variability in replicate measures of transport activity; (2) transformations of error-contaminated transport activity data prior to IC50 fitting (such as performed when determining an IC50 for inhibition of P-gp based on efflux ratio); and (3) the lack of well defined "no inhibition" and "complete inhibition" plateaus. The effect of the algorithm used in fitting the inhibition curve (e.g., two or three parameter fits) was also investigated. These simulations provide strong quantitative support for the recommendations provided in Bentz et al. (2013) for the determination of IC50 values for P-gp and demonstrate the adverse effect of data transformation prior to fitting. Furthermore, the simulations validate uniform statistical criteria for robust IC50 fits in general, which can be easily implemented across the industry. A calibration of the t-statistic is provided through calculation of confidence intervals associated with the t-statistic.

FINAL Report LTC-DOE DE-EE0000537

Energy Technology Data Exchange (ETDEWEB)

Gibbs, Michelle [Lakeshore Technical College, Cleveland, WI (United States)

2013-02-28

At the time of LTC’s application we were home to a small / mid-sized Wind Energy Research and Teaching Center, funded in part by We Energies, and offered the state of Wisconsin’s first Associate of Applied Science (A.A.S.) Degree in Wind Energy Technology. With President Obama promising investment in wind, LTC and its partners were uniquely situated to meet the challenge through an organized career pathways approach that utilized industry drivers and occupationally verified curriculum to train the workers who “transform our energy sector.” LTC’s employer partners validated the findings of the “20% Wind Energy by 2030: Increasing Wind Energy's Contribution to U.S. Electricity Supply” report by the US Department of Energy which recognized programs like LTC’s as an “excellent beginning,” noting that many more like them are necessary to meet the challenges of the 20% Wind scenario.One of the focuses of the study was the lack of trained technicians to work on installation and maintenance of renewables (and more specifically for our grant application wind turbines). LTC’s goal, made possible with the funding provided in this grant, was to increase the number of skilled graduates to help meet this national objective. LTC was already a leader in wind for the state of Wisconsin but wanted to upscale from a single school to a statewide (and potentially regional) center for wind energy. LTC planned to leverage our facilities, curriculum, and faculty expertise to meet this goal.

Synthesis and antiproliferative activity of diethyl 5- acetyl-4-methyl- 6 ...

African Journals Online (AJOL)

Diethyl 5-acetyl-4-methyl-6-(2-fluorophenylimino)-6H-thiopyran-2,3-dicarboxylate (3TM) was synthesized and the antiproliferative activity of 3TM is reported here. Compound 3TM inhibits the growth of human colon cancer HCT-15 with an IC50 value of 4.5 μM and breast cancer MCF-7 with an IC50 value of 7 μM in a ...

A European classification of services for long-term care—the EU-project eDESDE-LTC

Science.gov (United States)

Weber, Germain; Brehmer, Barbara; Zeilinger, Elisabeth; Salvador-Carulla, Luis

2009-01-01

Purpose and theory The eDESDE-LTC project aims at developing an operational system for coding, mapping and comparing services for long-term care (LTC) across EU. The projects strategy is to improve EU listing and access to relevant sources of healthcare information via development of SEMANTIC INTER-OPERABILITY in eHEALTH (coding and listing of services for LTC); to increase access to relevant sources of information on LTC services, and to improve linkages between national and regional websites; to foster cooperation with international organizations (OECD). Methods This operational system will include a standard classification of main types of care for persons with LTC needs and an instrument for mapping and standard description of services. These instruments are based on previous classification systems for mental health services (ESMS), disabilities services (DESDE) and ageing services (DESDAE). A Delphi panel made by seven partners developed a DESDE-LTC beta version, which was translated into six languages. The feasibility of DESDE-LTC is tested in six countries using national focal groups. Then the final version will be developed by the Delphi panel, a webpage, training material and course will be carried out. Results and conclusions The eDESDE-LTC system will be piloted in two EU countries (Spain and Bulgaria). Evaluation will focus primarily on usability and impact analysis. Discussion The added value of this project is related to the right of “having access to high-quality healthcare when and where it is needed” by EU citizens. Due to semantic variability and service complexity, existing national listings of services do not provide an adequate framework for patient mobility.

Identification of natural antimicrobial agents to treat dengue infection: In vitro analysis of latarcin peptide activity against dengue virus.

Science.gov (United States)

Rothan, Hussin A; Bahrani, Hirbod; Rahman, Noorsaadah Abd; Yusof, Rohana

2014-05-31

Although there have been considerable advances in the study of dengue virus, no vaccines or anti-dengue drugs are currently available for humans. Therefore, new approaches are necessary for the development of potent anti-dengue drugs. Natural antimicrobial peptides (AMPs) with potent antiviral activities are potential hits-to-leads for antiviral drug discovery. We performed this study to identify and characterise the inhibitory potential of the latarcin peptide (Ltc 1, SMWSGMWRRKLKKLRNALKKKLKGE) against dengue virus replication in infected cells. The Ltc 1 peptide showed a significantly inhibitory effect against the dengue protease NS2B-NS3pro at 37°C, a physiological human temperature, (IC50, 12.68 ± 3.2 μM), and greater inhibitory effect was observed at 40°C, a temperature similar to a high fever (IC50, 6.58 ± 4.1 μM). A greater reduction in viral load (p.f.u./ml) was observed at simultaneous (0.7 ± 0.3 vs. 7.2 ± 0.5 control) and post-treatment (1.8 ± 0.7 vs. 6.8 ± 0.6 control) compared to the pre-treatment (4.5 ± 0.6 vs. 6.9 ± 0.5 control). Treatment with the Ltc 1 peptide reduced the viral RNA in a dose-dependent manner with EC50 values of 8.3 ± 1.2, 7.6 ± 2.7 and 6.8 ± 2.5 μM at 24, 48 and 72 h, respectively. The Ltc 1 peptide exhibited significant inhibitory effects against dengue NS2B-NS3pro and virus replication in the infected cells. Therefore, further investigation is necessary to develop the Ltc 1 peptide as a new anti-dengue therapeutic.

Chemotaxis of primitive hematopoietic cells in response to stromal cell–derived factor-1

Science.gov (United States)

Jo, Deog-Yeon; Rafii, Shahin; Hamada, Tsuneyoshi; Moore, Malcolm A.S.

2000-01-01

Stromal cell–derived factor-1 (SDF-1) provides a potent chemotactic stimulus for CD34+ hematopoietic cells. We cultured mobilized peripheral blood (PB) and umbilical cord blood (CB) for up to 5 weeks and examined the migratory activity of cobblestone area–forming cells (CAFCs) and long-term culture–initiating cells (LTC-ICs) in a transwell assay. In this system, SDF-1 or MS-5 marrow stromal cells placed in the lower chamber induced transmembrane and transendothelial migration by 2- and 5-week-old CAFCs and LTC-ICs in 3 hours. Transmigration was blocked by preincubation of input CD34+ cells with antibody to CXCR4. Transendothelial migration of CB CAFCs and LTC-ICs was higher than that of PB. We expanded CD34+ cells from CB in serum-free medium with thrombopoietin, flk-2 ligand, and c-kit ligand, with or without IL-3 and found that CAFCs cultured in the absence of IL-3 had a chemotactic response equivalent to noncultured cells, even after 5 weeks. However, addition of IL-3 to the culture reduced this response by 20–50%. These data indicate that SDF-1 induces chemotaxis of primitive hematopoietic cells signaling through CXCR4 and that the chemoattraction could be downmodulated by culture ex vivo. PMID:10619866

Analysis of ATLAS LTC-04R Test for Loop Seal Reformation Phenomena using RELAP5

Energy Technology Data Exchange (ETDEWEB)

Lim, Sang-Gyu; Kim, Dae-Hun; Kim, Han-Gon [KHNP CRI, Daejeon (Korea, Republic of)

2016-10-15

The loop seal reformation issue was selected to be the analysis topic of the DSP-04 based on the technical discussion between the participants and the operating agencies (KAERI and KINS) and domestic experts meetings. After that, KAERI performed LTC-04R test which is 4 inch top-slot cold-leg break test using ATLAS facility in December 27, 2015. KHNP CRI, as a participant of the DSP-04, performed the blind calculation and open calculation using RELAP5/Mod3.3 patch 3. This paper deals with the results of open calculation for ATLAS LTC-04R test. The results of several sensitivity analyses such as the critical flow modeling sensitivity and break flow system modeling sensitivity will be discussed. Several possible factors in the loop seal reformation behavior are examined in the sensitivity analysis. Heat loss modeling, fine break system modeling, fine loop seal nodalization and off-take modeling are not significant factor in the loop seal reformation. Still critical flow model and discharge coefficient are dominant factors. Based on the ATLAS LTC-04R, Ransom-Trapp model shows better prediction in the break flow than the Henry-Fauske model.

Is there a role for leukotrienes as mediators of ethanol-induced gastric mucosal damage?

International Nuclear Information System (INIS)

Wallace, J.L.; Beck, P.L.; Morris, G.P.

1988-01-01

The role of leukotriene (LT) C 4 as a mediator of ethanol-induced gastric mucosal damage was investigated. Rats were pretreated with a number of compounds, including inhibitors of leukotriene biosynthesis and agents that have previously been shown to reduce ethanol-induced damage prior to oral administration of absolute ethanol. Ethanol administration resulted in a fourfold increase in LTC 4 synthesis. LTC 4 synthesis could be reduced significantly by pretreatment with L651,392 or dexamethosone without altering the susceptibility of the gastric mucosa to ethanol-induced damage. Furthermore, changes in LBT 4 synthesis paralleled the changes in LTC 4 synthesis observed after ethanol administration. The effects of ethanol on gastric eicosanoid synthesis were further examined using an ex vivo gastric chamber preparation that allowed for application of ethanol to only one side of the stomach. These studies confirm that ethanol can stimulate gastric leukotriene synthesis independent of the production of hemorrhagic damage. Inhibition of LTC 4 synthesis does not confer protection to the mucosa, suggesting that LTC 4 does not play an important role in the etiology of ethanol-induced gastric damage

Synthesis, docking and acetylcholinesterase inhibitory assessment of 2-(2-(4-Benzylpiperazin-1-yl)ethyl)isoindoline-1,3-dione derivatives with potential anti-Alzheimer effects

Science.gov (United States)

2013-01-01

Background Alzheimer’s disease (AD) as neurodegenerative disorder, is the most common form of dementia accounting for about 50-60% of the overall cases of dementia among persons over 65 years of age. Low acetylcholine (ACh) concentration in hippocampus and cortex areas of the brain is one of the main reasons for this disease. In recent years, acetylcholinesterase (AChE) inhibitors like donepezil with prevention of acetylcholine hydrolysis can enhance the duration of action of acetylcholine in synaptic cleft and improve the dementia associated with Alzheimer’s disease. Results Design, synthesis and assessment of anticholinesterase activity of 2-(2-(4-Benzylpiperazin-1-yl)ethyl)isoindoline-1,3-dione derivatives showed prepared compounds can function as potential acetylcholinesterase inhibitor. Among 12 synthesized derivatives, compound 4a with ortho chlorine moiety as electron withdrawing group exhibited the highest potency in these series (IC50 = 0.91 ± 0.045 μM) compared to donepezil (IC50 = 0.14 ± 0.03 μM). The results of the enzyme inhibition test (Ellman test) showed that electron withdrawing groups like Cl, F and NO2 can render the best effect at position ortho and para of the phenyl ring. But compound 4g with methoxy group at position 3(meta) afforded a favorable potency (IC50 = 5.5 ± 0.7 μM). Furthermore, docking study confirmed a same binding mode like donepezil for compound 4a. Conclusions Synthesized compounds 4a-4l could be proposed as potential anticholinesterase agents. PMID:23758724

Synthesis, Docking and Acetylcholinesterase Inhibitory Assessment of 2-(2-(4-Benzylpiperazin-1-YlEthylIsoindoline-1,3-Dione Derivatives with Potential Anti-Alzheimer Effects

Directory of Open Access Journals (Sweden)

Ahmad Mohammadi-Farani

2013-06-01

Full Text Available Background:Alzheimer’s disease (AD as neurodegenerative disorder, is the most common form of dementia accounting for about 50-60% of the overall cases of dementia among persons over 65 years of age. Low acetylcholine (ACh concentration in hippocampus and cortex areas of the brain is one of the main reasons for this disease. In recent years, acetylcholinesterase (AChE inhibitors like donepezil with prevention of acetylcholine hydrolysis can enhance the duration of action of acetylcholine in synaptic cleft and improve the dementia associated with Alzheimer’s disease.Results:Design, synthesis and assessment of anticholinesterase activity of 2-(2-(4-Benzylpiperazin-1-ylethylisoindoline-1,3-dione derivatives showed prepared compounds can function as potential acetylcholinesterase inhibitor. Among 12 synthesized derivatives, compound 4a with ortho chlorine moiety as electron withdrawing group exhibited the highest potency in these series (IC50 = 0.91 ± 0.045 μM compared to donepezil (IC50 = 0.14 ± 0.03 μM. The results of the enzyme inhibition test (Ellman test showed that electron withdrawing groups like Cl, F and NO2 can render the best effect at position ortho and para of the phenyl ring. But compound 4g with methoxy group at position 3(meta afforded a favorable potency (IC50 = 5.5 ± 0.7 μM. Furthermore, docking study confirmed a same binding mode like donepezil for compound 4a.Conclusions:Synthesized compounds 4a-4l could be proposed as potential anticholinesterase agents.

Nonlinear concentration gradients regulated by the width of channels for observation of half maximal inhibitory concentration (IC50) of transporter proteins.

Science.gov (United States)

Abe, Yuta; Kamiya, Koki; Osaki, Toshihisa; Sasaki, Hirotaka; Kawano, Ryuji; Miki, Norihisa; Takeuchi, Shoji

2015-08-21

This paper describes a simple microfluidic device that can generate nonlinear concentration gradients. We changed the "width" of channels that can drastically shorten the total microfluidic channel length and simplify the microfluidic network design rather than the "length" of channels. The logarithmic concentration gradients generated by the device were in good agreement with those obtained by simulation. Using this device, we evaluated a probable IC50 value of the ABC transporter proteins by the competitive transport assays at five different logarithmic concentrations. This probable IC50 value was in good agreement with an IC50 value (0.92 μM) obtained at the diluted concentrations of seven points.

Synthesis of 2,4,6-trichlorophenyl hydrazones and their inhibitory potential against glycation of protein.

Science.gov (United States)

Khan, Khalid Mohammed; Shah, Zarbad; Ahmad, Viqar Uddin; Khan, Momin; Taha, Muhammad; Rahim, Fazal; Jahan, Humera; Perveen, Shahnaz; Choudhary, M Iqbal

2011-11-01

2,4,6-Trichlorophenyl hydrazones 1-35 were synthesized and their in vitro antiglycation potential was evaluated. Compounds 14 (IC50 = 27.2 ± 0.00 μM), and 18 (IC50 = 55.7 ± 0.00 μM) showed an excellent activity against glycation of protein, better than the standard (rutin, IC50 = 70 ± 0.50 μM). This study thus identified a novel series of antiglycation agents. A structure-activity relationship has been studied, and all the compounds were characterized by spectroscopic techniques.

Focused library design and synthesis of 2-mercapto benzothiazole linked 1,2,4-oxadiazoles as COX-2/5-LOX inhibitors

Science.gov (United States)

Yatam, Satayanarayana; Gundla, Rambabu; Jadav, Surender Singh; Pedavenkatagari, Narayana reddy; Chimakurthy, Jithendra; Rani B, Namratha; Kedam, Thyagaraju

2018-05-01

Mercapto benzothiazole linked 1,2,4-oxadiazole derivatives were designed (4a-u) as new anti-inflammatory agents using bioisosteric approach and docking studies. The docking results clearly indicated that the compounds 4a-u shown good docking interaction towards COX-2 enzyme. In silico drug-like properties were also calculated for compounds (4a-u) and exhibited significant H-bond acceptor ratio. All compounds were synthesized and biologically evaluated using in vitro COX-1, COX-2 and 5-LOX assays. Compound 4k and 4q (IC50 = 6.8 μM and IC50 = 5.0 μM) found to be potent, selective COX-2 inhibitors and display better anti-inflammatory activity than standard Ibuprofen. Compound 4l and 4e found to be potent inhibitors against 5-LOX (IC50 = 5.1 μM and IC50 = 5.5 μM). The in vivo anti-inflammatory activity studies shown that the compounds 4q and 4k effectively reducing the paw edema volume at 3h and 5h than standard drug Ibuprofen. The DPPH radical scavenging activity provided anti-oxidant activity of compound 4e (IC50 = 25.6 μM) than reference standard Ascorbic acid.

Synthesis and antimalarial activity of new 4-amino-7-chloroquinolyl amides, sulfonamides, ureas and thioureas.

Science.gov (United States)

Ekoue-Kovi, Kekeli; Yearick, Kimberly; Iwaniuk, Daniel P; Natarajan, Jayakumar K; Alumasa, John; de Dios, Angel C; Roepe, Paul D; Wolf, Christian

2009-01-01

We report the synthesis and in vitro antimalarial activities of more than 50 7-chloro-4-aminoquinolyl-derived sulfonamides 3-8 and 11-26, ureas 19-22, thioureas 23-26, and amides 27-54. Many of the CQ analogues prepared for this study showed submicromolar antimalarial activity versus HB3 (chloroquine sensitive) and Dd2 (chloroquine resistant strains of Plasmodium falciparum) and low resistance indices were obtained in most cases. Systematic variation of the side chain length and introduction of fluorinated aliphatic and aromatic termini revealed promising leads that overcome CQ resistance. In particular, sulfonamide 3 exhibiting a short side chain with a terminal dansyl moiety combined high antiplasmodial potency with a low resistance index and showed IC(50)s of 17.5 and 22.7 nM against HB3 and Dd2 parasites.

Synthesis, antimicrobial and cytotoxic activities of 5-benzylidene-2-[(pyridine-4-ylmethylenehydrazono]-thiazolidin-4-one and 2-[(pyridine-4-ylmethylene hydrazono]-thiazolidin-4-one derivatives

Directory of Open Access Journals (Sweden)

Danniel Delmondes Feitoza

2012-01-01

Full Text Available A new series of 5-benzylidene-2-[(pyridine-4-ylmethylenehydrazono]-thiazolidin-4-ones 4a-l have been synthesized. These compounds were designed by a molecular hybridization approach. 2-[(Pyridine-4-ylmethylenehydrazono]-thiazolidin-4-ones 3a-d were also obtained and used as intermediates to give the target compounds. The in vitro antimicrobial and cytotoxic activities were evaluated for both series. The intermediate 3b showed considerable antibiotic activity against B. subtilis and C. albicans. In the cytotoxic activity compounds 3b (IC50= 4.25 ± 0.36 µg/mL and 4l (IC50= 1.38 ± 0.04 µg/mL were effective for inhibition of human erythromyeloblastoid leukemia (K-562 and human lung carcinoma (NCI-H292 cell lines, respectively.

LTC vacuum blasting machine (concrete): Baseline report

International Nuclear Information System (INIS)

1997-01-01

The LTC shot blast technology was tested and is being evaluated at Florida International University (FIU) as a baseline technology. In conjunction with FIU's evaluation of efficiency and cost, this report covers the evaluation conducted for safety and health issues. It is a commercially available technology and has been used for various projects at locations throughout the country. The LTC 1073 Vacuum Blasting Machine uses a high-capacity, direct-pressure blasting system which incorporates a continuous feed for the blast media. The blast media cleans the surface within the contained brush area of the blast. It incorporates a vacuum system which removes dust and debris from the surface as it is blasted. The safety and health evaluation during the testing demonstration focused on two main areas of exposure: dust and noise. Dust exposure during maintenance activities was minimal, but due to mechanical difficulties dust monitoring could not be conducted during operation. Noise exposure was significant. Further testing for each of these exposures is recommended because of the outdoor environment where the testing demonstration took place. This may cause the results to be inaccurate. It is feasible that the dust and noise levels will be higher in an enclosed environment. In addition, other safety and health issues found were ergonomics, heat stress, tripping hazards, electrical hazards, lockout/tagout, and arm-hand vibration

Synthesis, antimicrobial and cytotoxic activities of 5-benzylidene-2-[(pyridine-4-ylmethylene)hydrazono]-thiazolidin-4-one and 2-[(pyridine-4-ylmethylene) hydrazono]-thiazolidin-4-one derivatives

Energy Technology Data Exchange (ETDEWEB)

Feitoza, Danniel Delmondes; Alves, Antonio Jose; Lima, Jose Gildo de, E-mail: jgildolima@gmail.com [Departamento de Ciencias Farmaceuticas, Universidade Federal de Pernambuco, Recife - PE (Brazil); Araujo, Janete Magali; Aguiar, Jaciana Santos; Rodrigues, Maria do Desterro; Silva, Teresinha Goncalves; Nascimento, Silene Carneiro do; Goes, Alexandre Jose da Silva [Departamento de Antibioticos, Universidade Federal de Pernambuco, Recife - PE (Brazil)

2012-07-01

A new series of 5-benzylidene-2-[(pyridine-4-ylmethylene)hydrazono]-thiazolidin-4-ones 4a-l have been synthesized. These compounds were designed by a molecular hybridization approach. 2-[(Pyridine-4-ylmethylene)hydrazono]-thiazolidin-4-ones 3a-d were also obtained and used as intermediates to give the target compounds. The in vitro antimicrobial and cytotoxic activities were evaluated for both series. The intermediate 3b showed considerable antibiotic activity against B. subtilis and C. albicans. In the cytotoxic activity compounds 3b (IC{sub 50} = 4.25 +- 0.36 {mu}g/mL) and 4l (IC{sub 50} = 1.38 +- 0.04 {mu}g/mL) were effective for inhibition of human erythromyeloblastoid leukemia (K-562) and human lung carcinoma (NCI-H292) cell lines, respectively. (author)

2,2′,4,4′-Tetrabromodiphenyl ether (BDE-47) decreases progesterone synthesis through cAMP-PKA pathway and P450scc downregulation in mouse Leydig tumor cells

International Nuclear Information System (INIS)

Han, Xiumei; Tang, Rong; Chen, Xiaojiao; Xu, Bo; Qin, Yufeng; Wu, Wei; Hu, Yanhui; Xu, Bin; Song, Ling; Xia, Yankai; Wang, Xinru

2012-01-01

Polybrominated diphenyl ethers (PBDEs) are commonly used as flame retardants in textiles, plastics and electronics and represent a group of persistent environmental contaminants. They have been found to accumulate in human and marine mammals. Previous studies have shown that PBDEs have endocrine-disrupting properties and reproductive toxicity. However, the mechanisms under the reproductive disruptions are still not well understood. In this study, we explored the effects of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) on progesterone biosynthesis and possible mechanisms in mouse Leydig tumor cells (mLTC-1). Our results showed that BDE-47 could reduce progesterone production and decrease the intracellular cAMP level induced by hCG or forskolin. These suggested that BDE-47 decreasing progesterone production in mLTC-1 cells may be associated with the decline of intracellular cAMP level. Moreover, our data also indicated that the site G protein in cAMP-PKA pathway may be involved in this process. Furthermore, the addition of cAMP analog, 8-Br-cAMP, could not reverse the decrease of progesterone biosynthesis, indicating that a post-cAMP site (or sites) might be involved into the BDE-47-decreased progesterone production. In addition, we found BDE-47 reduced the activity of P450 side chain cleavage enzyme (P450scc), which was companied with the decline of P450scc mRNA and protein level in mLTC-1 cells. Put all together, these results suggested that progesterone synthesis decrease induced by BDE-47 may be associated with attenuation of cAMP generation and reduction of P450scc activity.

Design and synthesis of selective CDK8/19 dual inhibitors: Discovery of 4,5-dihydrothieno[3',4':3,4]benzo[1,2-d]isothiazole derivatives.

Science.gov (United States)

Ono, Koji; Banno, Hiroshi; Okaniwa, Masanori; Hirayama, Takaharu; Iwamura, Naoki; Hikichi, Yukiko; Murai, Saomi; Hasegawa, Maki; Hasegawa, Yuka; Yonemori, Kazuko; Hata, Akito; Aoyama, Kazunobu; Cary, Douglas R

2017-04-15

To develop a novel series of CDK8/19 dual inhibitors, we employed structure-based drug design using docking models based on a library compound, 4,5-dihydroimidazolo[3',4':3,4]benzo[1,2-d]isothiazole 16 bound to CDK8. We designed various [5,6,5]-fused tricyclic scaffolds bearing a carboxamide group to maintain predicted interactions with the backbone CO and NH of Ala100 in the CDK8 kinase hinge region. We found that 4,5-dihydrothieno[3',4':3,4]benzo[1,2-d]isothiazole derivative 29a showed particularly potent enzymatic inhibitory activity in both CDK8/19 (CDK8 IC 50 : 0.76nM, CDK19 IC 50 : 1.7nM). To improve the physicochemical properties and kinase selectivity of this compound, we introduced a substituted 3-pyridyloxy group into the scaffold 8-position. The resulting optimized compound 52h showed excellent in vitro potency (CDK8 IC 50 : 0.46nM, CDK19 IC 50 : 0.99nM), physicochemical properties, and kinase selectivity (only 5 kinases showed DMG activation loop. In vitro pharmacological evaluation of 52h revealed potent suppression of phosphorylated STAT1 in various cancer cells. The high oral bioavailability found for this compound enabled in vivo studies, in which we demonstrated a mechanism-based in vivo PD effect as well as tumor growth suppression in an RPMI8226 human hematopoietic and lymphoid xenograft model in mouse [T/C: -1% (2.5mg/kg, qd)]. Copyright © 2017 Elsevier Ltd. All rights reserved.

Design, synthesis and biological evaluations of N-Hydroxy thienopyrimidine-2,4-diones as inhibitors of HIV reverse transcriptase-associated RNase H.

Science.gov (United States)

Kankanala, Jayakanth; Kirby, Karen A; Huber, Andrew D; Casey, Mary C; Wilson, Daniel J; Sarafianos, Stefan G; Wang, Zhengqiang

2017-12-01

Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) is the only HIV enzymatic function not targeted by current antiviral drugs. Although various chemotypes have been reported to inhibit HIV RNase H, few have shown significant antiviral activities. We report herein the design, synthesis and biological evaluation of a novel N-hydroxy thienopyrimidine-2,3-dione chemotype (11) which potently and selectively inhibited RNase H with considerable potency against HIV-1 in cell culture. Current structure-activity-relationship (SAR) identified analogue 11d as a nanomolar inhibitor of RNase H (IC 50  = 0.04 μM) with decent antiviral potency (EC 50  = 7.4 μM) and no cytotoxicity (CC 50  > 100 μM). In extended biochemical assays compound 11d did not inhibit RT polymerase (pol) while inhibiting integrase strand transfer (INST) with 53 fold lower potency (IC 50  = 2.1 μM) than RNase H inhibition. Crystallographic and molecular modeling studies confirmed the RNase H active site binding mode. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

IC3 Internet and Computing Core Certification Global Standard 4 study guide

CERN Document Server

Rusen, Ciprian Adrian

2015-01-01

Hands-on IC3 prep, with expert instruction and loads of tools IC3: Internet and Computing Core Certification Global Standard 4 Study Guide is the ideal all-in-one resource for those preparing to take the exam for the internationally-recognized IT computing fundamentals credential. Designed to help candidates pinpoint weak areas while there's still time to brush up, this book provides one hundred percent coverage of the exam objectives for all three modules of the IC3-GS4 exam. Readers will find clear, concise information, hands-on examples, and self-paced exercises that demonstrate how to per

In vitro neuraminidase inhibitory concentration (IC50) of four neuraminidase inhibitors in the Japanese 2016-17 season: Comparison with the 2010-11 to 2015-16 seasons.

Science.gov (United States)

Ikematsu, Hideyuki; Kawai, Naoki; Iwaki, Norio; Kashiwagi, Seizaburo; Ishikawa, Yusuke; Yamaguchi, Hiroki; Shiosakai, Kazuhito

2018-05-11

To assess the extent of susceptibility to the four most commonly used neuraminidase inhibitors (NAIs) in the viruses epidemic in the 2016-17 Japanese influenza season, we measured the 50% inhibitory concentration (IC 50 ) of these NAIs for influenza virus isolates from patients and compared them with the results from the 2010-11 to 2015-16 seasons. Viral isolation was done with specimens obtained prior to treatment, and the type and subtype was determined by RT-PCR using type- and subtype-specific primers. The IC 50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. A total of 276 virus isolates, 6 A (H1N1)pdm09 (2.2%), 249 A (H3N2) (90.2%), and 21 B (7.6%), had the IC 50 measured for the four NAIs. B isolates included 11 (52.4%), 9 (42.9%), and one (4.8%) of the Victoria, Yamagata, and undetermined strains, respectively. No A (H1N1)pdm09 with highly reduced sensitivity for oseltamivir was found in the 2016-17 season. No isolate with highly reduced sensitivity to the four NAIs have been found for A (H3N2) or B from the 2010-11 to 2016-17 seasons. No significant trend of increase or decrease was found in the geometric mean IC 50 s of the four NAIs during the seven studied seasons. These results indicate that the sensitivity to the four commonly used NAIs has been maintained and that any change in the effectiveness of these NAIs would be minute. Common usage of NAIs for patient treatment has not been a driving force in the selection of NAI resistant viruses. Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Synthesis of chiral pyrazolo[4,3-e][1,2,4]triazine sulfonamides with tyrosinase and urease inhibitory activity.

Science.gov (United States)

Mojzych, Mariusz; Tarasiuk, Paweł; Kotwica-Mojzych, Katarzyna; Rafiq, Muhammad; Seo, Sung-Yum; Nicewicz, Michał; Fornal, Emilia

2017-12-01

A new series of sulfonamide derivatives of pyrazolo[4,3-e][1,2,4]triazine with chiral amino group has been synthesized and characterized. The compounds were tested for their tyrosinase and urease inhibitory activity. Evaluation of prepared derivatives demonstrated that compounds (8b) and (8j) are most potent mushroom tyrosinase inhibitors whereas all of the obtained compounds showed higher urease inhibitory activity than the standard thiourea. The compounds (8a), (8f) and (8i) exhibited excellent enzyme inhibitory activity with IC 50 0.037, 0.044 and 0.042 μM, respectively, while IC 50 of thiourea is 20.9 μM.

Green synthesis palladium nanoparticles mediated by white tea (Camellia sinensis extract with antioxidant, antibacterial, and antiproliferative activities toward the human leukemia (MOLT-4 cell line

Directory of Open Access Journals (Sweden)

Azizi S

2017-12-01

Full Text Available Susan Azizi,1 Mahnaz Mahdavi Shahri,2 Heshu Sulaiman Rahman,3–5 Raha Abdul Rahim,6 Abdullah Rasedee,5 Rosfarizan Mohamad1,7 1Department of Bioprocess Technology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, UPM Serdang, Selangor, Malaysia; 2Department of Chemistry, Shiraz Branch, Islamic Azad University, Shiraz, Iran; 3College of Veterinary Medicine, University of Sulaimani, Sulaimani Nwe, 4College of Health Science, Komar University of Science and Technology (KUST, Chaq-Chaq Qularaise, Sulaimani City, Iraq; 5Faculty of Veterinary Medicine, 6Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, 7Laboratory of Biopolymer and Derivatives, Institute of Tropical Forestry and Forest Products, Universiti Putra Malaysia, UPM Serdang, Selangor, Malaysia Abstract: Among nanoparticles used for medical applications, palladium nanoparticles (PdNPs are among the least investigated. This study was undertaken to develop PdNPs by green synthesis using white tea (W.tea; Camellia sinensis extract to produce the Pd@W.tea NPs. The Pd@W.tea NPs were characterized by UV–vis spectroscopy and X-ray diffractometry, and evaluated with transmission electron microscopy (TEM and scanning electron microscopy (SEM. The Pd@W.tea NPs were spherical (size 6–18 nm and contained phenols and flavonoids acquired from the W.tea extract. Pd@W.tea NPs has good 1-diphenyl-2-picrylhydrazyl (DPPH, OH, and NO-scavenging properties as well as antibacterial effects toward Staphylococcus epidermidis and Escherichia coli. MTT assay showed that Pd@W.tea NPs (IC50 =0.006 µM were more antiproliferative toward the human leukemia (MOLT-4 cells than the W.tea extract (IC50 =0.894 µM, doxorubicin (IC50 =2.133 µM, or cisplatin (IC50 =0.013 µM, whereas they were relatively innocuous for normal human fibroblast (HDF-a cells. The anticancer cell effects of Pd@W.tea NPs are mediated through the induction of apoptosis

Variability in P-Glycoprotein Inhibitory Potency (IC50) Using Various in Vitro Experimental Systems: Implications for Universal Digoxin Drug- Drug Interaction Risk Assessment Decision Criterias

NARCIS (Netherlands)

Bentz, J.; O'Connor, M.P.; Bednarczyk, D.; Coleman, J.; Lee, C.; Palm, J.; Pak, Y.A.; Perloff, E.S.; Reyner, E.; Balimane, P.; Brännström, M.; Chu, X.; Funk, C.; Guo, A.; Hanna, I.; Herédi-Szabó, K.; Hillgren, K.; Li, L.; Hollnack-Pusch, E.; Jamei, M.; Lin, X.; Mason, A.K.; Neuhoff, S.; Patel, A.; Podila, L.; Plise, E.; Rajaraman, G.; Salphati, L.; Sands, E.; Taub, M.E.; Taur, J.-S.; Weitz, D.; Wortelboer, H.M.; Xia, C.Q.; Xiao, G.; Yabut, J.; Yamagata, T.; Zhang, L.; Ellens, H.

2013-01-01

A P-glycoprotein (P-gp) IC50 working group was established with 23 participating pharmaceutical and contract research laboratories and one academic institution to assess interlaboratory variability in P-gp IC 50 determinations. Each laboratory followed its in-house protocol to determine in vitro

Synthesis and biological evaluation of 5-carbamoyl-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors.

Science.gov (United States)

Goto, Taiji; Shiina, Akiko; Yoshino, Toshiharu; Mizukami, Kiyoshi; Hirahara, Kazuki; Suzuki, Osamu; Sogawa, Yoshitaka; Takahashi, Tomoko; Mikkaichi, Tsuyoshi; Nakao, Naoki; Takahashi, Mizuki; Hasegawa, Masashi; Sasaki, Shigeki

2013-11-15

5-Carbamoyl-2-phenylpyrimidine derivative 2 has been identified as a phosphodiesterase 4 (PDE4) inhibitor with moderate PDE4B inhibitory activity (IC50=200 nM). Modification of the carboxylic acid moiety of 2 gave N-neopentylacetamide derivative 10f, which had high in vitro PDE4B inhibitory activity (IC50=8.3 nM) and in vivo efficacy against lipopolysaccharide (LPS)-induced pulmonary neutrophilia in mice (ID50=16 mg/kg, ip). Furthermore, based on the X-ray crystallography of 10f bound to the human PDE4B catalytic domain, we designed 7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one derivative 39 which has a fused bicyclic lactam scaffold. Compound 39 exhibited excellent inhibitory activity against LPS-induced tumor necrosis factor alpha (TNF-α) production in mouse splenocytes (IC50=0.21 nM) and in vivo anti-inflammatory activity against LPS-induced pulmonary neutrophilia in mice (41% inhibition at a dose of 1.0 mg/kg, i.t.). Copyright © 2013 Elsevier Ltd. All rights reserved.

Synthesis of 2',4-dihydroxy-3-methoxychalcone and 2',4',4-trihydroxy-3-methoxychalcone as a candidate anticancer against cervical (WiDr), colon (HeLa), and breast (T47d) cancer cell lines in vitro

Science.gov (United States)

Matsjeh, Sabirin; Swasono, Respati Tri; Anwar, Chairil; Solikhah, Eti Nurwening; Lestari, Endang

2017-03-01

The compound 2',4-dihydroxy-3-methoxychalcone and 2',4',4-trihydroxy-3-methoxychalcone have been synthesized through Claisen-Schmidt reaction from 2-hydroxyacetophenone and 2,4-dihydroxyacetophenone with 4-hydroxy-3-methoxy benzaldehida (vanillin) in aqueous KOH 40% and KSF montmorillonite as catalyst in methanol. All these products were characterized by FT-IR, TLC Scanner, GC-MS, MS-Direct, and 1H-NMR and 13C-NMR spectrometer. Both of these compounds were tested citotoxycity activity as an anticancer against cervical, colon, and breast cancer cells (Hela, WiDr, and T47D cell lines) using MTT assay in vitro. Dose series given test solution concentration on Hela, WiDr, and T47D cells started from 6,25; 25; 50 and 100 µg/mL with incubation treatment for 24 hours. The result of study showed that the 2',4-dihydroxy-3-methoxychalcone as bright yellow crystal with the melting point of 114-115 °C and the yield of 13.77% and the 2',4',4-trihydroxy-3-methoxychalcone as bright yellow crystals with the melting point of 195-197 °C and the yield of 6%. Other 2',4-dihydroxy-3-methoxychalcone and 2',4',4-trihydroxy-3-methoxychalcone also exhibited cytotoxic activity against the cancer cell lines, with the 2',4',4-trihydroxy-3-methoxychalcone showed greater activities than the 2',4-dihydroxy-3-methoxychalcone in WiDr cell lines. The 2',4-dihydroxy-3-methoxychalcone and 2',4',4-trihydroxy-3-methoxychalcone exhibited strong anticancer activities with IC50 value below 20 µg/mL. The activity of 2',4',4-trihydroxy-3-methoxychalcone showed the most active against Hela and WiDr cell lines with IC50 value 8.53 and 2.66 µg/mL respectively, than T47D cell lines with IC50 value 24.61 µg/mL. The test results cytotoxic of 2',4-dihydroxy-3-methoxychalcone showed the most active against Hela and WiDr cell lines with IC50 value 12.80, 19.57 µg/mL than T47D cell lines with IC50 value of 20.73 µg/mL. IC50 value indicated that 2',4-dihydroxy-3-methoxychalcone and 2',4',4-trihydroxy-3

Synthesis and Heme Polymerization Inhibitory Activity (HPIA Assay of Antiplasmodium of (1-N-(3,4-Dimethoxybenzyl-1,10-Phenanthrolinium Bromide from Vanillin

Directory of Open Access Journals (Sweden)

Dhina Fitriastuti

2014-03-01

Full Text Available The synthesis of (1-N-(3,4-dimethoxy-benzyl-1,10-phenanthrolinium bromide had been conducted from vanillin. Heme polymerization inhibitory activity assay of the synthesized antiplasmodium has also been carried out. The first step of reaction was methylation of vanillin using dimethylsulfate and NaOH. The mixture was refluxed for 2 h to yield veratraldehyde in the form of light yellow solid (79% yield. Methylation product was reduced using sodium borohydride (NaBH4 with grinding method and yielded veratryl alcohol in the form of yellow liquid (98% yield. Veratryl alcohol was brominated using PBr3 to yield yellowish black liquid (85% yield. The final step was benzylation of 1,10-phenanthroline monohydrate with the synthesized veratryl bromide under reflux condition in acetone for 14 h to afford (1-N-(3,4-dimethoxy-benzyl-1,10-phenanthrolinium bromide (84% as yellow solid with melting point of 166-177 °C. The structures of products were characterized by FT-IR, GC-MS and 1H-NMR spectrometers. The results of heme polymerization inhibitory activity assay of (1-N-(3,4-dimethoxybenzyl-1,10-phenanthrolinium bromide showed that it had IC50 HPIA of 3.63 mM, while chloroquine had IC50 of4.37 mM. These results indicated that (1-N-(3,4-dimethoxybenzyl-1,10-phenanthrolinium bromide was more potential antiplasmodium than chloroquine.

Development of brain injury criteria (BrIC).

Science.gov (United States)

Takhounts, Erik G; Craig, Matthew J; Moorhouse, Kevin; McFadden, Joe; Hasija, Vikas

2013-11-01

Rotational motion of the head as a mechanism for brain injury was proposed back in the 1940s. Since then a multitude of research studies by various institutions were conducted to confirm/reject this hypothesis. Most of the studies were conducted on animals and concluded that rotational kinematics experienced by the animal's head may cause axonal deformations large enough to induce their functional deficit. Other studies utilized physical and mathematical models of human and animal heads to derive brain injury criteria based on deformation/pressure histories computed from their models. This study differs from the previous research in the following ways: first, it uses two different detailed mathematical models of human head (SIMon and GHBMC), each validated against various human brain response datasets; then establishes physical (strain and stress based) injury criteria for various types of brain injury based on scaled animal injury data; and finally, uses Anthropomorphic Test Devices (ATDs) (Hybrid III 50th Male, Hybrid III 5th Female, THOR 50th Male, ES-2re, SID-IIs, WorldSID 50th Male, and WorldSID 5th Female) test data (NCAP, pendulum, and frontal offset tests) to establish a kinematically based brain injury criterion (BrIC) for all ATDs. Similar procedures were applied to college football data where thousands of head impacts were recorded using a six degrees of freedom (6 DOF) instrumented helmet system. Since animal injury data used in derivation of BrIC were predominantly for diffuse axonal injury (DAI) type, which is currently an AIS 4+ injury, cumulative strain damage measure (CSDM) and maximum principal strain (MPS) were used to derive risk curves for AIS 4+ anatomic brain injuries. The AIS 1+, 2+, 3+, and 5+ risk curves for CSDM and MPS were then computed using the ratios between corresponding risk curves for head injury criterion (HIC) at a 50% risk. The risk curves for BrIC were then obtained from CSDM and MPS risk curves using the linear relationship

Synthesis and biological evaluation of 4-(2-fluorophenoxy)-3,3'-bipyridine derivatives as potential c-met inhibitors.

Science.gov (United States)

Zhao, Sijia; Zhang, Yu; Zhou, Hongyang; Xi, Shuancheng; Zou, Bin; Bao, Guanglong; Wang, Limei; Wang, Jiao; Zeng, Tianfang; Gong, Ping; Zhai, Xin

2016-09-14

Six series of novel 4-(2-fluorophenoxy)-3,3'-bipyridine derivatives conjugated with aza-aryl formamide/amine scaffords were designed and synthesized through a structure-based molecular hybridization approach. The target compounds were evaluated for c-Met kinase inhibitory activities and cytotoxicity against four cancer cell lines (HT-29, A549, MKN-45 and MDA-MB-231) in vitro. Most compounds exhibited moderate to excellent potency, and the most promising candidate 26c (c-Met kinase IC50 = 8.2 nM) showed a 4.7-fold increase in cytotoxicity against c-Met-addicted MKN-45 cell line in vitro (IC50 = 3 nM), superior to that of Foretinib (IC50 = 23 nM). The preliminary structure-activity relationship indicated that a 1H-benzo [e] [1,3,4]thiadiazine-3-carboxamide-4,4-dioxide moiety as linker contributed to the antitumor potency. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Validation and Clinical Utility of the hERG IC50:Cmax Ratio to Determine the Risk of Drug-Induced Torsades de Pointes: A Meta-Analysis.

Science.gov (United States)

Lehmann, David F; Eggleston, William D; Wang, Dongliang

2018-03-01

Use of the QT interval corrected for heart rate (QTc) on the electrocardiogram (ECG) to predict torsades de pointes (TdP) risk from culprit drugs is neither sensitive nor specific. The ratio of the half-maximum inhibitory concentration of the hERG channel (hERG IC50) to the peak serum concentration of unbound drug (C max ) is used during drug development to screen out chemical entities likely to cause TdP. To validate the use of the hERG IC50:C max ratio to predict TdP risk from a culprit drug by its correlation with TdP incidence. Medline (between 1966 and March 2017) was accessed for hERG IC50 and C max values from the antihistamine, fluoroquinolone, and antipsychotic classes to identify cases of drug-induced TdP. Exposure to a culprit drug was estimated from annual revenues reported by the manufacturer. Inclusion criteria for TdP cases were provision of an ECG tracing that demonstrated QTc prolongation with TdP and normal serum values of potassium, calcium, and magnesium. Cases reported in patients with a prior rhythm disturbance and those involving a drug interaction were excluded. The Meta-Analysis of Observational Studies in Epidemiology checklist was used for epidemiological data extraction by two authors. Negligible risk drugs were defined by an hERG IC50:C max ratio that correlated with less than a 5% chance of one TdP event for every 100 million exposures (relative risk [RR] 1.0). The hERG IC50:C max ratio correlated with TdP risk (0.312; 95% confidence interval 0.205-0.476, pratio of 80 (RR 1.0). The RR from olanzapine is on par with loratadine; ziprasidone is comparable with ciprofloxacin. Drugs with an RR greater than 50 include astemizole, risperidone, haloperidol, and thioridazine. The hERG IC50:C max ratio was correlated with TdP incidence for culprit drugs. This validation provides support for the potential use of the hERG IC50:C max ratio for clinical decision making in instances of drug selection where TdP risk is a concern. © 2018

Synthesis and Biological Evaluation of 3-Benzylidene-4-chromanone Derivatives as Free Radical Scavengers and α-Glucosidase Inhibitors.

Science.gov (United States)

Takao, Koichi; Yamashita, Marimo; Yashiro, Aruki; Sugita, Yoshiaki

2016-01-01

A series of 3-benzylidene-4-chromanone derivatives (3-20) were synthesized and the structure-activity relationships for antioxidant and α-glucosidase inhibitory activities were evaluated. Among synthesized compounds, compounds 5, 13, 18, which contain catechol moiety, showed the potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity (5: EC50 13 µM; 13: EC50 14 µM; 18: EC50 13 µM). The compounds 12, 14, 18 showed higher α-glucosidase inhibitory activity (12: IC50 15 µM; 14: IC50 25 µM; 18: IC50 28 µM). The compound 18 showed both of potent DPPH radical scavenging and α-glucosidase inhibitory activities. These data suggest that 3-benzylidene-4-chromanone derivatives, such as compound 18, may serve as the lead compound for the development of novel α-glucosidase inhibitors with antioxidant activity.

Synthesis of 4-thiazolidinone analogs as potent in vitro anti-urease agents.

Science.gov (United States)

Rahim, Fazal; Zaman, Khalid; Ullah, Hayat; Taha, Muhammad; Wadood, Abdul; Javed, Muhammad Tariq; Rehman, Wajid; Ashraf, Muhammad; Uddin, Reaz; Uddin, Imad; Asghar, Humna; Khan, Aftab Ahmad; Khan, Khalid M

2015-12-01

4-Thiazolidinone analogs 1-20 were synthesized, characterized by (1)H NMR and EI-MS and investigated for urease inhibitory activity. All twenty (20) analogs exhibited varied degree of urease inhibitory potential with IC50 values 1.73-69.65μM, if compared with standard thiourea having IC50 value of 21.25±0.15μM. Among the series, eight derivatives 3, 6, 8, 10, 15, 17, 19, and 20 showed outstanding urease inhibitory potential with IC50 values of 9.34±0.02, 14.62±0.03, 8.43±0.01, 7.3±0.04, 2.31±0.002, 5.75±0.003, 8.81±0.005, and 1.73±0.001μM, respectively, which is better than the standard thiourea. The remaining analogs showed good to excellent urease inhibition. The binding interactions of these compounds were confirmed through molecular docking studies. Copyright © 2015 Elsevier Inc. All rights reserved.

Mobilization of primitive and committed hematopoietic progenitors in nonhuman primates treated with defibrotide and recombinant human granulocyte colony-stimulating factor.

Science.gov (United States)

Carlo-Stella, Carmelo; Di Nicola, Massimo; Longoni, Paolo; Milani, Raffaella; Milanesi, Marco; Guidetti, Anna; Haanstra, Krista; Jonker, Margaret; Cleris, Loredana; Magni, Michele; Formelli, Franca; Gianni, Alesssandro M

2004-01-01

The aim of this study was to evaluate the capacity of defibrotide in enhancing cytokine-induced hematopoietic mobilization in rhesus monkeys. Animals received recombinant human granulocyte colony-stimulating factor (rhG-CSF, 100 microg/kg/day SC for 5 days) and, after a 4- to 6-week washout period, were remobilized with defibrotide (15 mg/kg/hour continuous intravenous for 5 days) plus rhG-CSF. Hematopoietic mobilization was evaluated by complete blood counts, differential counts, as well as frequency and absolute numbers of colony-forming cells (CFCs), high-proliferative potential CFCs (HPP-CFCs), and long-term culture-initiating cells (LTC-ICs). Compared to baseline values, rhG-CSF increased circulating CFCs, HPP-CFCs, and LTC-ICs by 158-, 125-, and 67-fold, respectively; the same figures for defibrotide/rhG-CSF were 299-, 1452-, and 295-fold, respectively. Defibrotide/rhG-CSF treatment compared to rhG-CSF alone increased CFCs, HPP-CFCs, and LTC-ICs by 1.4- (35,089 vs 25,825, pdefibrotide treatment associated with a 5-day rhG-CSF treatment. Compared to rhG-CSF, defibrotide/rhG-CSF increased the mobilization of CFCs, HPP-CFCs, and LTC-ICs by 2- (31,128 vs 15,527, pdefibrotide enhances rhG-CSF-elicited mobilization of primitive and committed progenitors; and 2) a 2-day defibrotide injection is as effective as a 5-day injection.

Advanced closed loop combustion control of a LTC diesel engine based on in-cylinder pressure signals

International Nuclear Information System (INIS)

Carlucci, A.P.; Laforgia, D.; Motz, S.; Saracino, R.; Wenzel, S.P.

2014-01-01

Highlights: • We have proposed an in-cylinder pressure-based closed loop combustion control. • We have tested the control on an engine at the test bench. • We have tested the control on the engine equipping a Euro 6-compliant vehicle. • The control is effective in increasing torque stability and reduce engine noise. - Abstract: The adoption of diesel LTC combustion concepts is widely recognised as a practical way to reduce simultaneously nitric oxides and particulate emission levels from diesel internal combustion engines. However, several challenges have to be faced up when implementing diesel LTC concepts in real application vehicles. In particular, achieving acceptable performance concerning the drivability comfort, in terms of output torque stability and combustion noise during engine dynamic transients, is generally a critical point. One of the most promising solutions to improve the LTC combustion operation lays in the exploitation of closed loop combustion control, based on in-cylinder pressure signals. In this work, the application of an in-cylinder pressure-based closed loop combustion control to a Euro 6-compliant demonstrator vehicle has been developed. The main challenges deriving from the control of the LTC combustion, directly affecting the engine/vehicle performance, have been analysed in detail. In order to overcome these drawbacks, a new control function, integrated into the base closed loop system, has been designed. The performance of the new function have been experimentally tested at the engine test bench. Results showed a significant enhancement of the LTC operation, in terms of both combustion stability and noise reduction during engine transients. The new function was also implemented on a real vehicle, thus proving the potential of the new control concept in realistic operating conditions

HI observations of the irregular galaxy IC 10

International Nuclear Information System (INIS)

Shostak, G.S.; Woerden, H. van

1983-01-01

The authors have made radio synthesis observations of the galaxy IC 10 with resolutions of 30 arcsec and 8 km/sec in the neutral hydrogen line using the Westerbork telescope. These confirm Shostak's (1974) result that, in the central region of IC 10, the velocity gradient is opposite to that later measured by single-dish in the outer regions. The suggestion by Cohen (1979) that the velocity gradient reversal is due to IC 10 being nearly face-on and warped is consistent with the new data. (Auth.)

Synthesis, reactions and biological activity of some new bis-heterocyclic ring compounds containing sulphur atom

Science.gov (United States)

2013-01-01

Background The derivatives of thieno[2,3-b]thiophene belong to a significant category of heterocyclic compounds, which have shown a wide spectrum of medical and industrial application. Results A new building block with two electrophilic center of thieno[2,3-b]thiophene derivatives 2 has been reported by one-pot reaction of diketone derivative 1 with Br2/AcOH in excellent yield. A variety of heteroaromatics having bis(1H-imidazo[1,2a] benzimidazole), bis(1H-imidazo[1,2-b][1,2,4]triazole)-3-methyl-4-phenylthieno[2,3-b]thiophene derivatives, dioxazolo-, dithiazolo-, and 1H-imidazolo-3-methyl-4-phenylthieno[2,3-b]thiophene derivatives as well pyrrolo, thiazolo -3-methyl-4-phenylthieno[2,3-b]thiophene derivatives have been designed, synthesized, characterized, and evaluated for their biological activity. Compounds 3–9 showed good bioassay result. These new derivatives were evaluated for anti-cancer activity against PC-3 cell lines, in vitro antioxidant potential and β-glucuronidase and α-glucosidase inhibitory activities. Compound 3 (IC50 = 56.26 ± 3.18 μM) showed a potent DPPH radical scavenging antioxidant activity and found to be more active than standard N-acetylcystein (IC50 = 105.9 ± 1.1 μM). Compounds 8a (IC50 = 13.2 ± 0.34 μM) and 8b (IC50 = 14.1 ± 0.28 μM) found as potent inhibitor of α-glucusidase several fold more active than the standard acarbose (IC50 = 841 ± 1.73 μM). Most promising results were obtained in β-glucuronidase enzyme inhibition assay. Compounds 5 (IC50 = 0.13 ± 0.019 μM), 6 (IC50 = 19.9 ± 0.285 μM), 8a (IC50 = 1.2 ± 0.0785 μM) and 9 (IC50 = 0.003 ± 0.09 μM) showed a potent inhibition of β-glucuronidase. Compound 9 was found to be several hundred fold more active than standard D-Saccharic acid 1,4-lactone (IC50 = 45.75 ± 2.16 μM). Conclusions Synthesis, characterization, and in vitro biological activity of a series of

Novel 5-Fluorouracil Derivatives: Synthesis and Cytotoxic Activity of 2-Butoxy-4-Substituted 5-Fluoropyrimidines

International Nuclear Information System (INIS)

Sun, Jian; Zhou, Wei; Hu, Weixiao; Shan, Shang; Zhang, Shijie; Li, Haibo

2013-01-01

Twenty two new 5-fluorouracil (5-FU) derivatives, 2-butoxy-4-substituted 5-fluoropyrimidines, were synthesized and characterized by IR, 1 H NMR, MS, HRMS. All compounds were preliminarily evaluated by MTT assay on human liver BEL-7402 cancer cell line in vitro. Ten compounds were selected to test their cytotoxic activity against A549, HL-60 and MCF-7 cancer cell lines in vitro. These compounds were more sensitive to BEL-7402 than other cell lines, particularly, cytotoxic activity of compounds 6b, 6d-f, 6p, 6s-u were in sub-micromolar scale. The highest cytotoxic potency against A549, HL-60 and MCF-7 was shown by 2-butoxy-4-chloro-5-fluoropyrimidine (5) with IC 50 values of 0.10, 1.66 and 0.59 μM, respectively. Compounds 6d and 6e were effective against MCF-7 with IC 50 9.73 μM and HL-60 with IC 50 8.83 μM, respectively

An oligonucleotide complementary to the SL-B1 domain in the 3'-end of the minus-strand RNA of the hepatitis C virus inhibits in vitro initiation of RNA synthesis by the viral polymerase

International Nuclear Information System (INIS)

Reigadas, Sandrine; Ventura, Michel; Andreola, Marie-Line; Michel, Justine; Gryaznov, Sergei; Tarrago-Litvak, Laura; Litvak, Simon; Astier-Gin, Therese

2003-01-01

We describe oligonucleotides (ODNs) that inhibit hepatitis C virus (HCV) RNA synthesis in vitro. From a series of 13 ODNs complementary to the 3'-end of the minus-strand HCV RNA, only 4 inhibited RNA synthesis with IC 50 values lower than 1 μM. The inhibition was sequence-specific, since no effect was observed when the ODNs were used with a noncomplementary template. The introduction of a 2'-O-methyl modification increased the inhibitor activity 11-fold (IC 50 = 50 nM) in just 1 (ODN7) of the 4 inhibitory ODNs. ODNs did not inhibit RNA synthesis by interfering with the elongation process as no short RNAs products were detected. We also show that ODN7 did not prevent binding of NS5B to the template or cause polymerase trapping by the duplex RNA/ODN. Our data demonstrate that ODN7 inhibits the initiation process, most probably by modifying structural features present at the 3'-end of the minus-strand RNA

2-(2-(4-Benzoylpiperazin-1-ylethylisoindoline-1,3-dione derivatives: Synthesis, docking and acetylcholinesterase inhibitory evaluation as anti-alzheimer agents

Directory of Open Access Journals (Sweden)

Ahmad Mohammadi-Farani

2017-01-01

Full Text Available Objective(s: Alzheimer’s disease (AD as progressive cognitive decline and the most common form of dementia is due to degeneration of the cholinergic neurons in the brain. Therefore, administration of the acetylcholinesterase (AChE inhibitors such as donepezil is the first choice for treatment of the AD. In the present study, we focused on the synthesis and anti-cholinesterase evaluation of new donepezil like analogs. Materials and Methods: A new series of phthalimide derivatives (compounds 4a-4j were synthesized via Gabriel protocol and subsequently amidation reaction was performed using various benzoic acid derivatives. Then, the corresponding anti-acetylcholinesterase activity of the prepared derivatives (4a-4j was assessed by utilization of the Ellman's test and obtained results were compared to donepezil. Besides, docking study was also carried out to explore the likely in silico binding interactions.  Results: According to the obtained results, electron withdrawing groups (Cl, F at position 3 and an electron donating group (methoxy at position 4 of the phenyl ring enhanced the acetylcholinesterase inhibitory activity. Compound 4e (m-Fluoro, IC50 = 7.1 nM and 4i (p-Methoxy, IC50 = 20.3 nM were the most active compounds in this series and exerted superior potency than donepezil (410 nM. Moreover, a similar binding mode was observed in silico for all ligands in superimposition state with donepezil into the active site of acetylcholinesterase. Conclusion: Studied compounds could be potential leads for discovery of novel anti-Alzheimer agents in the future.

Proliferative status of primitive hematopoietic progenitors from patients with acute myelogenous leukemia (AML).

Science.gov (United States)

Guan, Y; Hogge, D E

2000-12-01

One possible explanation for the competitive advantage that malignant cells in patients with acute myelogenous leukemia (AML) appear to have over normal hematopoietic elements is that leukemic progenitors proliferate more rapidly than their normal progenitor cell counterparts. To test this hypothesis, an overnight 3H-thymidine (3H-Tdr) suicide assay was used to analyze the proliferative status of malignant progenitors detected in both colony-forming cell (CFC) and long-term culture initiating cell (LTC-IC) assays from the peripheral blood of nine patients with newly diagnosed AML. Culture of AML cells in serum-free medium with 100 ng/ml Steel factor (SF), 20 ng/ml interleukin 3 (IL-3) and 20 ng/ml granulocyte colony-stimulating factor (G-CSF) for 16-24 h maintained the number of AML-CFC and LTC-IC at near input values (mean % input +/- s.d. for CFC and LTC-IC were 78 +/- 33 and 126 +/- 53, respectively). The addition of 20 muCi/ml high specific activity 3H-Tdr to these cultures reduced the numbers of both progenitor cell types from most of the patient samples substantially: mean % kill +/- s.d. for AML-CFC and LTC-IC were 64 +/- 27 and 82 +/- 16, respectively, indicating that a large proportion of both progenitor populations were actively cycling. FISH analysis of colonies from CFC and LTC-IC assays confirmed that most cytogenetically abnormal CFC and LTC-IC were actively cycling (mean % kill +/- s.d.: 68 +/- 26 and 85 +/- 13, respectively). Interestingly, in six patient samples where a significant number of cytogenetically normal LTC-ICs were detected, the % kill of these cells (74 +/- 20) was similar to that of the abnormal progenitors. These data contrast with the predominantly quiescent cell cycle status of CFC and LTC-IC previously observed in steady-state peripheral blood from normal individuals but also provide evidence that a significant proportion of primitive malignant progenitors from AML patients are quiescent and therefore may be resistant to standard

Synthesis, crystal structure determination and antiproliferative activity of novel 2-amino-4-aryl-4,10-dihydro[1,3,5]triazino[1,2- a]benzimidazoles

Science.gov (United States)

Hranjec, Marijana; Pavlović, Gordana; Karminski-Zamola, Grace

2012-01-01

This manuscript describes the synthesis of novel 2-amino-4-aryl-4,10-dihydro-[1,3,5]triazino[1,2- a]benzimidazoles as hydrochloride salts 4a-n and 5b which were prepared in the reaction of cyclocondensation between 2-guanidinobenzimidazole and versatile heteroaromatic aldehydes. Structures of all prepared compounds have been studied by using 1H and 13C NMR, IR and UV/Vis spectroscopy. The crystal and molecular structure of 4f was determined by X-ray diffraction on single crystals. The molecule of 2-amino-4-(4'-methylphenyl)-4,10-dihydro[1,3,5]triazino[1,2- a]benzimidazole hydrochloride 4f (C 16H 16N 5+·Cl -) exists in the solid state in one of the possible tautomeric forms, being protonated at the one of the nitrogen atoms of the 1,4-dihydrotriazine ring. The molecule is highly delocalized within the 4,10-dihydro[1,3,5]triazino[1,2- a]benzimidazole moiety with the highest deviation from the plane for the methine carbon atom and the protonated nitrogen atom of the 1,4-dihydrotriazine ring. The cations are joined via N-H⋯N hydrogen bonds into R22(8) centrosymmetric dimers. Cation dimers are further connected with Cl - ions via N-H⋯Cl and C-H⋯Cl hydrogen bonds into 2D chains spreading along the b axis. The obtained single-crystal X-ray structure determination unequivocally confirms tautomeric form of the compound present in the solid-state and can represent tantative pattern for other prepared compounds. All prepared compounds were tested on their antiproliferative activity in vitro on several human cancer cell lines. Compound 4m was the most active one (IC 50 ≈ 20 μM), while compounds 4d, 4f, 4k, 4l4m showed moderate, but non-selective, antiproliferative activity with IC 50 25-60 μM.

Different effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors on sterol synthesis in various human cell types

NARCIS (Netherlands)

Vliet, A.K. van; Thiel, G.C.F. van; Huisman, R.H.; Moshage, H.; Yap, S.H.; Cohen, L.H.

1995-01-01

The three vastatins examined, lovastatin, simvastatin and pravastatin, are equally strong inhibitors of the sterol synthesis in human hepatocytes in culture with IC50-values of 4.1, 8.0 and 2.0 nM, respectively. However, in the human extrahepatic cells: umbilical vascular endothelial cells, retinal

Synthesis and preliminary evaluation of N-acylhydrazone compounds as antibacterial and antifungal agents

International Nuclear Information System (INIS)

Cachiba, Thomas Haruo; Carvalho, Bruno Demartini; Carvalho, Diogo Teixeira; Cusinato, Marina; Prado, Clara Gaviao; Dias, Amanda Latercia Tranches

2012-01-01

We describe the synthesis and evaluation of N-acylhydrazone compounds bearing different electron-donating groups in one of its aromatic rings, obtained using a four-step synthetic route. IC 50 values against pathogenic fungi and bacteria were determined by serial microdilution. Compounds showed low activity against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. By contrast, a derivative with a meta-oriented electron-donating group showed significant activity (IC50) against Candida albicans (17 μM), C. krusei (34 μM) and C. tropicalis (17 μM). Results suggest this is a promising lead-compound for synthesis of potent antifungal agents. (author)

6-Nitrobenzimidazole derivatives: potential phosphodiesterase inhibitors: synthesis and structure-activity relationship.

Science.gov (United States)

Khan, K M; Shah, Zarbad; Ahmad, V U; Ambreen, N; Khan, M; Taha, M; Rahim, F; Noreen, S; Perveen, S; Choudhary, M I; Voelter, W

2012-02-15

6-Nitrobenzimidazole derivatives (1-30) synthesized and their phosphodiesterase inhibitory activities determined. Out of thirty tested compounds, ten showed a varying degrees of phosphodiesterase inhibition with IC(50) values between 1.5±0.043 and 294.0±16.7 μM. Compounds 30 (IC(50)=1.5±0.043 μM), 1 (IC(50)=2.4±0.049 μM), 11 (IC(50)=5.7±0.113 μM), 13 (IC(50)=6.4±0.148 μM), 14 (IC(50)=10.5±0.51 μM), 9 (IC(50)=11.49±0.08 μM), 3 (IC(50)=63.1±1.48 μM), 10 (IC(50)=120.0±4.47 μM), and 6 (IC(50)=153.2±5.6 μM) showed excellent phosphodiesterase inhibitory activity, much superior to the standard EDTA (IC(50)=274±0.007 μM), and thus are potential molecules for the development of a new class of phosphodiesterase inhibitors. A structure-activity relationship is evaluated. All compounds are characterized by spectroscopic parameters. Copyright © 2011 Elsevier Ltd. All rights reserved.

Synthesis of tritium-labelled (-)-U50,488, a selective kappa opioid agonist

International Nuclear Information System (INIS)

Thurkauf, A.; Costa, B. de; Rice, K.C.

1989-01-01

The preparation of 3 H labelled (-)-trans-3,4-dichloro-N-methyl-N[2-(1-pyrrolidinyl) cyclohexyl]benzeneacetamide (U50,488) in four steps from N-methylcyclohexylaziridine is described. The synthesis of the pharmacologically active (-) isomer of U50, 488 was accomplished through the resolution of the intermediate 2-[1-(3-pyrrolinyl)]-N-methylcyclohexylamine using (+)-mandelic acid. (Author)

Tailored Multivalent Neo-Glycoproteins: Synthesis, Evaluation, and Application of a Library of Galectin-3-Binding Glycan Ligands

Czech Academy of Sciences Publication Activity Database

Laaf, D.; Bojarová, Pavla; Pelantová, Helena; Křen, Vladimír; Elling, L.

2017-01-01

Roč. 28, č. 11 (2017), s. 2832-2840 ISSN 1043-1802 R&D Projects: GA ČR GC15-02578J; GA MŠk(CZ) LTC17005 Institutional support: RVO:61388971 Keywords : HOMOTYPIC CELL-AGGREGATION * ONE-POT SYNTHESIS * GALACTOSE-OXIDASE Subject RIV: CE - Biochemistry OBOR OECD: Biochemistry and molecular biology Impact factor: 4.818, year: 2016

Synthesis, characterization and anti cancer activity of some fluorinated 3,6-diaryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles

Directory of Open Access Journals (Sweden)

Deepak Chowrasia

2017-05-01

Full Text Available A series of fluorinated 3,6-diaryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (2a–2i was synthesized by condensation of various substituted 4-amino-5-phenyl-4H-1,2,4-triazole-3-thiols (1a–1i with penta fluoro benzoic acid in good yields (60–80%. The synthesized compounds were screened for anticancer activity against three cancerous cell lines MCF7 (human breast cancer, SaOS-2 (human osteosarcoma and K562 (human myeloid leukemia. The compounds showed moderate to good antiproliferative potency against the studied cell lines. Among these, compound 2b showed higher antiproliferative activity (IC50 22.1, 19 and 15 μM against MCF7, SaOS-2 and K562, respectively while 2a exhibited least antiproliferative activity (IC50 30.2, 39 and 29.4 μM against MCF7, SaOS-2 and K562 cells, respectively. Therefore, the present study demonstrates that fluorine substituted 3,6-diaryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles would be a better prospective in the development of anticancer drugs.

Gold(III) chloride catalyzed regioselective synthesis of pyrano[3,4-b]indol-1(9H)-ones and evaluation of anticancer potential towards human cervix adenocarcinoma.

Science.gov (United States)

Praveen, Chandrasekaran; Ayyanar, Asairajan; Perumal, Paramasivan Thirumalai

2011-07-15

A highly regioselective synthesis of pyrano[3,4-b]indol-1(9H)-ones via gold(III) chloride catalyzed cycloisomerization of 3-ethynyl-indole-2-carboxylic acid was achieved in good to excellent yields. These compounds were screened for their in vitro cytotoxicity against human cervical (HeLa) cell lines. Out of ten compounds, three compounds (7d, 7e and 7j) showed comparable proliferation inhibitory activity against the standard drug cisplatin. Compound 7d was found to be the most efficacious with IC(50) value of 0.22μM. Copyright © 2011 Elsevier Ltd. All rights reserved.

Synthesis and evaluation of a dimer of 2-(4-pyridylmethyl)-1-indanone as a novel nonsteroidal aromatase inhibitor.

Science.gov (United States)

Gupta, Ranju; Jindal, Dharam Paul; Jit, Birinder; Narang, Gaurav; Palusczak, Anja; Hartmann, Rolf W

2004-07-01

A novel dimer of 2-(4-pyridylmethyl)-1-indanone (2) was obtained while carrying out aldol condensation of 1-indanone with pyridine-4-carboxaldehyde in potassium hydroxide. The structure of dimer 3 has been established using various spectral techniques and was screened for its ability to inhibit the cytochrome P(450) enzyme aromatase. The dimer showed strong inhibition of human placental aromatase and was found 3 times more potent (RP = 3, IC(50) = 10.2 microM) as compared to aminoglutethimide (RP = 1, IC(50) = 18.5 microM.

Identification and characterization of luekotriene C4 and D4 receptors on a cultured smooth muscle cell line, BC3H-1

International Nuclear Information System (INIS)

Tamura, N.; Agrawal, D.K.; Townley, R.G.

1987-01-01

The authors studied the characteristics of the leukotriene (LT) C 4 and D 4 receptors on a cultured smooth muscle cell line, BC3H-1. Specific [ 3 H]LTC 4 binding to the cell membrane was greater than 80% of total binding and saturable at a density of 3.96 +/- 0.39 pmol/mg protein, with an apparent dissociation constant(Kd) of 14.3 +/- 2.0 nM (n=9). The association and dissociation of [ 3 H]LTC 4 binding were rapid and apparent equilibrium conditions were established within 5 min. Calculated Kd value of [ 3 H]LTC binding from the kinetic analysis was 9.9 nM. From the competition analysis, calculated Ki value of unlabeled LTC 4 to compete for the specific binding of [ 3 H]LTC 4 was 9.2 nM and was in good agreement with the Kd value obtained from the Scatchard plots or kinetic analysis. The maximum number of binding sites (Bmax) of [ 3 H]LTD 4 in the membrane of BC3H-1 cell line was about 11 times lower than that of the [ 3 H]LTC 4 . The calculated values of Kd and Bmax of [ 3 H]LTD 4 binding were 9.3 +/- 0.8 nM and 0.37 +/- 0.04 pmol/mg proteins, respectively (n=3). These findings demonstrate that BC3H-1 cell line possess both LTC 4 and LTD 4 receptors with a predominance of LTC 4 receptors. Thus, BC3H-1 cell line is a good model to study the regulation of LTC 4 and LTD 4 receptors. 34 references, 5 figures, 1 table

DECONVOLUTION OF IMAGES FROM BLAST 2005: INSIGHT INTO THE K3-50 AND IC 5146 STAR-FORMING REGIONS

International Nuclear Information System (INIS)

Roy, Arabindo; Netterfield, Calvin B.; Ade, Peter A. R.; Griffin, Matthew; Hargrave, Peter C.; Mauskopf, Philip; Bock, James J.; Brunt, Christopher M.; Chapin, Edward L.; Gibb, Andrew G.; Halpern, Mark; Marsden, Gaelen; Devlin, Mark J.; Dicker, Simon R.; Klein, Jeff; France, Kevin; Gundersen, Joshua O.; Hughes, David H.; Martin, Peter G.; Olmi, Luca

2011-01-01

We present an implementation of the iterative flux-conserving Lucy-Richardson (L-R) deconvolution method of image restoration for maps produced by the Balloon-borne Large Aperture Submillimeter Telescope (BLAST). Compared to the direct Fourier transform method of deconvolution, the L-R operation restores images with better-controlled background noise and increases source detectability. Intermediate iterated images are useful for studying extended diffuse structures, while the later iterations truly enhance point sources to near the designed diffraction limit of the telescope. The L-R method of deconvolution is efficient in resolving compact sources in crowded regions while simultaneously conserving their respective flux densities. We have analyzed its performance and convergence extensively through simulations and cross-correlations of the deconvolved images with available high-resolution maps. We present new science results from two BLAST surveys, in the Galactic regions K3-50 and IC 5146, further demonstrating the benefits of performing this deconvolution. We have resolved three clumps within a radius of 4.'5 inside the star-forming molecular cloud containing K3-50. Combining the well-resolved dust emission map with available multi-wavelength data, we have constrained the spectral energy distributions (SEDs) of five clumps to obtain masses (M), bolometric luminosities (L), and dust temperatures (T). The L-M diagram has been used as a diagnostic tool to estimate the evolutionary stages of the clumps. There are close relationships between dust continuum emission and both 21 cm radio continuum and 12 CO molecular line emission. The restored extended large-scale structures in the Northern Streamer of IC 5146 have a strong spatial correlation with both SCUBA and high-resolution extinction images. A dust temperature of 12 K has been obtained for the central filament. We report physical properties of ten compact sources, including six associated protostars, by fitting

Synthesis and antiplasmodial evaluation of novel (4-aminobutyloxy)quinolines.

Science.gov (United States)

Vandekerckhove, Stéphanie; Müller, Christian; Vogt, Dieter; Lategan, Carmen; Smith, Peter J; Chibale, Kelly; De Kimpe, Norbert; D'hooghe, Matthias

2013-01-01

A variety of 5-, 6- and 8-(4-aminobutyloxy)quinolines as novel oxygen analogues of known 4- and 8-(4-aminobutylamino)quinoline antimalarial drugs was generated from hydroxyquinolines through a three-step approach with a rhodium-catalyzed hydroformylation as the key step. Antiplasmodial assays of these new quinolines revealed micromolar potency for all representatives against a chloroquine-sensitive strain of Plasmodium falciparum, and three compounds showed submicromolar activity against a chloroquine-resistant strain of P. falciparum with IC(50)-values ranging between 150 and 680 nM. Copyright © 2012 Elsevier Ltd. All rights reserved.

Convergent Synthesis of the Potent P2Y Receptor Antagonist MG 50-3-1 Based on a Regioselective Ullmann Coupling Reaction

Directory of Open Access Journals (Sweden)

Christa E. Müller

2012-03-01

Full Text Available MG 50-3-1 (3, trisodium 1-amino-4-{4-[4-chloro-6-(2-sulfophenylamino-1,3,5-triazin-2-ylamino]-2-sulfophenylamino}-9,10-dioxo-9,10-dihydroanthracene 2-sulfonate is the most potent and selective antagonist (IC50 4.6 nM for “P2Y1-like” nucleotide-activated membrane receptors in guinea-pig taenia coli responsible for smooth muscle relaxation. Full characterization of the compound, however, e.g., at the human P2Y1 receptor, which is a novel potential target for antithrombotic drugs, as well as other P2 receptor subtypes, has been hampered due to difficulties in synthesizing the compound in sufficient quantity. MG 50-3-1 would be highly useful as a biological tool for detailed investigation of signal transduction in the gut. We have now developed a convenient, fast, mild, and efficient convergent synthesis of 3 based on retrosynthetic analysis. A new, regioselective Ullmann coupling reaction under microwave irradiation was successfully developed to obtain 1-amino-4-(4-amino-2-sulfophenylamino-9,10-dioxo-9,10-dihydro­anthracene 2-sulfonate (8. Four different copper catalysts (Cu, CuCl, CuCl2, and CuSO4 were investigated at different pH values of sodium phosphate buffer, and in water in the absence or presence of base. Results showed that CuSO4 in water in the presence of triethylamine provided the best conditions for the regioselective Ullmann coupling reaction yielding the key intermediate compound 8. A new synthon (sodium 2-(4,6-dichloro-1,3,5-triazin-2-ylaminobenzenesulfonate, 13 which can easily be obtained on a gram scale was prepared, and 13 was successfully coupled with 8 yielding the target compound 3.

SUPER-LUMINOUS TYPE Ic SUPERNOVAE: CATCHING A MAGNETAR BY THE TAIL

International Nuclear Information System (INIS)

Inserra, C.; Smartt, S. J.; Jerkstrand, A.; Fraser, M.; Wright, D.; Smith, K.; Chen, T.-W.; Kotak, R.; Nicholl, M.; Valenti, S.; Pastorello, A.; Benetti, S.; Bresolin, F.; Kudritzki, R. P.; Burgett, W. S.; Chambers, K. C.; Flewelling, H.; Botticella, M. T.; Ergon, M.; Fynbo, J. P. U.

2013-01-01

We report extensive observational data for five of the lowest redshift Super-Luminous Type Ic Supernovae (SL-SNe Ic) discovered to date, namely, PTF10hgi, SN2011ke, PTF11rks, SN2011kf, and SN2012il. Photometric imaging of the transients at +50 to +230 days after peak combined with host galaxy subtraction reveals a luminous tail phase for four of these SL-SNe. A high-resolution, optical, and near-infrared spectrum from xshooter provides detection of a broad He I λ10830 emission line in the spectrum (+50 days) of SN2012il, revealing that at least some SL-SNe Ic are not completely helium-free. At first sight, the tail luminosity decline rates that we measure are consistent with the radioactive decay of 56 Co, and would require 1-4 M ☉ of 56 Ni to produce the luminosity. These 56 Ni masses cannot be made consistent with the short diffusion times at peak, and indeed are insufficient to power the peak luminosity. We instead favor energy deposition by newborn magnetars as the power source for these objects. A semi-analytical diffusion model with energy input from the spin-down of a magnetar reproduces the extensive light curve data well. The model predictions of ejecta velocities and temperatures which are required are in reasonable agreement with those determined from our observations. We derive magnetar energies of 0.4 ∼ 51 erg) ∼ ej (M ☉ ) ∼< 8.6. The sample of five SL-SNe Ic presented here, combined with SN 2010gx—the best sampled SL-SNe Ic so far—points toward an explosion driven by a magnetar as a viable explanation for all SL-SNe Ic.

2-(2-Pyridyl) Benzimidazole Analogs and their beta-Glucuronidase Inhibitory Activity

International Nuclear Information System (INIS)

Kamil, A.; Noureen, S.

2015-01-01

Synthesis of 2-(2-Pyridyl) benzimidazole analogs 1-11 have been carried out and evaluated for in vitro beta-glucuronidase inhibitory potential. The compounds 4 (IC/sub 50/ = 4.06 ± 0.34 meuM), 5 (IC/sub 50/ = 09.63 ± 0.81 meuM), 1 (IC/sub 50/ = 19.66 ± 0.44 meuM), 7 (IC/sub 50/ = 24.75 ± 0.25 meuM), 6 (IC/sub 50/ = 26.30 ± 1.37 meuM), and 3 (IC/sub 50/ = 32.11 ± 0.89 meuM), showed beta-glucuronidase inhibitory activity superior to the standard D-saccharic acid 1,4-lactone, with (IC/sub 50/ = 48.4 ± 1.25 meuM). Based on structure-activity relationship, we discover a new class of potent beta-glucuronidase inhibitors. (author)

Synthesis of novel amides based on acridone scaffold with interesting antineoplastic activity.

Science.gov (United States)

Mahajan, Anand A; Rane, Rajesh A; Amritkar, Anish A; Naphade, Shital S; Miniyar, Pankaj B; Bangalore, Pavan Kumar; Karpoormath, Rajshekhar

2015-01-01

In search of novel cytotoxic agents based on acridone scaffold, twenty five derivatives of acridone-2- carboxamide were synthesized and evaluated against a panel of eleven cancer cell lines by using MTT assay. Amides, A5 and A8 (IC50 = 0.3 µM) exhibited good cytotoxicity against MCF7. Compound A22 (IC50 = 4.3 µM) was found to be selectively cytotoxic against cancer cell line MCF7 and KB403. Particularly, promising cytotoxic activities were shown by amides A6 (IC50 = 0.7 µM), A16 (IC50 = 6.3 µM), A8 (IC50 = 0.9 µM ), A21 (IC50 = 1.3 µM), A5 (IC50 = 2.9 µM), A8 (IC50 = 2.8 µM), A14 (IC50 = 0.8 µM), A9 (IC50 = 0.8 µM) and A8 (IC50 = 0.4 µM) against cell lines; PA1, WRL68, CaCO2, TK-10, K-562, PC-3, HOP-92, ECV-304 and UACC-257, respectively. The favorable cytotoxic profile and non-toxicity towards normal human cells displayed by the derivative revealed their potential for further anticancer drug developments.

Practice variation in the Dutch long-term care and the role of supply-sensitive care: Is access to the Dutch long-term care equitable?

Science.gov (United States)

Duell, Daisy; Koolman, Xander; Portrait, France

2017-12-01

Universal access and generous coverage are important goals of the Dutch long-term care (LTC) system. It is a legal requirement that everyone eligible for LTC should be able to receive it. Institutional care (IC) made up for 90% of Dutch LTC spending. To investigate whether access to IC is as equitable as the Dutch government aspires, we explored practice variation in entitlements to IC across Dutch regions. We used a unique dataset that included all individual applications for Dutch LTC in January 2010-December 2013 (N = 3,373,358). This dataset enabled an accurate identification of the need for care. We examined the local variation in the probability of being granted long-term IC and in the intensity of the care granted given that individuals have applied for LTC. We also investigated whether the variation observed was related to differences in the local availability of care facilities. Although our analyses indicated the presence of some practice variation, its magnitude was very small by national and international standards (up to 3%). Only a minor part of the practice variation could be accounted for by local supply differences in care facilities. Overall, we conclude that, unlike many other developed countries, the Dutch system ensured equitable access to long-term IC. © 2017 The Authors. Health Economics Published by John Wiley & Sons Ltd.

Synthesis of 7-hydroxy-4'-methoxyflavanone and 7-hydroxy-4'-methoxyflavone as a candidate anticancer against cervical (HeLa) cancer cell and colon (WiDr) cancer cell by in vitro

Science.gov (United States)

Matsjeh, Sabirin; Anwar, Chairil; Solikhah, Eti Nurwening; Farah, Harra Ismi; Nurfitria, Kurnia

2017-03-01

The compound 7-hydroxy-4'-methoxyflavanone and 7-hydroxy-4'-methoxyflavone have been synthesized through cyclization reaction of 2 ', 4'-dihydroxy-4-methoxychalcone (1,3-diphenyl-2-propene-1-one). The 2 ', 4'-dihydroxy-4-methoxychalcone were synthesized through Claisen-Schmidt condensation from 2,4-dihydroxyacetophenone and 4-methoxybenzaldehyde (anisaldehyde) in aqueous KOH as a catalyst in ethanol. The 7-hydroxy-4'-methoxyflavanone has been synthesized through cyclization reaction of 2 ', 4'-dihydroxy-4-methoxychalcone by Oxa-Michael addition reaction with sulfuric acid as a catalyst in ethanol. The 7-hydroxy-4'-methoxyflavone has been synthesized through oxidative cyclization reaction of 2 ', 4'-dihydroxy-4-methoxychalcone using I2 in DMSO as a catalyst with a mole ratio (1: 1) mol. All these producets were characterized by FT-IR, GC-MS, and 1H-NMR and 13C-NMR spectrometer. Both of these compounds were tested citotoxycity activity as an anticancer against cervical and colon cancer cells (HeLa and WiDr cell lines) using MTT assay in vitro. Dose series given test solution concentration on HeLa and WiDr cells starting from 0,78; 1,56; 3,12; 6,25; 12,50; 25; 50 and 100 µg/mL with a long incubation treatment for 24 hours. The results study showed that the 7-hydroxy-4'-methoxyflavanone as bright yellow crystals with a melting point 172-174 ° C and a yield of 56.67% and the 7-hydroxy-4'-methoxyflavone as bright yellow crystals with a yield of 88, 31%, and a melting point of 263-265 ° C. The test results cytotoxic 7-hydroxy-4-methoxyflavone showed active against HeLa cells with IC50 value of 25.73 µg/mL and was quite active in the WiDr cells with IC50 value of 83.75 µg/mL. The result of the activity of 7-hydroxy-4-methoxyflavanone show active cytotoxic activity against HeLa and WiDr cell growth with IC50 value of 40.13 µg/mL and 37.85 µg/mL. IC50 value indicated that 7-hydroxy-4'-methoxyflavone and 7-hydroxy-4'-methoxyflavanone potential as inhibitors in HeLa and

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

Science.gov (United States)

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

2016-06-01

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

New Synthesis and Antiparasitic Activity of Model 5-Aryl-1-methyl-4-nitroimidazoles

Directory of Open Access Journals (Sweden)

Mustafa M. El-Abadelah

2009-07-01

Full Text Available A number of 5-aryl-1-methyl-4-nitroimidazoles 5a-f have been synthesized in good yields by the Suzuki coupling reaction between 5-chloro-1-methyl-4-nitroimidazole (3 and arylboronic acids 4a-f, aided by dichlorobis-(triphenylphosphinepalladium(II, K2CO3, and tetrabutylammonium bromide in water at 70-80 °C. Compounds 5a-f were characterized by elemental analysis, NMR and MS spectral data. On the basis of in vitro screening data, 5-(3-chlorophenyl-1-methyl-4-nitro-1H-imidazole (5fexhibited potent lethal activity against Entamoeba histolytica and Giardia intestinalis with IC50 = 1.47 µM/mL, a value lower by a factor of two than that of the standard drug, metronidazole. The boosted activity of 5f was not accompanied by any increased cytotoxicity.The rest of the series also exhibited potent antiparasitic activity with IC50 valuesin the 1.72-4.43 µM/mL range. The cytotoxicity of the derivatives 5c and 5e was increased compared to the precursor compound, metronidazole, although they remain non-cytotoxic at concentrations much higher than the antiparasitic concentration of the two derivatives.

New synthesis and antiparasitic activity of model 5-aryl-1-methyl-4-nitroimidazoles.

Science.gov (United States)

Saadeh, Haythem A; Mosleh, Ibrahim M; El-Abadelah, Mustafa M

2009-07-27

A number of 5-aryl-1-methyl-4-nitroimidazoles 5a-f have been synthesized in good yields by the Suzuki coupling reaction between 5-chloro-1-methyl-4-nitroimidazole (3) and arylboronic acids 4a-f, aided by dichlorobis-(triphenylphosphine)palladium(II), K(2)CO(3, )and tetrabutylammonium bromide in water at 70-80 degrees C. Compounds 5a-f were characterized by elemental analysis, NMR and MS spectral data. On the basis of in vitro screening data, 5-(3-chlorophenyl)-1-methyl-4-nitro-1H-imidazole (5f) exhibited potent lethal activity against Entamoeba histolytica and Giardia intestinalis with IC(50) = 1.47 microM/mL, a value lower by a factor of two than that of the standard drug, metronidazole. The boosted activity of 5f was not accompanied by any increased cytotoxicity.The rest of the series also exhibited potent antiparasitic activity with IC(50 ) values in the 1.72-4.43 microM/mL range. The cytotoxicity of the derivatives 5c and 5e was increased compared to the precursor compound, metronidazole, although they remain non-cytotoxic at concentrations much higher than the antiparasitic concentration of the two derivatives.

Determining the size and concentration dependence of gold nanoparticles in vitro cytotoxicity (IC50) test using WST-1 assay

International Nuclear Information System (INIS)

Rosli, Nur Shafawati binti; Rahman, Azhar Abdul; Aziz, Azlan Abdul; Shamsuddin, Shaharum

2015-01-01

Gold nanoparticles (AuNPs) received a great deal of attention for biomedical applications, especially in diagnostic imaging and therapeutics. Even though AuNPs have potential benefits in biomedical applications, the impact of AuNPs on human and environmental health still remains unclear. The use of AuNPs which is a high-atomic-number materials, provide advantages in terms of radiation dose enhancement. However, before this can become a clinical reality, cytotoxicity of the AuNPs has to be carefully evaluated. Cytotoxicity test is a rapid, standardized test that is very sensitive to determine whether the nanoparticles produced are harmful or benign on cellular components. In this work the size and concentration dependence of AuNPs cytotoxicity in breast cancer cell lines (MCF-7) are tested by using WST-1 assay. The sizes of AuNPs tested were 13 nm, 50 nm, and 70 nm. The cells were seeded in the 96-well plate and were treated with different concentrations of AuNPs by serial dilution for each size of AuNPs. The high concentration of AuNPs exhibit lower cell viability compared to low concentration of AuNPs. We quantified the toxicity of AuNPs in MCF-7 cell lines by determining the IC 50 values in WST-1 assays. The IC 50 values (inhibitory concentrations that effected 50% growth inhibition) of 50 nm AuNPs is lower than 13 nm and 70 nm AuNPs. Mean that, 50nm AuNPs are more toxic to the MCF-7 cells compared to smaller and larger sizes AuNPs. The presented results clearly indicate that the cytotoxicity of AuNPs depend not only on the concentration, but also the size of the nanoparticles

Spitzer Observations Of IC 2118

Science.gov (United States)

2010-09-01

Micron All-Sky Survey ( 2MASS ; Skrutskie et al. 2006) photometric data in an effort to segregate YSOs from background galaxies. While one previously known T...Spectral Typea Other names IRAS 04591−0856 05 01 30.2 −08 52 14 . . . HHL 17, G13 2MASS 05020630−0850467 05 02 06.3 −08 50 47 M2 IV . . . RXJ 0502.4−0744b...05 02 20.8 −07 44 10 . . . 2MASS 05022084−0744099 2MASS 05060574−0646151c 05 06 05.7 −06 46 15 G8: (May not be a member of IC 2118; see Kun et al

Design, Synthesis and Biological Evaluation of 1,4-Disubstituted-3,4-dihydroisoquinoline Compounds as New Tubulin Polymerization Inhibitors

Directory of Open Access Journals (Sweden)

Ling Zhang

2015-05-01

Full Text Available A series of 1,4-disubstituted-3,4-dihydroisoquinoline derivatives designed as tubulin polymerization inhibitors were synthesized. Their cytotoxic activities against the CEM leukemia cell line were evaluated. Most of them displayed moderate cytotoxic activities, and compounds 21 and 32 showed good activities with IC50 of 4.10 and 0.64 μM, respectively. The most potent compound 32 was further confirmed to be able to inhibit tubulin polymerization, and its hypothetical binding mode with tubulin was obtained by molecular docking.

Design, Synthesis and Evaluation of Antiproliferative Activity of New Benzimidazolehydrazones

Directory of Open Access Journals (Sweden)

Valentina Onnis

2016-04-01

Full Text Available The synthesis and antiproliferative activity of new benzimidazole derivatives bearing an hydrazone mojety at the 2-position is described. The new N′-(4-arylidene-1H-benzo[d]imidazole-2-carbohydrazides were evaluated for their cytostatic activity toward the murine leukemia (L1210, human T-cell leukemia (CEM, human cervix carcinoma (HeLa and human pancreas carcinoma cells (Mia Paca-2. A preliminary structure-activity relationship could be defined. Some of the compounds possess encouraging and consistent antiproliferative activity, having IC50 values in the low micromolar range.

Determining the size and concentration dependence of gold nanoparticles in vitro cytotoxicity (IC{sub 50}) test using WST-1 assay

Energy Technology Data Exchange (ETDEWEB)

Rosli, Nur Shafawati binti; Rahman, Azhar Abdul [School of Physics, Universiti Sains Malaysia, 11800, Pulau Pinang (Malaysia); Aziz, Azlan Abdul [School of Physics, Universiti Sains Malaysia, 11800, Pulau Pinang (Malaysia); Nano-Biotechnology Research and Innovation (NanoBRI), Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, 11800, Pulau Pinang (Malaysia); Shamsuddin, Shaharum [Nano-Biotechnology Research and Innovation (NanoBRI), Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, 11800, Pulau Pinang (Malaysia); School of Health Sciences, Health Campus, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan (Malaysia)

2015-04-24

Gold nanoparticles (AuNPs) received a great deal of attention for biomedical applications, especially in diagnostic imaging and therapeutics. Even though AuNPs have potential benefits in biomedical applications, the impact of AuNPs on human and environmental health still remains unclear. The use of AuNPs which is a high-atomic-number materials, provide advantages in terms of radiation dose enhancement. However, before this can become a clinical reality, cytotoxicity of the AuNPs has to be carefully evaluated. Cytotoxicity test is a rapid, standardized test that is very sensitive to determine whether the nanoparticles produced are harmful or benign on cellular components. In this work the size and concentration dependence of AuNPs cytotoxicity in breast cancer cell lines (MCF-7) are tested by using WST-1 assay. The sizes of AuNPs tested were 13 nm, 50 nm, and 70 nm. The cells were seeded in the 96-well plate and were treated with different concentrations of AuNPs by serial dilution for each size of AuNPs. The high concentration of AuNPs exhibit lower cell viability compared to low concentration of AuNPs. We quantified the toxicity of AuNPs in MCF-7 cell lines by determining the IC{sub 50} values in WST-1 assays. The IC{sub 50} values (inhibitory concentrations that effected 50% growth inhibition) of 50 nm AuNPs is lower than 13 nm and 70 nm AuNPs. Mean that, 50nm AuNPs are more toxic to the MCF-7 cells compared to smaller and larger sizes AuNPs. The presented results clearly indicate that the cytotoxicity of AuNPs depend not only on the concentration, but also the size of the nanoparticles.

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

Science.gov (United States)

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

2017-06-01

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

Efficient synthesis and evaluation of bis-pyridinium/bis-quinolinium metallosalophens as antibiotic and antitumor candidates

Science.gov (United States)

Elshaarawy, Reda F. M.; Eldeen, Ibrahim M.; Hassan, Eman M.

2017-01-01

Inspired with the pharmacological diversity of salophens and in our endeavor to explore a new strategy which may conflict the invasion of drug resistance, we report herein efficient synthetic routes for the synthesis of new RO-salophen(Cl), pyridinium/quinolinium-based salophens (3a-e) and metallosalophens (4a-j). These new architectures have been structurally characterized by elemental and spectral analysis as well pharmacologically evaluated for their in vitro antimicrobial, against a common panel of pathogenic bacterial and fungal strains, and anticancer activities against human colon carcinoma (HCT-116) cell lines. Antimicrobial assay results revealed that all tested compounds exhibited moderate to superb broad-spectrum efficacy in comparison to the standard antibiotic with a preferential ability to perform as a fungicides than to act as bactericides. Noteworthy, VO(II)-salophens are more effective in reduction HCT-116 cell viability than Cu(II)-salophens. For example, VO(II)-salophen3 (4f) (IC50 = 2.13 μg/mL) was ca. 10-fold more efficient than Cu(II)-salophen3 (4e) (IC50 = 20.30 μg/mL).

Synthesis and biological evaluation of novel 5-hydroxylaminoisoxazole derivatives as lipoxygenase inhibitors and metabolism enhancing agents.

Science.gov (United States)

Averina, Elena B; Vasilenko, Dmitry A; Gracheva, Yulia A; Grishin, Yuri K; Radchenko, Eugene V; Burmistrov, Vladimir V; Butov, Gennady M; Neganova, Margarita E; Serkova, Tatyana P; Redkozubova, Olga M; Shevtsova, Elena F; Milaeva, Elena R; Kuznetsova, Tamara S; Zefirov, Nikolay S

2016-02-15

A versatile synthesis of novel 5-hydroxylaminoisoxazoles bearing adamantane moieties has been accomplished using the heterocyclization reactions of readily available unsaturated esters by the treatment with tetranitromethane in the presence of triethylamine and subsequent reduction of resulting 5-nitroisoxazoles by SnCl2 with the participation of THF. A number of obtained isoxazole derivatives were evaluated for their antioxidative activity, inhibition of lipoxygenases and impact on the rat liver mitochondria. The majority of tested compounds demonstrated moderate antiradical activity in DPPH test (up to EC50 16μM). The same compounds strongly inhibited soybean lipoxygenase (up to IC50 0.4μM) and Fe(2+)- and Fe(3+)-induced lipid peroxidation (LP) of rat brain cortex homogenate (up to IC50 0.3μM). All tested isoxazole derivatives promoted the phosphorylating respiratory activity simultaneously with maximal stimulated respiratory activity of mitochondria and do not reveal any toxicity towards the primary culture of rat cortex neurons. Copyright © 2015 Elsevier Ltd. All rights reserved.

Synthesis and biological evaluation of some novel pyrido[1,2-a]pyrimidin-4-ones as antimalarial agents.

Science.gov (United States)

Mane, Uttam R; Mohanakrishnan, D; Sahal, Dinkar; Murumkar, Prashant R; Giridhar, Rajani; Yadav, Mange Ram

2014-05-22

Novel pyrido[1,2-a]pyrimidin-4-ones have been synthesized and evaluated for their antimalarial activity by SYBR Green I assay against erythrocytic stages of chloroquine (CQ) sensitive Pf 3D7 strain. The antimalarial screening of 42 different compounds revealed that 3-Fluorobenzyl(4-oxo-4H-pyrido [1,2-a]pyrimidin-3-yl)carbamate (21, IC50 value 33 μM) and 4-Oxo-N-[4-(trifluoromethyl)benzyl]-4H-pyrido[1,2-a]pyrimidine-3-carboxamide (37, IC50 value 37 μM) showed moderate antimalarial activity. Cytotoxicity study was performed against mammalian cell line (Huh-7) by using the MTT assay for the moderately active compounds. Structural activity relationship (SAR) studies displayed that B-ring unsubstituted pyrido[1,2-a]pyrimidine scaffold is responsible for the antimalarial activities of the evaluated derivatives. This SAR based antimalarial screening supported that pyrido[1,2-a]pyrimidin-4-one can be considered as a lead heterocyclic structure for further development of more potent derivatives for antimalarial activity. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Synthesis and preliminary evaluation of N-acylhydrazone compounds as antibacterial and antifungal agents; Sintese e avaliacao preliminar da atividade antibacteriana e antifungica de derivados N-acilidrazonicos

Energy Technology Data Exchange (ETDEWEB)

Cachiba, Thomas Haruo; Carvalho, Bruno Demartini; Carvalho, Diogo Teixeira [Universidade Federal de Alfenas, MG (Brazil). Fac. de Ciencias Farmaceuticas. Dept. de Alimentos e Medicamentos; Cusinato, Marina; Prado, Clara Gaviao; Dias, Amanda Latercia Tranches, E-mail: diogo.carvalho@unifal-mg.edu.br [Universidade Federal de Alfenas, MG (Brazil). Inst. de Ciencias Biomedicas

2012-07-01

We describe the synthesis and evaluation of N-acylhydrazone compounds bearing different electron-donating groups in one of its aromatic rings, obtained using a four-step synthetic route. IC{sub 50} values against pathogenic fungi and bacteria were determined by serial microdilution. Compounds showed low activity against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. By contrast, a derivative with a meta-oriented electron-donating group showed significant activity (IC50) against Candida albicans (17 {mu}M), C. krusei (34 {mu}M) and C. tropicalis (17 {mu}M). Results suggest this is a promising lead-compound for synthesis of potent antifungal agents. (author)

Safety systems I/C equipment reliability analyses of the Kozloduy NPP units 3 and 4

Energy Technology Data Exchange (ETDEWEB)

Halev, G; Christov, N [Risk Engineering Ltd., Sofia (Bulgaria)

1996-12-31

The purpose of the analysis is to assess the safety systems I/C equipment reliability. The assessment includes: quantification of the safety systems unavailability due to component failures; definition of the minimal cut sets leading to the analysed safety systems failure; quantification of the I/C equipment importance measures of the dominant contribution components. The safety systems I/C equipment reliability has been analysed using PSAPACK (a code for probabilistic safety assessment). Fault trees for the following safety systems of the Kozloduy-3 and Kozloduy-4 reactors have been constructed: neutron flow control equipment, reactor protection system, main coolant pumps, pressurizer safety valves `Sempell`, steam dump systems, spray system, low pressure injection system, emergency feeding water system, essential service water system. THree separate reports have been issued containing the performed analyses and results. 1 ref.

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

DEFF Research Database (Denmark)

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

1995-01-01

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

Cold injury, blood-brain barrier changes, and leukotriene synthesis: Inhibition by phenidone

International Nuclear Information System (INIS)

Robichaud, L.J.; Marcoux, F.W.

1990-01-01

Transcranial cold injury in rats and guinea pigs induced cerebral extravasation of albumin labeled with Evans blue dye or 125 I, respective indicators of the area and amount of blood-brain barrier (BBB) disruption. Radioimmunoassay of brain extracts showed that cold injury induced leukotriene (LT)C4 in rat and guinea pig brains 15 min after injury. In guinea pigs, the LT synthesis inhibitor phenidone (30 mg/kg, i.p.) completely blocked cold-induced LTC4 in brain. Phenidone (30 and 100 mg/kg) also inhibited cerebral tissue accumulation of 125 I-albumin and dye in rats and guinea pigs. Phenidone is reported to show antioxidant properties and selective lipoxygenase inhibition of arachidonic acid metabolism compared to cyclooxygenase inhibitors, meclofenamate sodium, and other nonsteroidal anti-inflammatory agents. Since several oxygen and hydroxyl radical scavengers and the cyclooxygenase inhibitor, meclofenamate sodium, did not inhibit protein extravasation, the findings support a role for LT as a mediator of cold-induced changes in BBB permeability in rats and guinea pigs and suggest that the inhibitory effects of phenidone on BBB permeability may be due to inhibition of LT production

PREFACE: 4th International Conference on Mathematical Modeling in Physical Sciences (IC-MSquare2015)

Science.gov (United States)

Vlachos, Dimitrios; Vagenas, Elias C.

2015-09-01

The 4th International Conference on Mathematical Modeling in Physical Sciences (IC-MSQUARE) took place in Mykonos, Greece, from Friday 5th June to Monday 8th June 2015. The Conference was attended by more than 150 participants and hosted about 200 oral, poster, and virtual presentations. There were more than 600 pre-registered authors. The 4th IC-MSQUARE consisted of different and diverging workshops and thus covered various research fields where Mathematical Modeling is used, such as Theoretical/Mathematical Physics, Neutrino Physics, Non-Integrable Systems, Dynamical Systems, Computational Nanoscience, Biological Physics, Computational Biomechanics, Complex Networks, Stochastic Modeling, Fractional Statistics, DNA Dynamics, Macroeconomics etc. The scientific program was rather intense as after the Keynote and Invited Talks in the morning, three parallel oral and one poster session were running every day. However, according to all attendees, the program was excellent with a high quality of talks creating an innovative and productive scientific environment for all attendees. We would like to thank the Keynote Speaker and the Invited Speakers for their significant contribution to IC-MSQUARE. We also would like to thank the Members of the International Advisory and Scientific Committees as well as the Members of the Organizing Committee.

Catecholic amides as potential selective phosphodiesterase 4D inhibitors: Design, synthesis, pharmacological evaluation and structure-activity relationships.

Science.gov (United States)

Zhou, Zhong-Zhen; Ge, Bing-Chen; Chen, Yu-Fang; Shi, Xiu-Dong; Yang, Xue-Mei; Xu, Jiang-Ping

2015-11-15

In this study, a series of catechol-based amides (8a-n) with different amide linkers linking the catecholic moiety to the terminal phenyl ring was designed and synthesized as potent phosphodiesterase (PDE) 4D inhibitors. The inhibitory activities of these compounds were evaluated against the core catalytic domains of human PDE4 (PDE4CAT), full-length PDE4B1 and PDE4D7 enzymes, and other PDE family members. The results indicated the majority of compounds 8a-n displayed moderate to good inhibitory activities against PDE4CAT. Among these compounds, compound 8 j with a short amide linker (-CONHCH2-) displayed comparable PDE4CAT inhibitory activity (IC50=410 nM) with rolipram. More interestingly, compound 8 g, a potent and selective PDE4D inhibitor (IC50=94 nM), exhibited a 10-fold selectivity over the PDE4B subtypes and an over 1000-fold selectivity against other PDE family members. Docking simulations suggested that 8 g forms three extra H-bonds with the N-H of residue Asn487 and two water molecules. Copyright © 2015 Elsevier Ltd. All rights reserved.

Synthesis, biological evaluation and docking studies of 2,3-dihydroquinazolin-4(1H)-one derivatives as inhibitors of cholinesterases.

Science.gov (United States)

Sarfraz, Muhammad; Sultana, Nargis; Rashid, Umer; Akram, Muhammad Safwan; Sadiq, Abdul; Tariq, Muhammad Ilyas

2017-02-01

In search of potent inhibitors of cholinesterases, we have synthesized and evaluate a number of 2,3-dihydroquinazolin-4(1H)-one derivatives. The synthetic approach provided an efficient synthesis of the target molecules with excellent yield. All the tested compounds showed activity against both the enzymes in micromolar range. In many case, the inhibition of both enzymes are higher than or comparable to the standard drug galatamine. With the selectivity index of 2.3 for AChE, compound 5f can be considered as a potential lead compound with a feature of dual AChE/BChE inhibition with IC 50 =1.6±0.10μM (AChE) and 3.7±0.18μM (BChE). Binding modes of the synthesized compounds were explored by using GOLD (Genetic Optimization for Ligand Docking) suit v5.4.1. The computed binding modes of these compounds in the active site of AChE and BChE provide an insight into the mechanism of inhibition of these two enzyme. Copyright © 2017 Elsevier Inc. All rights reserved.

What are the beliefs, attitudes and practices of front-line staff in long-term care (LTC facilities related to osteoporosis awareness, management and fracture prevention?

Directory of Open Access Journals (Sweden)

Adachi Jonathan D

2010-10-01

, 44.4% strongly felt their patients should be prescribed vitamin D supplementation. Conclusion Bisphosphonates are quite effective in increasing the bone mineral density of LTC patients, and may reduce fracture rates, but it is only effective if properly administered. In our study, proper administration of bisphosphonate therapy was less than optimal. In summary, although the education of health providers has improved since the mid-1990's, this area still requires further attention and the subject of future quality assurance research.

Synthesis, crystal structures, molecular docking, and in vitro biological activities evaluation of transition metal complexes with 4-(3,4-dichlorophenyl) piperazine-1-carboxylic acid

Science.gov (United States)

Chen, Zhi-Jian; Chen, Ya-Na; Xu, Chun-Na; Zhao, Shan-Shan; Cao, Qi-Yue; Qian, Shao-Song; Qin, Jie; Zhu, Hai-Liang

2016-08-01

Three novel mononuclear complexes, [MⅡ(L)2·2H2O], (M = Cu, Ni or Cd; HL = 4-(3,4-dichlorophenyl)piperazine-1-carboxylic acid)were synthesized and structurally determined by single-crystal X-ray diffraction. Molecular docking study preliminarily revealed that complex 1 had potential urease inhibitory activity. In accordance with the result of calculation, in vitro tests of the inhibitory activities of complexes 1-3 against jack bean urease showed complex 1 (IC50 = 8.17 ± 0.91 μM) had better inhibitory activities than the positive reference acetohydroxamic acid (AHA) (IC50 = 26.99 ± 1.43 μM), while complexes 2 and 3 showed no inhibitory activities., kinetics study was carried out to explore the mechanism of the inhibiting of the enzyme, and the result indicated that complex 1 was a competitive inhibitor of urease. Albumin binding experiment and in vitro toxicity evaluation of complex 1 were implemented to explore its Pharmacological properties.

On the truth of Ksub(IC) values, taken from RD 50-260-81 methodical instructions

International Nuclear Information System (INIS)

Ivanova, V.S.

1984-01-01

Ways to evaluate correctness of Ksub(Ic) values, taking into account self-similarity of prefracture zone and stability of critical density of strain energy, as well as necessity to introduce corrections for plastic strain zone, are considered. Correctness of Ksub(Ic) values and temperature range of tough (hole) fracture mechanism realization, taking into account the effect of plastic strain compression degree for the Ksub(Ic) vaclue established in the basic experiment; necessity to introduce on the basis of similarity theory approaches the method of plastic strain compression degree during the development of state standard project, so as to decrease data spread and to increase information value of separate experiments, when studying crack resistance of plastic materials, have been confirmed

Design, synthesis and molecular modeling of new 4-phenylcoumarin derivatives as tubulin polymerization inhibitors targeting MCF-7 breast cancer cells.

Science.gov (United States)

Batran, Rasha Z; Kassem, Asmaa F; Abbas, Eman M H; Elseginy, Samia A; Mounier, Marwa M

2018-07-23

A new set of 4-phenylcoumarin derivatives was designed and synthesized aiming to introduce new tubulin polymerization inhibitors as anti-breast cancer candidates. All the target compounds were evaluated for their cytotoxic effects against MCF-7 cell line, where compounds 2f, 3a, 3b, 3f, 7a and 7b, showed higher cytotoxic effect (IC 50  = 4.3-21.2 μg/mL) than the reference drug doxorubicin (IC 50  = 26.1 μg/mL), additionally, compounds 1 and 6b exhibited the same potency as doxorubicin (IC 50  = 25.2 and 28.0 μg/mL, respectively). The thiazolidinone derivatives 3a, 3b and 3f with potent and selective anticancer effects towards MCF-7 cells (IC 50  = 11.1, 16.7 and 21.2 μg/mL) were further assessed for tubulin polymerization inhibition effects which showed that the three compounds were potent tubulin polymerization suppressors with IC 50 values of 9.37, 2.89 and 6.13 μM, respectively, compared to the reference drug colchicine (IC 50  = 6.93 μM). The mechanistic effects on cell cycle progression and induction of apoptosis in MCF-7 cells were determined for compound 3a due to its potent and selective cytotoxic effects in addition to its promising tubulin polymerization inhibition potency. The results revealed that compound 3a induced cell cycle cessation at G2/M phase and accumulation of cells in pre-G1 phase and prevented its mitotic cycle, in addition to its activation of caspase-7 mediating apoptosis of MCF-7 cells. Molecular modeling studies for compounds 3a, 3b and 3f were carried out on tubulin crystallography, the results indicated that the compounds showed binding mode similar to the co-crystalized ligand; colchicine. Moreover, pharmacophore constructed models and docking studies revealed that thiazolidinone, acetamide and coumarin moieties are crucial for the activity. Molecular dynamics (MD) studies were carried out for the three compounds over 100 ps. MD results of compound 3a showed that it reached the stable state

Design, synthesis, and biological testing of thiosalicylamides as a novel class of calcium channel blockers.

Science.gov (United States)

Mehanna, Ahmed S; Kim, Jin Yung

2005-07-01

The current research aimed to investigate the importance of the heterocyclic ring system in the structure of the cardiovascular drug diltiazem for its calcium channel blocking activity. The manuscript describes the design, synthesis, and biological testing of a total of 10 S-(p-methoxybenzyl), N-substituted thiosalicylamides as a series of non-cyclic compounds derived from diltiazem's structure. The new compounds maintained all diltiazem pharmacophores except the thiazepine ring system. In vitro evaluation of the new series for calcium channel blocking effects revealed moderate activities with IC50 values in the range of 4.8-56.0 microM. The data suggest that the ring system is not essential for activity; however, its absence leads to a considerable drop of activity relative to that of diltiazem (IC50=0.3 microM). Compounds of the current series showed optimum activity when the aliphatic alkyl chain on the salicylamide nitrogen is part of a piperidine or piperazine ring system substituted at the terminal nitrogen with a benzyl group.

Synthesis, characterization and in vitro antitrypanosomal activities of new carboxamides bearing quinoline moiety.

Directory of Open Access Journals (Sweden)

David Izuchukwu Ugwu

Full Text Available The reported toxicities of current antitrypanosomal drugs and the emergence of drug resistant trypanosomes underscore the need for the development of new antitrypanosomal agents. We report herein the synthesis and antitrypanosomal activity of 24 new amide derivatives of 3-aminoquinoline, bearing substituted benzenesulphonamide. Nine of the new derivatives showed comparable antitrypanosomal activities at IC50 range of 1-6 nM (melarsoprol 5 nM. Compound 11n and 11v are more promising antitrypanosomal agents with IC50 1.0 nM than the rest of the reported derivatives. The novel compounds showed satisfactory predicted physico-chemical properties including oral bioavailability, permeability and transport properties.

Synthesis and biological assessment of novel acylhydrazone derivatives of 2-methyl-1,4-naphthoquinone

Directory of Open Access Journals (Sweden)

Kamal Bouhadir

2017-10-01

Full Text Available Naphthoquinones are medicinally important molecules with a diverse array of biological properties such as antimicrobial, antifungal, antiviral, anti-inflammatory, anti-artherosclerotic and anticarcinogenic activities. In this study, we report the simple and direct preparation of a new group of novel menadione-hydrazone conjugates by reaction of 2-methyl-1,4-naphthoquinones with several aliphatic, aromatic and nucleobase hydrazides. The menadione-hydrazone conjugates were produced in excellent yields and characterized by IR, NMR and HRMS. The menadione derivatives were tested for their anticancer effects against human colon cancer HCT116 and human breast cancer MCF-7 cell lines. Interestingly, the molecules displayed disparate activities against both cell lines; the menadione hydrazones derived from the lipophilic myristic hydrazide and stearic hydrazide exhibited the most potent activity against HCT116 cell lines with IC50 of 89 and 64 μM. The most effective compounds against MCF-7 cells were the lauric hydrazide and benzoic hydrazide-derived menadione hydrazones with IC50 of 56 µM.

Design and synthesis of N-(4-aminopyridin-2-yl)amides as B-Raf(V600E) inhibitors.

Science.gov (United States)

Li, Xiaokai; Shen, Jiayi; Tan, Li; Zhang, Zhang; Gao, Donglin; Luo, Jinfeng; Cheng, Huimin; Zhou, Xiaoping; Ma, Jie; Ding, Ke; Lu, Xiaoyun

2016-06-15

B-Raf(V600E) was an effective target for the treatment of human cancers. Based on a pan-Raf inhibitor TAK-632, a series of N-(4-aminopyridin-2-yl)amide derivatives were designed as novel B-Raf(V600E) inhibitors. Detailed structure-activity studies of the compounds revealed that most of the compounds displayed potent enzymatic activity against B-Raf(V600E), and good selectivity over B-Raf(WT). One of the most promising compound 4l exhibited potent inhibitory activity with an IC50 value of 38nM for B-raf(V600E), and displayed antiproliferative activities against colo205 and HT29 cells with IC50 values of 0.136 and 0.094μM, respectively. It also displayed good selectivity on both enzymatic and cellular assays over B-Raf(WT). These inhibitors may serve as lead compounds for further developing novel B-Raf(V600E) inhibitors as anticancer drugs. Copyright © 2016 Elsevier Ltd. All rights reserved.

Design, synthesis, and biological evaluation of 2-substituted-2,3,4,9-tetrahydrospiro-β-carboline-3-carboxylic acid derivatives as first-in-class mast cell stabilizers.

Science.gov (United States)

Singh, Jatinder; Shah, Ramanpreet; Singh, Dhandeep; Jaggi, Amteshwar S; Singh, Nirmal

2018-05-01

Mast cell degranulation plays a momentous role in myriad diseases like asthma, eczema, allergic rhinitis, and conjunctivitis as well as anaphylactic shock; hence, there is an unmet need for developing new mast cells stabilizers. The reported mast cell stabilizers have a heterocyclic moiety and an acidic group. Furthermore, the role of tryptophan in suppression of mast cell activation is established. Hence, we prepared constrained analogs of tryptophan, which are derivatives of 2,3,4,9-tetrahydrospiro-β-carboline-3-carboxylic acid, and evaluated them for ex vivo inhibition of compound 48/80-induced mast degranulation activity. By comparing IC 50 (μM) values with that of the standard drug sodium cromoglycate (IC 50  = 0.489 ± 0.003 μM), compounds with bulky groups like heptyl (compound 9; IC 50  = 0.389 ± 0.015 μM) and octyl (compound 10; IC 50  = 0.354 ± 0.023 μM) were found to be of similar potency as sodium cromoglycate. Furthermore, the polar group-containing compounds like the chloropropyl (compound 16; IC 50  = 0.382 ± 0.083 μM) and benzoyl derivative (compound 14; IC 50  = 00.469 ± 0.032 μM) were also found to be of similar potency as sodium cromoglycate. This is a seminal study of spiro-β-carboline mast cell stabilization having a wider scope in mast cell research; yet, the mechanism of action remains elusive. © 2018 Deutsche Pharmazeutische Gesellschaft.

Thieno[3,2-c]pyran-4-one based novel small molecules: their synthesis, crystal structure analysis and in vitro evaluation as potential anticancer agents.

Science.gov (United States)

Nakhi, Ali; Adepu, Raju; Rambabu, D; Kishore, Ravada; Vanaja, G R; Kalle, Arunasree M; Pal, Manojit

2012-07-01

Novel thieno[3,2-c]pyran-4-one based small molecules were designed as potential anticancer agents. Expeditious synthesis of these compounds was carried out via a multi-step sequence consisting of few steps such as Gewald reaction, Sandmeyer type iodination, Sonogashira type coupling followed by iodocyclization and then Pd-mediated various C-C bond forming reactions. The overall strategy involved the construction of thiophene ring followed by the fused pyranone moiety and then functionalization at C-7 position of the resultant thieno[3,2-c]pyran-4-one framework. Some of the compounds synthesized showed selective growth inhibition of cancer cells in vitro among which two compounds for example, 5d and 6c showed IC(50) values in the range of 2.0-2.5 μM. The crystal structure analysis of an active compound along with hydrogen bonding patterns and molecular arrangement present within the molecule is described. Copyright © 2012 Elsevier Ltd. All rights reserved.

The Synthesis and Antiproliferative Activities of New Arylidene-Hydrazinyl-Thiazole Derivatives

Directory of Open Access Journals (Sweden)

Adriana Grozav

2014-12-01

Full Text Available New and known arylidene-hydrazinyl-thiazole derivatives have been synthesized by a convenient Hantzsch condensation. All compounds were evaluated for their in vitro cytotoxicity on two carcinoma cell lines, MDA-MB231 and HeLa. Significant antiproliferative activity for 2-(2-benzyliden-hydrazinyl-4-methylthiazole on both MDA-MB-231 (IC50: 3.92 µg/mL and HeLa (IC50: 11.4 µg/mL cell lines, and for 2-[2-(4-methoxybenzylidene hydrazinyl]-4-phenylthiazole on HeLa (IC50: 11.1 µg/mL cell line is reported. Electrophoresis experiments showed no plasmid DNA (pTZ57R cleavage in the presence of the investigated thiazoles.

Hydrothermal synthesis, off-axis electron holography and magnetic properties of Fe3O4 nanoparticles

DEFF Research Database (Denmark)

Almeida, Trevor P.; Muxworthy, Adrian R.; Williams, Wyn

2014-01-01

The hydrothermal synthesis of Fe3O4 nanoparticles (NPs) (<50 nm) from mixed FeCl3 / FeCl2 precursor solution at pH ~ 12 has been confirmed using complementary characterisation techniques of transmission electron microscopy and X-ray diffractometry. Off-axis electron holography allowed for visuali......The hydrothermal synthesis of Fe3O4 nanoparticles (NPs) (holography allowed...

Facile synthesis and herbicidal evaluation of 2-aryl-4h-3, 1-benzoxazin-4-ones

International Nuclear Information System (INIS)

Hussain, Z.; Khan, Z.A.

2013-01-01

The present work deals with the synthesis of 4H-3,1-benzoxazin-4-ones carrying an aryl functional group at position-2. Synthesized compounds tested for herbicidal activity at three different doses (500 micro g/mL, 50 micro g/mL and 5 micro g/mL). Most of the compounds exhibited significant herbicidal activity against Lemna aequinocitalis welv at higher dose (500 micro g/mL). Among the tested compounds 2-phenyl-4H-3,1-benzoxazin-4-one (3a) and 2-(3-chlorophenyl)-4H-3,1-benzoxazin-4-one (3l) completely inhibited the plant growth at 500 and 50 micro g/mL concentrations. All the synthetic compounds were characterized by FT-IR, 1H NMR, EI-MS and elemental analysis. (author)

New isochaetochromin, an inhibitor of triacylglycerol synthesis in mammalian cells, produced by Penicillium sp. FKI-4942: I. Taxonomy, fermentation, isolation and biological properties.

Science.gov (United States)

Ugaki, Narihiro; Matsuda, Daisuke; Yamazaki, Hiroyuki; Nonaka, Kenichi; Masuma, Rokuro; Omura, Satoshi; Tomoda, Hiroshi

2012-01-01

A new bis-naphtho-γ-pyrone isomer named isochaetochromin A(1) was isolated along with known isochaetochromins B(1) and B(2) from the culture broth of Penicillium sp. FKI-4942 by solvent extraction, silica gel column chromatography and HPLC. Among them, isochaetochromin B(1) showed the most potent inhibitory activity of triacylglycerol synthesis with an IC(50) value of 5.6 μM, followed by isochaetochromins B(2) (IC(50), 11 μM) and A(1) (33 μM).

Chemo-Enzymatic Synthesis of Branched N-Acetyllactosamine Glycan Oligomers for Galectin-3 Inhibition

Czech Academy of Sciences Publication Activity Database

Laaf, D.; Steffens, H.; Pelantová, Helena; Bojarová, Pavla; Křen, Vladimír; Elling, L.

2017-01-01

Roč. 359, č. 22 (2017), s. 4015-4024 ISSN 1615-4150 R&D Projects: GA ČR GC15-02578J; GA MŠk(CZ) LTC17005 Institutional support: RVO:61388971 Keywords : biomimetic synthesis * galectin-3 * glycosylation Subject RIV: CE - Biochemistry OBOR OECD: Biochemistry and molecular biology Impact factor: 5.646, year: 2016

New 5-benzylidenethiazolidin-4-one inhibitors of bacterial MurD ligase: design, synthesis, crystal structures, and biological evaluation.

Science.gov (United States)

Zidar, Nace; Tomašić, Tihomir; Šink, Roman; Kovač, Andreja; Patin, Delphine; Blanot, Didier; Contreras-Martel, Carlos; Dessen, Andréa; Premru, Manica Müller; Zega, Anamarija; Gobec, Stanislav; Mašič, Lucija Peterlin; Kikelj, Danijel

2011-11-01

Mur ligases (MurC-MurF), a group of bacterial enzymes that catalyze four consecutive steps in the formation of cytoplasmic peptidoglycan precursor, are becoming increasingly adopted as targets in antibacterial drug design. Based on the crystal structure of MurD cocrystallized with thiazolidine-2,4-dione inhibitor I, we have designed, synthesized, and evaluated a series of improved glutamic acid containing 5-benzylidenerhodanine and 5-benzylidenethiazolidine-2,4-dione inhibitors of MurD with IC(50) values up to 28 μM. Inhibitor 37, with an IC(50) of 34 μM, displays a weak antibacterial activity against S. aureus ATCC 29213 and E. faecalis ATCC 29212 with minimal inhibitory concentrations of 128 μg/mL. High-resolution crystal structures of MurD in complex with two new inhibitors (compounds 23 and 51) reveal details of their binding modes within the active site and provide valuable information for further structure-based optimization. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Synthesis of Some O-Substituted Derivatives of Natural 6-hydroxymethyl-4-methoxy-2H-pyran-2-one (opuntiol)

International Nuclear Information System (INIS)

Shahzadi, T.; Akhtar, M.; Rehman, A.; Riaz, T.; Ashraf, M.

2013-01-01

This manuscript reports the synthesis of a series of new O-substituted derivatives of opuntiol (1) which is a naturally occurring compound isolated from a plant Opuntia dillenii Haw belonging to family Cactaceae. These derivatives 3a-t, were characterized by FAB-MS, IR, and 1H-NMR and then screened against acetylcholinesterase, butyrylcholinesterase, lipoxygenase and H-chymotrypsin enzymes. The screening results revealed that 6-(acetyloxy) methyl- 4-methoxy-2H-pyran-2-one (3b) and N-(2,5-dimethylphenyl)-2-((4-methoxy-6-oxo-2H-pyran-2-yl) methoxy)acetamide (3p) were found to be the inhibitor of butyrylcholinesterase while 6-(acetyloxy) methyl- 4-methoxy-2H-pyran-2-one (3b), 6-(ethoxymethyl)-4-methoxy-2H-pyran-2-one (3c), 4-methoxy-6-((phenylmethoxy)methyl)-2H-pyran-2-one (3g), 6-((2-bromoethyloxy)methyl)-4-methoxy-2H-pyran-2-one (3j), N-(5-chloro-2-ethoxyphenyl)-2-((4-methoxy-6-oxo-2H-pyran-2-yl)methoxy) acetamide (3r), N-(3,4-dimethylphenyl)-2-((4-methoxy-6-oxo-2H-pyran-2-yl)methoxy)acetamide (3s) N-(3,5-dimethylphenyl)-2-((4-methoxy-6-oxo-2H-pyran-2-yl)methoxy)acetamide (3t) were found to be active against H-chymotrypsin and among these 3s was the good inhibitor of this enzyme having IC50 value of 142.71 +- 0.22 micro moles/L. (author)

Lower leukotriene C4 levels in bronchoalveolar lavage fluid of asthmatic subjects after 2.5 years of inhaled corticosteroid therapy

Directory of Open Access Journals (Sweden)

Y. Oosterhoff

1995-01-01

Full Text Available Long-term treatment with inhaled corticosteroids has been shown to result in improvement of symptoms and lung function in subjects with asthma. Arachidonic acid (AA metabolites are thought to play a role in the pathophysiology of asthma. It was assessed whether differences could be found in bronchoalveolar lavage (BAL AA metabolite levels between subjects with asthma who were treated for 2.5 years with inhaled bronchodilators alone or in combination with inhaled corticosteroids. Prostaglandin (PGD2, PGF2α, 6-keto-PGF1α, thromboxane B2, leukotriene (LTC4 and LTB4 levels and cell numbers were assessed in BAL fluid from 22 non-smoking asthmatic subjects. They were participating in a randomized, double-blind multicentre drug trial over a period of 2.5 years. Results of the group treated with inhaled corticosteroids (CS+: beclomethasone 200 μg four times daily were compared with the other group (CS− which was treated with either ipratropium bromide (40 μg four times daily or placebo. BAL LTC4 levels of asthmatic subjects were significantly lower after 2.5 years inhaled corticosteroid therapy (CS+, 9(1–17 pg/ml vs. CS−, 16(6-53 pg/ml; p = 0.01. The same trend was observed for the PGD2 levels. The results suggest that inhaled corticosteroids may exert their beneficial effect on lung function via a mechanism in which inhibition of LTC4 synthesis in the airways is involved.

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

Science.gov (United States)

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

2016-10-01

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

Synthesis and Docking Studies of 2,4,6-Trihydroxy-3-Geranylacetophenone Analogs as Potential Lipoxygenase Inhibitor

Directory of Open Access Journals (Sweden)

Chean Hui Ng

2014-08-01

Full Text Available The natural product molecule 2,4,6-trihydroxy-3-geranyl-acetophenone (tHGA isolated from the medicinal plant Melicope ptelefolia was shown to exhibit potent lipoxygenase (LOX inhibitory activity. It is known that LOX plays an important role in inflammatory response as it catalyzes the oxidation of unsaturated fatty acids, such as linoleic acid to form hydroperoxides. The search for selective LOX inhibitors may provide new therapeutic approach for inflammatory diseases. Herein, we report the synthesis of tHGA analogs using simple Friedel-Craft acylation and alkylation reactions with the aim of obtaining a better insight into the structure-activity relationships of the compounds. All the synthesized analogs showed potent soybean 15-LOX inhibitory activity in a dose-dependent manner (IC50 = 10.31–27.61 μM where compound 3e was two-fold more active than tHGA. Molecular docking was then applied to reveal the important binding interactions of compound 3e in soybean 15-LOX binding site. The findings suggest that the presence of longer acyl bearing aliphatic chain (5Cs and aromatic groups could significantly affect the enzymatic activity.

Crowdsourcing Disease Biomarker Discovery Research: The IP4IC Study.

Science.gov (United States)

Chancellor, Michael B; Bartolone, Sarah N; Veerecke, Andrew; Lamb, Laura E

2018-05-01

Biomarker discovery is limited by readily assessable, cost efficient human samples available in large numbers that represent the entire heterogeneity of the disease. We developed a novel, active participation crowdsourcing method to determine BP-RS (Bladder Permeability Defect Risk Score). It is based on noninvasive urinary cytokines to discriminate patients with interstitial cystitis/bladder pain syndrome who had Hunner lesions from controls and patients with interstitial cystitis/bladder pain syndrome but without Hunner lesions. We performed a national crowdsourcing study in cooperation with the Interstitial Cystitis Association. Patients answered demographic, symptom severity and urinary frequency questionnaires on a HIPAA (Health Insurance Portability and Accountability Act) compliant website. Urine samples were collected at home, stabilized with a preservative and sent to Beaumont Hospital for analysis. The expression of 3 urinary cytokines was used in a machine learning algorithm to develop BP-RS. The IP4IC study collected a total of 448 urine samples, representing 153 patients (147 females and 6 males) with interstitial cystitis/bladder pain syndrome, of whom 54 (50 females and 4 males) had Hunner lesions. A total of 159 female and 136 male controls also participated, who were age matched. A defined BP-RS was calculated to predict interstitial cystitis/bladder pain syndrome with Hunner lesions or a bladder permeability defect etiology with 89% validity. In this novel participation crowdsourcing study we obtained a large number of urine samples from 46 states, which were collected at home, shipped and stored at room temperature. Using a machine learning algorithm we developed BP-RS to quantify the risk of interstitial cystitis/bladder pain syndrome with Hunner lesions, which is indicative of a bladder permeability defect etiology. To our knowledge BP-RS is the first validated urine biomarker assay for interstitial cystitis/bladder pain syndrome and one of the

Synthesis, structure combined with conformational analysis, biological activities and docking studies of bis benzylidene cyclohexanone derivatives

Directory of Open Access Journals (Sweden)

Gehad Lotfy

2017-07-01

Full Text Available We report the synthesis and biological evaluation of bis benzylidne cyclohexanone derivatives 2,6-di(4-fluorobenzylidenecyclohexanone 3a and (2E,6E‐2,6‐bis({[4‐(trifluoromethylphenyl]methylidene}cyclohexanone 3b. Compound 3b crystallized in the monoclinic space group P21/n with unit cell parameters a = 29.3527(12 Å, b = 8.3147(3 Å, c = 32.7452(14 Å, β = 112.437(2°, and V = 7386.8(5 Å3, Z = 16, and Rint = 0.072 at T = 100 K. The asymmetric unit contains four independent molecules, each of which has slight differences in the bond lengths and angles. One non-classical C11D–H11F⋯F3A hydrogen bond connects the molecules. Density functional theory was used to optimize the structures and calculate the natural charges, dipole moments, frontier molecular orbitals, and NMR and UV–Vis spectroscopic properties, which are discussed and compared with the experimental data. The synthetic derivatives were evaluated for α-glucosidase inhibitory activity, and we found that compound 3a (IC50 = 96.3 ± 0.51 μM is a potent α-glucosidase inhibitor, showing superior activity to the standard drug acarbose (IC50 = 841 ± 1.73 μM. Compound 3b (IC50 = 7.92 ± 1.3 μg/mL was found to be a potent antileishmanial compound, especially compared to the antileishmanial drugs pentamidine (IC50 = 5.09 ± 0.04 μM and amphotericine B (IC50 = 0.29 ± 0.05 μg/mL. In addition, 3a and 3b have cytotoxic effects against PC3 (prostate cancer, HeLa (cervical cancer, and MCF-3 (breast cancer cell lines. Docking study for compounds activity was performed with Openeye software in order to understanding their pose of interaction in the target receptors.

5-Acetyl-6-methyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones: As potent urease inhibitors; synthesis, in vitro screening, and molecular modeling study.

Science.gov (United States)

Shamim, Shahbaz; Khan, Khalid Mohammed; Salar, Uzma; Ali, Farman; Lodhi, Muhammad Arif; Taha, Muhammad; Khan, Farman Ali; Ashraf, Sajda; Ul-Haq, Zaheer; Ali, Muhammad; Perveen, Shahnaz

2018-02-01

5-Acetyl-6-methyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones 1-43 were synthesized in a "one-pot" three component reaction and structurally characterized by various spectroscopic techniques such as 1 H, 13 C NMR, EI-MS, HREI-MS, and IR. All compounds were evaluated for their in vitro urease inhibitory activity. It is worth mentioning that except derivatives 1, 11, 12, and 14, all were found to be more potent than the standard thiourea (IC 50  = 21.25 ± 0.15 µM) and showed their urease inhibitory potential in the range of IC 50  = 3.70 ± 0.5-20.14 ± 0.1 µM. Structure-activity relationship (SAR) was rationalized by looking at the varying structural features of the molecules. However, molecular modeling study was performed to confirm the binding interactions of the molecules (ligand) with the active site of enzyme. Copyright © 2017 Elsevier Inc. All rights reserved.

Mod 1 ICS TI Report: ICS Conversion of a 140% HPGe Detector

Energy Technology Data Exchange (ETDEWEB)

Bounds, John Alan [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

2016-07-05

This report evaluates the Mod 1 ICS, an electrically cooled 140% HPGe detector. It is a custom version of the ORTEC Integrated Cooling System (ICS) modified to make it more practical for us to use in the field. Performance and operating characteristics of the Mod 1 ICS are documented, noting both pros and cons. The Mod 1 ICS is deemed a success. Recommendations for a Mod 2 ICS, a true field prototype, are provided.

Inhibition of prostaglandin synthesis after metabolism of menadione by cultured porcine endothelial cells.

OpenAIRE

Barchowsky, A; Tabrizi, K; Kent, R S; Whorton, A R

1989-01-01

We have examined the effects of menadione on porcine aortic endothelial cell prostaglandin synthesis. Addition of 1-20 microM menadione caused a dose- and time-dependent inhibition of stimulated prostaglandin synthesis with an IC50 of 5 microM at 15 min. Concentrations greater than 100 microM menadione were necessary to increase 51Cr release from prelabeled cells. Recovery of enzyme inactivated by menadione required a 6-h incubation in 1% serum. In a microsomal preparation, menadione was show...

Synthesis, crystal structures, molecular docking, in vitro monoamine oxidase-B inhibitory activity of transition metal complexes with 2-{4-[bis (4-fluorophenyl)methyl]piperazin-1-yl} acetic acid

Science.gov (United States)

Yang, Dan-dan; Wang, Riu; Zhu, Jin-long; Cao, Qi-yue; Qin, Jie; Zhu, Hai-liang; Qian, Shao-song

2017-01-01

Three novel complexes, [Cu(L)2(H2O)](1), [Zn(L)2(H2O)2]·CH3OH·1.5H2O(2), and [Ni(L)2(H2O)1.8]·CH3OH·1.2H2O (3) (HL = 2-{4-[bis(4-fluorophenyl)methyl]pipera-zin-1-yl} acetic acid), were synthesized and structurally determined by single-crystal X-ray diffraction. Molecular docking study preliminarily revealed that complex 1 had potential Monoamine oxidase B inhibitory activity. All acquired compounds were tested against rat brain MAO-B in vitro. In accordance with the result of calculation, it showed complex 1 (IC50 = 1.85 ± 0.31 μM) have good inhibitory activity against MAO-B at the same micromolar concentrations with positive control Iproniazid Phosphate (IP, IC50 = 7.59 ± 1.17 μM). These results indicated that complex 1 was a potent MAO-B inhibitor.

Task 4 - EMI/RFI Issues Potentially Impacting Electromagnetic Compatibility of I&C Systems (NRCHQ6014D0015)

Energy Technology Data Exchange (ETDEWEB)

Wood, Richard Thomas [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Ewing, Paul D. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

2015-05-01

The U.S. Nuclear Regulatory Commission’s (NRC’s) regulations in Part 50, “Domestic Licensing of Production and Utilization Facilities,” of Title 10 of the Code of Federal Regulations (10 CFR Part 50) state that structures, systems, and components important to safety in a nuclear power plant are to be designed to accommodate the effects of environmental conditions (i.e., remain functional under all postulated service conditions) and that design control measures such as testing are to be used to check the adequacy of design. Regulatory Guide (RG) 1.180 was developed to provide guidance to licensees and applicants on methods acceptable to the NRC staff for complying with the NRC’s regulations on design, installation, and testing practices for addressing the effects of electromagnetic and radio-frequency interference (EMI/RFI) and power surges on safety-related instrumentation and control (I&C) systems. The first revision of RG 1.180 was issued in January 2000 and a second revision was issued in October 2003*. The second revision differed from the first revision in endorsing Military Standard (MIL-STD)-461E and the International Electrotechnical Commission (IEC) Standard (Std) 61000 series of EMI/RFI test methods, extending the guidance to cover signal line testing, incorporating frequency ranges where portable communications devices are experiencing increasing use, and relaxing the operating envelopes (test levels) when experience and confirmatory research warranted. It also offered exemptions from specific test criteria based on technical considerations such as plant conditions and the intended location of the safety-related I&C equipment. Since the last revision, new requirements have been identified, associated RGs have been created and updated, and additional industry guidance has been developed. Additionally, the operational environment has changed with the increase in wireless communication technology for both personal (smartphone) and industrial

Bioactivity-Guided Metabolite Profiling of Feijoa ( Acca sellowiana) Cultivars Identifies 4-Cyclopentene-1,3-dione as a Potent Antifungal Inhibitor of Chitin Synthesis.

Science.gov (United States)

Mokhtari, Mona; Jackson, Michael D; Brown, Alistair S; Ackerley, David F; Ritson, Nigel J; Keyzers, Robert A; Munkacsi, Andrew B

2018-06-06

Pathogenic fungi continue to develop resistance against current antifungal drugs. To explore the potential of agricultural waste products as a source of novel antifungal compounds, we obtained an unbiased GC-MS profile of 151 compounds from 16 commercial and experimental cultivars of feijoa peels. Multivariate analysis correlated 93% of the compound profiles with antifungal bioactivities. Of the 18 compounds that significantly correlated with antifungal activity, 5 had not previously been described from feijoa. Two novel cultivars were the most bioactive, and the compound 4-cyclopentene-1,3-dione, detected in these cultivars, was potently antifungal (IC 50 = 1-2 μM) against human-pathogenic Candida species. Haploinsufficiency and fluorescence microscopy analyses determined that the synthesis of chitin, a fungal-cell-wall polysaccharide, was the target of 4-cyclopentene-1,3-dione. This fungal-specific mechanism was consistent with a 22-70-fold reduction in antibacterial activity. Overall, we identified the agricultural waste product of specific cultivars of feijoa peels as a source of potential high-value antifungal compounds.

New Sorafenib Derivatives: Synthesis, Antiproliferative Activity Against Tumour Cell Lines and Antimetabolic Evaluation

Directory of Open Access Journals (Sweden)

Branka Zorc

2012-01-01

Full Text Available Sorafenib is a relatively new cytostatic drug approved for the treatment of renal cell and hepatocellular carcinoma. In this report we describe the synthesis of sorafenib derivatives 4a–e which differ from sorafenib in their amide part. A 4-step synthetic pathway includes preparation of 4-chloropyridine-2-carbonyl chloride hydrochloride (1, 4-chloro-pyridine-2-carboxamides 2a–e, 4-(4-aminophenoxy-pyridine-2-carboxamides 3a–e and the target compounds 4-[4-[[4-chloro-3-(trifluoromethylphenyl]carbamoylamino]-phenoxy]-pyridine-2-carboxamides 4a–e. All compounds were fully chemically characterized and evaluated for their cytostatic activity against a panel of carcinoma, lymphoma and leukemia tumour cell lines. In addition, their antimetabolic potential was investigated as well. The most prominent antiproliferative activity was obtained for compounds 4a–e (IC50 = 1-4.3 μmol·L−1. Their potency was comparable to the potency of sorafenib, or even better. The compounds inhibited DNA, RNA and protein synthesis to a similar extent and did not discriminate between tumour cell lines and primary fibroblasts in terms of their anti-proliferative activity.

Solid phase synthesis and antiprotozoal evaluation of di- and trisubstituted 5'-carboxamidoadenosine analogues.

Science.gov (United States)

Rodenko, Boris; Detz, Remko J; Pinas, Victorine A; Lambertucci, Catia; Brun, Reto; Wanner, Martin J; Koomen, Gerrit-Jan

2006-03-01

The rapid increase of resistance to drugs commonly used in the treatment of tropical diseases such as malaria and African sleeping sickness calls for the prompt development of new safe and efficacious drugs. The pathogenic protozoan parasites lack the capability of synthesising purines de novo and they take up preformed purines from their host through various transmembrane transporters. Adenosine derivatives constitute a class of potential therapeutics due to their selective internalisation by these transporters. Automated solid-phase synthesis can speed up the process of lead finding and we pursued the solid-phase synthesis of di- and trisubstituted 5'-carboxamidoadenosine derivatives by using a safety-catch approach. While efforts with Kenner's sulfonamide linker remained fruitless, successful application of the hydrazide safety-catch linker allowed the construction of two representative combinatorial libraries. Their antiprotozoal evaluation identified two compounds with promising activity: N(6)-benzyl-5'-N-phenylcarboxamidoadenosine with an IC(50) value of 0.91 microM against Trypanosoma brucei rhodesiense and N(6)-diphenylethyl-5'-phenylcarboxamidoadenosine with an IC(50) value of 1.8 microM against chloroquine resistant Plasmodium falciparum.

Antioxidant and Cytotoxic Effects of Crude Extract, Fractions and 4-Nerolidylcathecol from Aerial Parts of Pothomorphe umbellata L. (Piperaceae

Directory of Open Access Journals (Sweden)

Andrey P. Lopes

2013-01-01

Full Text Available The crude ethanolic extract from aerial parts of Pothomorphe umbellata L. (Piperaceae and fractions obtained by partitions sequentially among water-methanol, methylene chloride, and ethyl acetate, as well as the major constituent, 4-nerolidylcatechol, were, respectively, evaluated and evidenced for antioxidant and cytotoxic effects through fluorometric microplate and microculture tetrazolium assays in HL-60 cells. The crude ethanolic extract demonstrated the preeminent antioxidant activity (IC50=1.2 μg/mL against exogenous cytoplasmic reactive oxygen species, followed by the water-methanolic (IC50=4.5 μg/mL, methylene chloride (IC50=5.9 μg/mL, ethyl acetate (IC50=8.0 μg/mL, 4-nerolidylcatechol (IC50=8.6 μg/mL, and the sterol fractions (IC50>12.5 μg/mL. Vitamin C, the positive control used in this assay, presented IC50 value equivalent to 1.7 μg/mL. 4-Nerolidylcatechol (IC50=0.4 μg/mL and methylene chloride fraction (IC50=2.3 μg/mL presented considerable cytotoxicity probably because of the presence of an o-quinone, an auto-oxidation by product of the catechol. Polar compounds, present in the ethanol extract, appear to increase the solubility and stability of the major active constituent, acting synergistically with 4-nerolidylcatechol, improving its pharmacokinetic parameters and increasing significantly its antioxidant activity which, in turn, suggests that the aqueous-ethanolic extract, used in folklore medicine, is safe and effective.

2,4,6-Trichlorophenylhydrazine Schiff bases as DPPH radical and super oxide anion scavengers.

Science.gov (United States)

Khan, Khalid Mohammed; Shah, Zarbad; Ahmad, Viqar Uddin; Khan, Momin; Taha, Muhammad; Rahim, Fazal; Ali, Sajjad; Ambreen, Nida; Perveen, Shahnaz; Choudhary, M Iqbal; Voelter, Wolfgang

2012-05-01

Syntheses of thirty 2,4,6-trichlorophenylhydrazine Schiff bases 1-30 were carried out and evaluated for their in vitro DPPH radical and super oxide anion scavenging activities. Compounds 1-30 have shown a varying degree of DPPH radical scavenging activity and their IC50 values range between 4.05-369.30 µM. The compounds 17, 28, 18, 14, 8, 15, 12, 2, 29, and 7 exhibited IC50 values ranging between 4.05±0.06-24.42±0.86 µM which are superior to standard n-propylgallate (IC50=30.12±0.27 µM). Selected compounds have shown a varying degree of superoxide anion radical scavenger activity and their IC50 values range between 91.23-406.90 µM. The compounds 28, 8, 17, 15, and 14, showed IC50 values between 91.23±1.2-105.31±2.29 µM which are superior to standard n-propylgallate (IC50=106.34±1.6 µM).

K/sub Ic/ and J/sub Ic/ of Westerly granite: effects of thickness and in-plane dimensions

International Nuclear Information System (INIS)

Schmidt, R.A.; Lutz, T.J.

1978-01-01

An investigation is described in which tensile properties, fracture toughness, and critical J integral are measured for Westerly granite, a rock that is widely used in rock mechanics studies. This was primarily a parameter sensitivity study in which the effects of specimen dimensions and testing techniques were assessed. It is hoped that this study will aid in establishing tentative standards and guidelines for fracture toughness testing of rock as well as indicate the feasibility of using a J integral fracture criterion for this material. ASTM standard specimen configurations of the compact and bend types were tested with compact specimens ranging in width from W = 25.4 mm to W = 406.4 mm (0.5T to 8T) and with thickness ranging from 13 mm to 100 mm. A series of 4T compact specimens were tested to assess the effects of thickness and fatigue precracking. Techniques are described that enable several values of K/sub Ic/, a complete J vs crack growth curve, and a J/sub Ic/ value to be obtained from each sample. Direct-pull tension tests on shaped specimens of Westerly granite are described which indicate a high degree of nonlinear, inelastic behavior. This fact raises questions about the use of LEFM, but the J/sub Ic/ data presented appear to validate the K/sub Ic/ measurements

A Green Synthesis of Chalcones As an Antioxidant and Anticancer

Science.gov (United States)

Susanti VH, Elfi; Agustina Eko Setyowati, Widiastuti

2018-01-01

Three chalcones (4’-amino-4-methoxy chalcone, 4’-amino-3,4-dimethoxy chalcone and 4’-amino-3,4,5-trimethoxy chalcone) has been synthesized by a green chemistry approach using grinding technique. Antioxidant activity of the chalcones were assessed using 1,1-biphenyl-2-picrylhydrazyl (DPPH) radical scavenging method. Cytotoxicity of chalcones sythesized was evaluated using a tetrazolium (MTT) colorimetric assay against cervical cancer cell line, HeLa. The antioxidant activity test showed that 4’-amino-4-methoxy chalcone had a stronger activity than the 4’-amino-3,4-dimethoxy chalcone and 4’-amino-3,4,5-trimethoxy chalcone, respectively with IC50 58.85, 64.79 and 210.3 μg/mL. These results indicate that there is a relationship between the structure of chalcone with antioxidant activity, the more methoxy groups in the ring B of the chalcone, antioxidant activity is getting smaller. The chalcone synthesized showed cytotoxicity against HeLa cell line with IC50 value of 31.75, 36.65, 49.04 μg/mL, respectively. It was observed that the highest cytotoxic activity was found at 4’-amino-4-methoxy chalcone (IC50 31.75 μg/mL). Lower activity was showed by 4’-amino-3,4,5-trimethoxy chalcone with IC50 value of 49,04 μg/mL. There is a relationship cytotoxicity with chalcone structure, the more the number of methoxy groups in ring B chalcone, will decrease the activity of cytotoxicity.

Studies on the Total Synthesis of Amphidinolide O (II): A Stereoselective Synthesis of C1-C11 Fragment

Energy Technology Data Exchange (ETDEWEB)

Jang, Mi Yeon; Kim, Jong Woo; Lee, Duck Hyung [Sogang University, Seoul (Korea, Republic of)

2005-10-15

Two ketones and, the C1-C11 fragment of Amphidinolide O, were prepared stereoselectively via 14 and 16 step sequences in 8.7% and 2.0% overall yield, respectively. The amphidinolides were isolated from the marine dinoflagellate Amphidinium sp., which produces a host of secondary metabolites endowed with potent cytotoxicity against various cancer cell lines. Amphidinolide O displayed potent in vitro cytotoxicity against L1210 marine leukemia cells and human epidermoid carcinoma KB cells with 1.7 and 3.6 μg/mL of IC50s, respectively. In addition to our recent reports regarding to the synthesis of C12-C17 and C3-C11 fragments of amphidinolide O, we describe herein a new route to diastereoselective synthesis of C1-C11 fragment of. The retrosynthetic analysis of led to the C1-C11 fragment and C12-C17 fragment. The hemiketal was expected from acyclic precursor 4 which, in turn, would be derived by diastereoselective aldol reaction between ketone and aldehyde.

6-Substituted 3,4-dihydro-naphthalene-2-carboxylic acids: synthesis and structure-activity studies in a novel class of human 5alpha reductase inhibitors.

Science.gov (United States)

Baston, Eckhard; Salem, Ola I A; Hartmann, Rolf W

2002-10-01

Novel 3,4-dihydro-naphthalene-2-carboxylic acids were synthesized and evaluated for 5alpha reductase inhibitory activity. This enzyme exists in two isoforms and is a pharmacological target for the treatment of benign prostatic hyperplasia, male pattern baldness and acne. In the present study non-steroidal compounds capable of mimicking the transition state of the steroidal substrates were prepared. The synthetic strategy for the preparation of compounds 1-6 consisted of triflation followed by subsequent Heck-type carboxylation or methoxy carbonylation for 6-phenyl-3,4-dihydronaphthalen-2(1H)-one 1c. A Negishi-type coupling reaction between 6-(trifluoro-methanesulfonyloxy)-3,4-dihydro-naphthalene-2-carboxylic acid methyl ester 7b and various aryl bromides led, after further transformations, to 6-substituted 3,4-dihydro-naphthalene-2-carboxylic acids 7-15. In a similar way the corresponding naphthalene-2-carboxylic acids 16 and 17 were obtained. The DU 145 cell line and prostate homogenates served as enzyme sources for the human type 1 and type 2 isozymes, whereas ventral prostate was employed to evaluate rat isozyme inhibitory potency. The most active inhibitors identified in this study were 6-[4-(N,N-dicyclohexylaminocarbonyl)phenyl]-3,4-dihydro-naphthalene-2-carboxylic acid (3) (IC50 = 0.09 microM, rat type 1), 6-[3-(N,N-dicyclohexylaminocarbonyl)phenyl]-3,4-dihydro-naphthalene-2-carboxylic acid (13) (IC50 = 0.75 microM, human type 2; IC50 = 0.81 microM, human type 1) and 6-[4-(N,N-diisopropylamino-carbonyl)phenyl]naphthalene-2-carboxylic acid (16) (IC50 = 0.2 microM, human type 2). The latter compound was shown to deactivate the enzyme in an uncompetitive manner (Ki = 90 nM; Km, Testosterone = 0.8-1.0 microM) similar to the steroidal inhibitor Epristeride. Select inhibitors (13 and 16) were tested in vivo using testosterone propionate-treated, juvenile, orchiectomized SD-rats. None of the compounds was active at a dose of 25 mg/kg. This result might in part be

LTC: a novel algorithm to improve the efficiency of contig assembly for physical mapping in complex genomes

Directory of Open Access Journals (Sweden)

Feuillet Catherine

2010-11-01

Full Text Available Abstract Background Physical maps are the substrate of genome sequencing and map-based cloning and their construction relies on the accurate assembly of BAC clones into large contigs that are then anchored to genetic maps with molecular markers. High Information Content Fingerprinting has become the method of choice for large and repetitive genomes such as those of maize, barley, and wheat. However, the high level of repeated DNA present in these genomes requires the application of very stringent criteria to ensure a reliable assembly with the FingerPrinted Contig (FPC software, which often results in short contig lengths (of 3-5 clones before merging as well as an unreliable assembly in some difficult regions. Difficulties can originate from a non-linear topological structure of clone overlaps, low power of clone ordering algorithms, and the absence of tools to identify sources of gaps in Minimal Tiling Paths (MTPs. Results To address these problems, we propose a novel approach that: (i reduces the rate of false connections and Q-clones by using a new cutoff calculation method; (ii obtains reliable clusters robust to the exclusion of single clone or clone overlap; (iii explores the topological contig structure by considering contigs as networks of clones connected by significant overlaps; (iv performs iterative clone clustering combined with ordering and order verification using re-sampling methods; and (v uses global optimization methods for clone ordering and Band Map construction. The elements of this new analytical framework called Linear Topological Contig (LTC were applied on datasets used previously for the construction of the physical map of wheat chromosome 3B with FPC. The performance of LTC vs. FPC was compared also on the simulated BAC libraries based on the known genome sequences for chromosome 1 of rice and chromosome 1 of maize. Conclusions The results show that compared to other methods, LTC enables the construction of highly

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

Science.gov (United States)

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

2012-08-01

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

Utilization of Snail (Achatina fulica Shell Waste for Synthesis of Calcium Tartrate Tetrahydrate (CaC4H4O6.4H2O Single Crystals in Silica Gel

Directory of Open Access Journals (Sweden)

Imam Sakdi

2012-01-01

Full Text Available Snail (Achatina fulica shell waste is massively produced by many home industries in Indonesia, especially in East Java. The snail shell is known for high calcium; therefore it is potential to be used as calcium source of supernatant in the synthesis of piezoeletric material, such as single crystal of calcium tartrate tetrahydrate (CaTT. The aim of this research is to study the synthesis and characterization of CaTT or CaC4H4O6.4H2O from snail shell waste in silica gel. Supernatant solution of CaCl2 was prepared from CaO, which previously made by calcinating the shell at 1000°C, and then reacted with HCl 1,5M. Synthesis of CaTT was conducted in a single-tube reaction at room temperature in which silica gel was used as growth medium with gelling time of 10 days and growth time of 2 weeks. The pH of gel and CaCl2 concentration were varied, 3.00; 3.50; 4.00; 4.50; 5.00; and 0.27; 0.36; 0.45; 0.54 M respectively, in order to obtain optimum condition of the synthesis, which is indicated from crystal yields. The synthesized crystals were characterized by atomic adsorption spectrophotometry (AAS, infrared spectroscopy (IR and powder X-ray diffraction (XRD. Experimental data shows that optimum condition was obtained at pH of 3.50 and [CaCl2] of 0.45M with yield of 69.37%. The obtained single crystal has clear color and octahedral-like shape with size ranged between 4 – 9 mm. Analysis data by FTIR and powder XRD confirmed that the obtained crystal was CaTT single crystals with crystal system of orthorhombic.

Cysteinyl leukotrienes C4 and D4 downregulate human mast cell expression of toll-like receptors 1 through 7.

Science.gov (United States)

Karpov, V; Ilarraza, R; Catalli, A; Kulka, M

2018-01-01

Cysteinyl leukotrienes (CysLT) are potent inflammatory lipid molecules that mediate some of the pathophysiological responses associated with asthma such as bronchoconstriction, vasodilation and increased microvascular permeability. As a result, CysLT receptor antagonists (LRA), such as montelukast, have been used to effectively treat patients with asthma. We have recently shown that mast cells are necessary modulators of innate immune responses to bacterial infection and an important component of this innate immune response may involve the production of CysLT. However, the effect of LRA on innate immune receptors, particularly on allergic effector cells, is unknown. This study determined the effect of CysLT on toll-like receptor (TLR) expression by the human mast cell line LAD2. Real-time PCR analysis determined that LTC4, LTD4 and LTE4 downregulated mRNA expression of several TLR. Specifically in human CD34+-derived human mast cells (HuMC), LTC4 inhibited expression of TLR1, 2, 4, 5, 6 and 7 while LTD4 inhibited expression of TLR1-7. Montelukast blocked LTC4-mediated downregulation of all TLR, suggesting that these effects were mediated by activation of the CysLT1 receptor (CysLT1R). Flow cytometry analysis confirmed that LTC4 downregulated surface expression of TLR2 which was blocked by montelukast. These data show that CysLT can modulate human mast cell expression of TLR and that montelukast may be beneficial for innate immune responses mediated by mast cells.

Long-term control medication use and asthma control status among children and adults with asthma.

Science.gov (United States)

Zahran, Hatice S; Bailey, Cathy M; Qin, Xiaoting; Johnson, Carol

2017-12-01

Uncontrolled asthma decreases quality of life and increases health care use. Most people with asthma need daily use of long-term control (LTC) medications for asthma symptoms and to prevent asthma attacks. Ongoing assessment of a person's level of asthma control and medication use is important in determining the effectiveness of current treatment to decrease the frequency and intensity of symptoms and functional limitations. To assess the use of LTC medication among children and adults with current asthma and identify contributing factors for LTC medication use. We used the 2006-2010 Behavioral Risk Factor Surveillance System (BRFSS) child and adult Asthma Call-back Survey (ACBS) data to assess the level of asthma control and LTC medication use. Asthma control was classified as well controlled and uncontrolled using guideline-based measures. We used multivariable logistic regression models to identify contributing factors for LTC medication use and having uncontrolled asthma. Among persons with current asthma, 46.0% of children and 41.5% of adults were taking LTC medications and 38.4% of children and 50.0% of adults had uncontrolled asthma. Among children who had uncontrolled asthma (38.4%), 24.1% were taking LTC medications and 14.3% were not taking LTC medications. Among adults who had uncontrolled asthma (50.0%), 26.7% were taking LTC medications and 23.3% were not taking LTC medications. Using BRFSS ACBS data to assess the level of asthma control and LTC medication use can identify subpopulations of persons with asthma who receive suboptimal treatment, for which better asthma-related medical treatment and management are needed.

Vastatins have a distinct effect on sterol synthesis and progesterone secretion in human granulosa cells in vitro

NARCIS (Netherlands)

Vliet, A.K. van; Thiel, G.C.F. van; Naaktgeboren, N.; Cohen, L.H.

1996-01-01

Lovastatin and simvastatin are strong inhibitors of cholesterol synthesis in cultured human granulosa cells, as measured within 6 days after isolation, with IC50-values of respectively 27.0 and 18.2 nM obtained after 3.5 hours of incubation with the drugs. Pravastatin is a much weaker inhibitor of

Synthesis and biological evaluation of conformationally restricted σ(1) receptor ligands with 7,9-diazabicyclo[4.2.2]decane scaffold.

Science.gov (United States)

Sunnam, Sunil K; Schepmann, Dirk; Rack, Elisabeth; Fröhlich, Roland; Korpis, Katharina; Bednarski, Patrick J; Wünsch, Bernhard

2010-12-21

The key step in the synthesis of the 7,9-diazabicyclo[4.2.2]decane system was a modified Dieckmann condensation of piperazinebutyrate 11, which makes use of trapping the first cyclized intermediate with TMS-Cl. Reduction of the bicyclic ketone 14 with LiBH(4) at -90 °C provided diastereoselectively (>99 : 1) the syn-configured alcohol 15a, which was converted into the final alcohol and ethers 16a-g. The configuration at the 2-position was established by X-ray structure analysis of methyl and ethyl ethers 15b and 15c. In contrast to bicyclic systems with a three-carbon bridge, inversion of the configuration at the 2-position of the alcohol 15a failed to give the inverted alcohol 19a. However, an unselective reduction of the ketone 24 with L-Selectride led to the diastereomeric alcohols 16a and 25a in the ratio 36 : 64. LiAlH(4) reduction of the tosylate 20 and the alkene 18 yielded the diazabicyclo-decane 26 and -decene 27 without further substituents at the four-carbon bridge. The σ(1) and σ(2) receptor affinities were investigated in receptor binding studies with radioligands. All test compounds showed a lower σ(1) affinity than the corresponding bicyclic derivatives with a three-membered bridge. The reduced σ(1) receptor affinity is attributed to the larger four-membered bridge. This hypothesis is supported by the alkene 27, which represents the most potent σ(1) ligand of this series (K(i) = 7.5 nM). In the alkene 27 the size and flexibility of the bridge is considerably reduced by the double bond. The methyl ether 25b and the unsubstituted derivatives 26 and 27 revealed moderate inhibition of the growth of the human tumor cell lines A-427, 5637 and MCF-7. Again, these compounds are less potent than the analogues with a three-membered bridge. The IC(50)-value of the most potent σ(1) ligand 27 against the small cell lung cancer cell line A-427 (IC(50) = 10 μM) should be emphasized, since this cell line is particularly sensitive to homologues with a

DNA-Directed alkylating agents. 7. Synthesis, DNA interaction, and antitumor activity of bis(hydroxymethyl)- and bis(carbamate)-substituted pyrrolizines and imidazoles.

Science.gov (United States)

Atwell, G J; Fan, J Y; Tan, K; Denny, W A

1998-11-19

A series of bis(hydroxymethyl)-substituted imidazoles, thioimidazoles, and pyrrolizines and related bis(carbamates), linked to either 9-anilinoacridine (intercalating) or 4-(4-quinolinylamino)benzamide (minor groove binding) carriers, were synthesized and evaluated for sequence-specific DNA alkylation and cytotoxicity. The imidazole and thioimidazole analogues were prepared by initial synthesis of [(4-aminophenyl)alkyl]imidazole-, thioimidazole-, or pyrrolizine dicarboxylates, coupling of these with the desired carrier, and reduction to give the required bis(hydroxymethyl) alkylating moiety. The pyrrolizines were the most reactive alkylators, followed by the thioimidazoles, while the imidazoles were unreactive. The pyrrolizines and some of the thioimidazoles cross-linked DNA, as measured by agarose gel electrophoresis. Strand cleavage assays showed that none of the compounds reacted at purine N7 or N3 sites in the gpt region of the plasmid gpt2Eco, but the polymerase stop assay showed patterns of G-alkylation in C-rich regions. The corresponding thioimidazole bis(carbamates) were more selective than the bis(hydroxymethyl) pyrrolizines, with high-intensity bands at 5'-NCCN, 5'-NGCN and 5'-NCGN sequences in the PCR stopping assay ( indicates block sites). The data suggest that these targeted compounds, like the known thioimidazole bis(carbamate) carmethizole, alkylate exclusively at guanine residues via the 2-amino group, with little or no alkylation at N3 and N7 guanine or adenine sites. The cytotoxicities of the compounds correlated broadly with their reactivities, with the bis(hydroxymethyl)imidazoles being the least cytotoxic (IC50s >1 microM; P388 leukemia) and with the intercalator-linked analogues being more cytotoxic than the corresponding minor-groove-targeted ones. This was true also for the more reactive thioimidazole bis(carbamates) (IC50s 0.8 and 11 microM, respectively), but both were more active than the analogous "untargeted" carmethizole (IC50 20

Extracellular calcium alters the effects of retinoic acid on DNA synthesis in cultured murine keratinocytes

International Nuclear Information System (INIS)

Tong, P.; Mayes, D.; Wheeler, L.

1986-01-01

The rate of proliferation of epidermal keratinocytes was manipulated by growing the cells in medium containing high or low concentrations of calcium. Keratinocytes cultured in high extracellular Ca ++ (1.4 mM and 2.8 mM) proliferated twice as fast as those grown in low Ca ++ medium (0.09 mM) as measured by incorporation of [ 3 H] thymidine into DNA. Exposure of high calcium keratinocytes to all-trans retinoic acid for 4 days caused a dose-related inhibition of DNA synthesis with an IC 50 of about 10 μM. In contrast, incubating low calcium keratinocytes with all-trans retinoic acid caused a dose-related stimulation of DNA synthesis with maximum increase of 278% over control at 10 μM. This increase was accompanied by increases in culture confluency with maximum increase of 109% in cell number of control at 10 μM. These results are of importance since they suggest Ca ++ may influence the effect of retinoids on keratinocytes

Synthesis and biological evaluation of novel thiadiazole amides as potent Cdc25B and PTP1B inhibitors.

Science.gov (United States)

Li, Yingjun; Yu, Yang; Jin, Kun; Gao, Lixin; Luo, Tongchuan; Sheng, Li; Shao, Xin; Li, Jia

2014-09-01

A series of novel thiadiazole amide derivatives have been synthesized and evaluated for inhibitory activities against Cdc25B and PTP1B. Most of them showed inhibitory activities against Cdc25B (IC50=1.18-8.01 μg/mL) and PTP1B (IC50=0.85-8.75 μg/mL), respectively. Moreover, compounds 5b and 4l were most potent with IC50 values of 1.18 and 0.85 μg/mL for Cdc25B and PTP1B, respectively, compared with reference drugs Na3VO4 (IC50=0.93 μg/mL) and oleanolic acid (IC50=0.85 μg/mL). The results of selectivity experiments showed that the target compounds were selective inhibitors against PTP1B and Cdc25B. Enzyme kinetic experiments demonstrated that compound 5k was a specific inhibitor with the typical characteristics of a mixed inhibitor. Copyright © 2014 Elsevier Ltd. All rights reserved.

Synthesis and antiviral activities of a novel class of thioflavone and flavonoid analogues

Directory of Open Access Journals (Sweden)

Dajun Zhang

2012-12-01

Full Text Available A novel class of thioflavone and flavonoid derivatives has been prepared and their antiviral activities against enterovirus 71 (EV71 and the coxsackievirus B3 (CVB3 and B6 (CVB6 were evaluated. Compounds 7d and 9b showed potent antiviral activities against EV71 with IC50 values of 8.27 and 5.48 μM, respectively. Compound 7f, which has been synthesized for the first time in this work, showed the highest level of inhibitory activity against both CVB3 and CVB6 with an IC50 value of 0.62 and 0.87 μM. Compounds 4b, 7a, 9c and 9e also showed strong inhibitory activities against both the CVB3 and CVB6 at low concentrations (IC50=1.42−7.15 μM, whereas compounds 4d, 7c, 7e and 7g showed strong activity against CVB6 (IC50=2.91–3.77 μM together with low levels of activity against CVB3. Compound 7d exhibited stronger inhibitory activity against CVB3 (IC50=6.44 μM than CVB6 (IC50>8.29 μM. The thioflavone derivatives 7a, 7c, 7d, 7e, 7f and 7g, represent a new class of lead compounds for the development of novel antiviral agents.

Characterization of guinea pig myocardial leukotriene C4 binding sites. Regulation by cations and sulfhydryl-directed reagents

International Nuclear Information System (INIS)

Hogaboom, G.K.; Mong, S.; Stadel, J.M.; Crooke, S.T.

1985-01-01

Using [ 3 H]leukotriene C4 (LTC4) and radioligand-binding techniques, specific leukotriene C4 binding sites have been identified in membranes derived from guinea pig ventricular myocardium. High performance liquid chromatography analyses indicated that, in the presence of the gamma-glutamyl transpeptidase inhibitor L-serine-borate (80 mM), less than 2% of membrane-bound [ 3 H]LTC4 was converted at 20 degrees to [ 3 H]leukotriene D4 or [ 3 H]leukotriene E4. The specific binding of 4 nM [ 3 H]LTC4, in the presence of 80 mM L-serine-borate, reached a stable steady state within 15 min at 20 degrees (pH 7.5). A monophasic Scatchard plot of saturation binding data yielded a dissociation constant (Kd) of 27.5 +/- 6.0 nM and a maximum number of binding sites (Bmax) of 19.9 +/- 5.2 pmol/mg of membrane protein. Competition binding studies of [ 3 H]LTC4 with synthetic leukotriene C4, leukotriene D4, and leukotriene E4 and the putative peptidoleukotriene antagonists FPL 55712, SKF 88046, and 4R-hydroxy-5S-1-cysteinylglycine-6Z-nonadecanoic acid revealed an order of potency of leukotriene C4 much greater than 4R-hydroxy-5S-1-cysteinylglycine-6Z-nonadecanoic acid greater than SKF 88046 greater than LTE4 greater than LTD4 greater than FPL 55712. The specific [ 3 H]LTC4 binding was stimulated by the divalent cations Ca2+, Mg2+, and Mn2+ and to a lesser degree by the monovalent cations Na+, K+, Li+, and NH4+. CaCl2 (3 mM) and NaCl (150 mM) stimulated the LTC4 binding by increasing the Bmax to 42.6 +/- 5.9 and 35.0 +/- 2.0 pmol/mg, respectively, but had minimal effects on Kd

Umbelliprenin-coated Fe3O4 magnetite nanoparticles: Antiproliferation evaluation on human Fibrosarcoma cell line (HT-1080)

International Nuclear Information System (INIS)

Khorramizadeh, M.R.; Esmail-Nazari, Z.; Zarei-Ghaane, Z.; Shakibaie, M.; Mollazadeh-Moghaddam, K.; Iranshahi, M.; Shahverdi, A.R.

2010-01-01

The potential applications of Fe 3 O 4 magnetite nanoparticles (MNPs) in nanomedicine as drug delivery systems are well known. In this study we prepared umbelliprenin-coated Fe 3 O 4 MNPs and evaluated the antiproliferative effect of combination in vitro. After synthesis of Fe 3 O 4 MNPs, particles were characterized by transmission electron microscopy, energy-dispersive spectroscopy, and X-ray diffraction spectroscopy techniques. The natural candidate compound - umbelliprenin- was isolated and identified and umbelliprenin-coated Fe 3 O 4 MNPs were prepared, using precipitation method. The surface chemistry of umbelliprenin-coated Fe 3 O 4 MNPs as well as their thermal decomposition characteristics was examined using Fourier transform infrared spectroscopy and Thermogravimetric Analyzer equipment, respectively. HT-1080 cells were cultured until the logarithmic phase of growth, and MTT assay was successfully carried out to evaluate the possible cytotoxic effects of umbelliprenin-coated Fe 3 O 4 MNPs in viable cells in vitro. The results demonstrated that umbelliprenin has moderate antiproliferative effects with IC 50 value of 50 μg/mL. However, the combination of umbelliprenin and Fe 3 O 4 MNPs showed the IC 50 value of 9 μg/mL. In other words, cell proliferation decreased to the remarkably-low proportion of 45% after treating cells with umbelliprenin-coated Fe 3 O 4 MNPs. This suggests that with the aid of nanoparticles as carriers, natural products may have even broader range of medical applications in future.

(3,5-Dimethylpyrazol-1-yl-[4-(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylaminophenyl]methanone

Directory of Open Access Journals (Sweden)

Rania B. Bakr

2016-11-01

Full Text Available In an attempt to enhance cytotoxic activity of pyrazolo[3,4-d]pyrimidine core, we synthesized (3,5-dimethylpyrazol-1-yl-[4-(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylaminophenyl]methanone (4 by reacting 4-(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylaminobenzohydrazide (3 with acetylacetone. Antiproliferative activity of this compound was screened against breast (MCF-7, colon (HCT-116, and liver (HEPG-2 cancer cell lines. The tested compound exhibited cytotoxic activity with IC50 = 5.00–32.52 μM. Moreover, inhibitory activity of this compound was evaluated against the epidermal growth factor receptor (EGFR, the fibroblast growth factor receptor (FGFR, the insulin receptor (IR, and the vascular endothelial growth factor receptor (VEGFR. This target compound showed potent inhibitory activity, especially against FGFR with IC50 = 5.18 μM.

The novel imidazopyridine 2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine (BYK191023) is a highly selective inhibitor of the inducible nitric-oxide synthase.

Science.gov (United States)

Strub, Andreas; Ulrich, Wolf-Rüdiger; Hesslinger, Christian; Eltze, Manfrid; Fuchss, Thomas; Strassner, Jochen; Strand, Susanne; Lehner, Martin D; Boer, Rainer

2006-01-01

We have identified imidazopyridine derivatives as a novel class of NO synthase inhibitors with high selectivity for the inducible isoform. 2-[2-(4-Methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine (BYK191023) showed half-maximal inhibition of crudely purified human inducible (iNOS), neuronal (nNOS), and endothelial (eNOS) NO synthases at 86 nM, 17 microM, and 162 microM, respectively. Inhibition of inducible NO synthase was competitive with l-arginine, pointing to an interaction of BYK191023 with the catalytic center of the enzyme. In radioligand and surface plasmon resonance experiments, BYK191023 exhibited an affinity for iNOS, nNOS, and eNOS of 450 nM, 30 microM, and >500 microM, respectively. Inhibition of cellular nitrate/nitrite synthesis in RAW, rat mesangium, and human embryonic kidney 293 cells after iNOS induction showed 40- to 100-fold higher IC(50) values than at the isolated enzyme, in agreement with the much higher l-arginine concentrations in cell culture media and inside intact cells. BYK191023 did not show any toxicity in various rodent and human cell lines up to high micromolar concentrations. The inhibitory potency of BYK191023 was tested in isolated organ models of iNOS (lipopolysaccharide-treated and phenylephrine-precontracted rat aorta; IC(50) = 7 microM), eNOS (arecaidine propargyl ester-induced relaxation of phenylephrine-precontracted rat aorta; IC(50) > 100 microM), and nNOS (field-stimulated relaxation of phenylephrine-precontracted rabbit corpus cavernosum; IC(50) > 100 microM). These data confirm the high selectivity of BYK191023 for iNOS over eNOS and nNOS found at isolated enzymes. In summary, we have identified a new highly selective iNOS inhibitor structurally unrelated to known compounds and l-arginine. BYK191023 is a valuable tool for the investigation of iNOS-mediated effects in vitro and in vivo.

Synthesis and Anticancer Activity of Some New Pyrazolo[3,4-d]pyrimidin-4-one Derivatives

Directory of Open Access Journals (Sweden)

Khaled R. A. Abdellatif

2014-03-01

Full Text Available 3,6-Dimethyl-1-phenyl-1H-pyrazolo[3,4-d][1,3]oxazin-4-one (3 was prepared by hydrolysis of ethyl 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carboxylate (1 to afford the corresponding carboxylic acid 2, which was reacted with acetic anhydride to give 3. The pyrazolo[3,4-d][1,3]oxazin-4-one 3 was reacted with hydroxylamine hydrochloride, urea, thiourea, thiosemicarbazide, phenylhydrazine and aromatic amines to afford the corresponding pyrazolo[3,4-d]pyrimidin-4-ones 4, 5a,b, 6, 7, 8a–e, respectively. Condensation of pyrazoloxazine derivative 3 with 99% hydrazine hydrate afforded the 5-aminopyrazolo[3,4-d] pyrimidine derivative 9. Coupling of 9 with aromatic aldehydes yielded a series of 3,6-dimethyl-5-(4-substitutedbenzylideneamino-1-phenyl-1,5-dihydropyrazolo[3,4-d]pyrimidin- 4-ones 10a–e. The new compounds were tested for their antitumor activity on the MCF-7 human breast adenocarcinoma cell line. Almost all the tested compounds revealed antitumor activity, especially 3,6-dimethyl-5-(4-nitrobenzylideneamino-1-phenyl-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one (10e which displayed the most potent inhibitory activity with a half maximal inhibitory concentration (IC50 of 11 µM.

Children and IC

Science.gov (United States)

... Cola, and Orange Crush, for example), Kool-Aid, chocolate, and many fruits, fruit juices and drinks (including ... Guideline IC Treatments IC Diet & Self Management Physical Therapy Antidepressants Antihistamines Pentosan Polysulfate Sodium Bladder Instillations Immunosuppresants ...

Resistance of essential fatty acid-deficient rats to endotoxin-induced increases in vascular permeability

International Nuclear Information System (INIS)

Li, E.J.; Cook, J.A.; Spicer, K.M.; Wise, W.C.; Rokach, J.; Halushka, P.V.

1990-01-01

Resistance to endotoxin in essential fatty acid-deficient (EFAD) rats is associated with reduced synthesis of certain arachidonic acid metabolites. It was hypothesized that EFAD rats would manifest decreased vascular permeability changes during endotoxemia as a consequence of reduced arachidonic acid metabolism. To test this hypothesis, changes in hematocrit (HCT) and mesenteric localization rate of technetium-labeled human serum albumin (99mTc-HSA) and red blood cells (99mTc-RBC) were assessed in EFAD and normal rats using gamma-camera imaging. Thirty minutes after Salmonella enteritidis endotoxin, EFAD rats exhibited less hemoconcentration as determined by % HCT than normal rats. Endotoxin caused a less severe change in permeability index in the splanchnic region in EFAD rats than in normal rats (1.2 +/- 0.6 x 10(-3)min-1 vs. 4.9 +/- 1.7 x 10(-3)min-1 respectively, P less than 0.05). In contrast to 99mTc-HSA, mesenteric localization of 99mTc-RBC was not changed by endotoxin in control or EFAD rats. Supplementation with ethyl-arachidonic acid did not enhance susceptibility of EFAD rats to endotoxin-induced splanchnic permeability to 99mTc-HSA. Leukotrienes have been implicated as mediators of increased vascular permeability in endotoxin shock. Since LTC3 formation has been reported to be increased in EFA deficiency, we hypothesized that LTC3 may be less potent than LTC4. Thus the effect of LTC3 on mean arterial pressure and permeability was compared to LTC4 in normal rats. LTC3-induced increases in peak mean arterial pressure were less than LTC4 at 10 micrograms/kg (39 +/- 5 mm Hg vs. 58 +/- 4 mm Hg respectively, P less than 0.05) and at 20 micrograms/kg (56 +/- 4 mm Hg vs. 75 +/- 2 mm Hg respectively, P less than 0.05). LY171883 (30 mg/kg), an LTD4/E4 receptor antagonist, attenuated the pressor effect of LTC4, LTD4, and LTC3

Design, Synthesis, and Evaluation of Novel Ferroquine and Phenylequine Analogues as Potential Antiplasmodial Agents.

Science.gov (United States)

Jacobs, Leon; de Kock, Carmen; de Villiers, Katherine A; Smith, Peter J; Smith, Vincent J; van Otterlo, Willem A L; Blackie, Margaret A L

2015-12-01

7-Chloroquinoline-based antimalarial drugs are effective in the inhibition of hemozoin formation in the food vacuole of the Plasmodium parasite, the causative agent of malaria. We synthesized five series of ferroquine (FQ) and phenylequine (PQ) derivatives, which display good in vitro efficacy toward both the chloroquine-sensitive (CQS) NF54 (IC50 : 4.2 nm) and chloroquine-resistant (CQR) Dd2 (IC50 : 33.7 nm) strains of P. falciparum. Several compounds were found to have good inhibitory activity against β-hematin formation in an NP-40 detergent assay, with IC50 values ranging between 10.4 and 19.2 μm. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Structure-activity relationship of new antimalarial 1-aryl-3-susbtituted propanol derivatives: Synthesis, preliminary toxicity profiling, parasite life cycle stage studies, target exploration, and targeted delivery.

Science.gov (United States)

Quiliano, Miguel; Pabón, Adriana; Moles, Ernest; Bonilla-Ramirez, Leonardo; Fabing, Isabelle; Fong, Kim Y; Nieto-Aco, Diego A; Wright, David W; Pizarro, Juan C; Vettorazzi, Ariane; López de Cerain, Adela; Deharo, Eric; Fernández-Busquets, Xavier; Garavito, Giovanny; Aldana, Ignacio; Galiano, Silvia

2018-05-25

Design, synthesis, structure-activity relationship, cytotoxicity studies, in silico drug-likeness, genotoxicity screening, and in vivo studies of new 1-aryl-3-substituted propanol derivatives led to the identification of nine compounds with promising in vitro (55, 56, 61, 64, 66, and 70-73) and in vivo (66 and 72) antimalarial profiles against Plasmodium falciparum and Plasmodium berghei. Compounds 55, 56, 61, 64, 66 and 70-73 exhibited potent antiplasmodial activity against chloroquine-resistant strain FCR-3 (IC 50 s activity in chloroquine-sensitive and multidrug-resistant strains (IC 50 s antimalarial compounds. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Men and IC

Science.gov (United States)

... Bowel Syndrome Lupus Pelvic Floor Dysfunction Pudendal Neuralgia Sjogren’s Syndrome Vulvodynia Newly Diagnosed Toolkit IC Awareness Toolkit Know ... Bowel Syndrome Lupus Pelvic Floor Dysfunction Pudendal Neuralgia Sjogren’s Syndrome Vulvodynia Newly Diagnosed Toolkit IC Awareness Toolkit Know ...

General IC Symptoms

Science.gov (United States)

... Bowel Syndrome Lupus Pelvic Floor Dysfunction Pudendal Neuralgia Sjogren’s Syndrome Vulvodynia Newly Diagnosed Toolkit IC Awareness Toolkit Know ... Bowel Syndrome Lupus Pelvic Floor Dysfunction Pudendal Neuralgia Sjogren’s Syndrome Vulvodynia Newly Diagnosed Toolkit IC Awareness Toolkit Know ...

The synthesis of no-carrier-added DL-4-[18F]fluorodeprenyl via the nucleophilic aromatic substitution reaction

International Nuclear Information System (INIS)

Plenevaux, Alain; Guillaume, Marcel

1991-01-01

No-carrier-added DL-α-methyl-β-4-[ 18 F]fluorophenyl-N-methyl-N-propynylethylamine (DL-4-[ 18 F]fluorodeprenyl) was synthesized via a 3-step procedure. The overall yield was 11%, the synthesis time was 90 min and the specific activity >0.57 Ci/μmol (end of synthesis). This synthesis approach, the conversion of an aromatic aldehyde to a homologous methyl ketone, extends the flexibility of the nucleophilic aromatic substitution reaction by applying it to the synthesis of radiotracers which do not bear electron-withdrawing activating groups on the aromatic ring. The tissue distribution of DL-4-[ 18 F]fluorodeprenyl in mice at 1, 10 and 50 min was also measured and showed that metabolic defluorination was not significant. Clearance or radioactivity from brain after injection of DL-4-[ 18 F]fluorodeprenyl was more rapid than that previously observed for [ 11 C]L-deprenyl. (author)

Pregnancy and IC

Science.gov (United States)

... have not already done so, try to identify foods, beverages, and supplements that are irritating to your bladder ... Other Medicines Over-the-counter Medicines Pain Management Management of IC ... Diet Food Diaries Least and Most Bothersome Foods IC-Friendly ...

19 CFR 4.50 - Passenger lists.

Science.gov (United States)

2010-04-01

... VESSELS IN FOREIGN AND DOMESTIC TRADES Passengers on Vessels § 4.50 Passenger lists. (a) The master of... passenger and crew lists, as required by § 4.7(a) of this part. If the vessel is arriving from noncontiguous... 19 Customs Duties 1 2010-04-01 2010-04-01 false Passenger lists. 4.50 Section 4.50 Customs Duties...

Synthesis and pharmacological properties of new derivatives of 4-alkoxy-6-methyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones.

Science.gov (United States)

Sladowska, Helena; Sabiniarz, Aleksandra; Sapa, Jacek; Filipek, Barbara

2009-01-01

Synthesis of 2-(2-hydroxy-3-amino)propyl derivatives of 4-alkoxy-6-methyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones (24-35) is described. The chlorides used in the above synthesis exist mainly in the cyclic forms (18, 20-23). Only chloride with benzhydryl substituent at the nitrogen atom of piperazine has the chain structure (19). Among the studied imides the most active analgesics in the "writhing" syndrome test proved to be compounds 30 and 31 (with LD50 > 2000 mg/kg) containing 4-benzylpiperidino group. Furthermore, all imides suppressed significantly spontaneous locomotor activity of mice.

Synthesis and Cytotoxic Evaluation of 1H-1,2,3-Triazol-1-ylmethyl-2,3-dihydronaphtho[1,2-b]furan-4,5-diones

Directory of Open Access Journals (Sweden)

INGRID C. CHIPOLINE

2018-02-01

Full Text Available ABSTRACT The 1,2-naphthoquinone compound was previously considered active against solid tumors. Moreover, glycosidase inhibitors such as 1,2,3-1H triazoles has been pointed out as efficient compounds in anticancer activity studies. Thus, a series of eleven 1,2-naphthoquinones tethered in C2 to 1,2,3-1H-triazoles 9a-k were designed, synthesized and their cytotoxic activity evaluated using HCT-116 (colon adenocarcinoma, MCF-7 (breast adenocarcinoma and RPE (human nontumor cell line from retinal epithelium. The chemical synthesis was performed from C-3 allylation of lawsone followed by iodocyclization with subsequent nucleophilic displacement with sodium azide and, finally, the 1,3-dipolar cycloaddition catalyzed by Cu(I with terminal alkynes led to the formation of 1H-1,2,3-Triazol-1-ylmethyl-2,3-dihydronaphtho[1,2-b]furan-4,5-diones in good yields. Compounds containing aromatic group linked to 1,2,3-triazole ring (9c, 9d, 9e, 9i presented superior cytotoxic activity against cancer cell lines with IC50 in the range of 0.74 to 4.4 µM indicating that the presence of aromatic rings substituents in the 1,2,3-1H-triazole moiety is probably responsible for the improved cytotoxic activity.

Synthesis and biological evaluation of glycogen synthase kinase 3 (GSK-3) inhibitors: an fast and atom efficient access to 1-aryl-3-benzylureas.

Science.gov (United States)

Monte, Fabio Lo; Kramer, Thomas; Boländer, Alexander; Plotkin, Batya; Eldar-Finkelman, Hagit; Fuertes, Ana; Dominguez, Juan; Schmidt, Boris

2011-09-15

The glycogen synthase kinase 3 (GSK-3) is implicated in multiple cellular processes and has been linked to the pathogenesis of Alzheimer's disease (AD). In the course of our research topic we synthesized a library of potent GSK-3 inhibitors. We utilized the urea scaffold present in the potent and highly selective GSK-3 inhibitor AR-A014418 (AstraZeneca). This moiety suits both (a) a convergent approach utilizing readily accessible building blocks and (b) a divergent approach based on a microwave heating assisted Suzuki coupling. We established a chromatography-free purification method to generate products with sufficient purity for the biological assays. The structure-activity relationship of the library provided the rationale for the synthesis of the benzothiazolylurea 66 (IC(50)=140 nM) and the pyridylurea 62 (IC(50)=98 nM), which displayed two to threefold enhanced activity versus the reference compound 18 (AR-A014418: IC(50)=330 nM) in our assays. Copyright © 2011. Published by Elsevier Ltd.

Synthesis, conformational analysis, and biological activity of new analogues of thiazole-4-carboxamide adenine dinucleotide (TAD) as IMP dehydrogenase inhibitors.

Science.gov (United States)

Franchetti, Palmarisa; Cappellacci, Loredana; Pasqualini, Michela; Petrelli, Riccardo; Jayaprakasan, Vetrichelvan; Jayaram, Hiremagalur N; Boyd, Donald B; Jain, Manojkumar D; Grifantini, Mario

2005-03-15

Thiazole-4-carboxamide adenine dinucleotide (TAD) analogues T-2'-MeAD (1) and T-3'-MeAD (2) containing, respectively, a methyl group at the ribose 2'-C-, and 3'-C-position of the adenosine moiety, were prepared as potential selective human inosine monophosphate dehydrogenase (IMPDH) type II inhibitors. The synthesis of heterodinucleotides was carried out by CDI-catalyzed coupling reaction of unprotected 2'-C-methyl- or 3'-C-methyl-adenosine 5'-monophosphate with 2',3'-O-isopropylidene-tiazofurin 5'-monophosphate, and then deisopropylidenation. Biological evaluation of dinucleotides 1 and 2 as inhibitors of recombinant human IMPDH type I and type II resulted in a good activity. Inhibition of both isoenzymes by T-2'-MeAD and T-3'-MeAD was noncompetitive with respect to NAD substrate. Binding of T-3'-MeAD was comparable to that of parent compound TAD, while T-2'-MeAD proved to be a weaker inhibitor. However, no significant difference was found in inhibition of the IMPDH isoenzymes. T-2'-MeAD and T-3'-MeAD were found to inhibit the growth of K562 cells (IC(50) 30.7 and 65.0muM, respectively).

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

Science.gov (United States)

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

2014-03-21

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

Synthesis and Free Radical Scavenging Activity of New Hydroxybenzylidene Hydrazines.

Science.gov (United States)

Sersen, Frantisek; Gregan, Fridrich; Kotora, Peter; Kmetova, Jarmila; Filo, Juraj; Loos, Dusan; Gregan, Juraj

2017-05-29

Hydroxybenzylidene hydrazines exhibit a wide spectrum of biological activities. Here, we report synthesis and free radical scavenging activity of nine new N-(hydroxybenzylidene)-N'-[2,6-dinitro-4-(trifluoromethyl)]phenylhydrazines. The chemical structures of these compounds were confirmed by 1H-NMR, 13C-NMR, 19F-NMR, IR spectroscopy, LC-MS, and elemental analysis. The prepared compounds were tested for their activity to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH), galvinoxyl radical (GOR), and 2,2'-azino-bis(3-ethylbenzothiazoline)-6-sulphonic acid (ABTS) radicals. The free radical scavenging activity expressed as SC50 values of these compounds varied in a wide range, from a strong to no radical scavenging effect. The most effective radical scavengers were hydroxybenzylidene hydrazines containing three hydroxyl groups in the benzylidene part of their molecules. The prepared compounds were also tested for their activity to inhibit photosynthetic electron transport in spinach chloroplasts. IC50 values of these compounds varied in wide range, from an intermediate to no inhibitory effect.

New anthrarobin acyl derivatives as butyrylcholinesterase inhibitors: synthesis, in vitro and in silico studies

Directory of Open Access Journals (Sweden)

Mehreen Lateef

2017-07-01

Full Text Available To treat Alzheimer's disease (AD, the available candidates are effective only against mild AD or have side effects. So, a study was planned to synthesis new candidates that may have good potential to treat AD. A series of new anthrarobin acyl derivatives (2–8 were synthesized by the reaction of anthrarobin (1 and acetic anhydride/acyl chlorides. The product were characterized by 1H NMR and EI-MS, and evaluated for butyrylcholinesterase (BuChE inhibition activity. Compounds 5 and 4 showed notable BuChE inhibitory potential with IC50 5.3 ± 1.23 and 17.2 ± 0.47 μM, respectively when compared with the standard eserine (IC50 7.8 ± 0.27 μM, compound 5 showed potent BuChE inhibition potential than the standard eserine. The active compounds 5 and 4 have acyl groups at 2-OH and 10-OH positions which may be responsible for inhibitory potential as this orientation is absent in other products. In silico studies of 5 and 4 products revealed the high inhibitory potential due to stable binding of ligand with the BuChE active sites with docking energy score −18.8779 kcal/mol and −23.1159 kcal/mol, respectively. Subsequently, compound 5 that have potent BuChE inhibitory activity could be the potential candidate for drug development for Alzheimer’s disease.

Synthesis and biological evaluation of (3-arylisoxazol-5-yl methyl 6-fluoro-4-oxo-4H-chromene-2-carboxylates as antioxidant and antimicrobial agents

Directory of Open Access Journals (Sweden)

Battula Kumaraswamy

2017-01-01

Full Text Available A series of novel (3-aryl-1,2-oxazol-5-yl methyl 6-fluoro-4-oxo-4H- -chromene-2-carboxylate derivatives (C1-C12 were synthesized by Cu (I catalyzed reaction of in situ generated nitrile oxides with prop-2-yn-1-yl 6-fluoro-4-oxo-4H-chromene-2-carboxylate in good yields and investigated their antioxidant and antimicrobial activities. Among all the synthesized compounds, C1 (IC50: 16.43 ± 0.57 μM and C12 (IC50:15.98 ± 0.72 μM have registered good antioxidant activity as compared to the standard drug Trolox. Compound-C1, C3, and C6 have registered very good inhibition against all gram-positive and gram-negative bacterial strains with MIC values ranging from 9.375 to 37.5 (μg mL-1. Compound-C7, C8, C9, C10, and C11 have registered good inhibition against B. subtilis and S. aureus with MIC values ranging from 18.75 to 37.5 (μg mL-1. Compound-C10 and C11 against P. aero-ginosa have shown prominent activity than the standard drug Penicillin (MIC: 12.5 μg mL-1 with MIC 9.375 μg mL-1 (~ 1.33 fold potent than Penicillin. Compound-C7, C8, and C9 have registered good to moderate antifungal activity against four tested fungal strains with MIC values ranging from 18.75 and 37.5 μg mL-1

Fisetin, a flavonol, inhibits TH2-type cytokine production by activated human basophils.

Science.gov (United States)

Higa, Shinji; Hirano, Toru; Kotani, Mayumi; Matsumoto, Motonobu; Fujita, Akihito; Suemura, Masaki; Kawase, Ichiro; Tanaka, Toshio

2003-06-01

Activation of mast cells and basophils through allergen stimulation releases chemical mediators and synthesizes cytokines. Among these cytokines, IL-4, IL-13, and IL-5 have major roles in allergic inflammation. We sought to determine the potency of flavonoids (astragalin, fisetin, kaempferol, myricetin, quercetin, and rutin) for the inhibition of cytokine expression and synthesis by human basophils. The inhibitory effect of flavonoids on cytokine expression by stimulated KU812 cells, a human basophilic cell line, and freshly purified peripheral blood basophils was measured by means of semiquantitative RT-PCR and ELISA assays. The effects of flavonoids on transcriptional activation of the nuclear factor of activated T cells were assessed by means of electrophoretic mobility shift assays. Fisetin suppressed the induction of IL-4, IL-13, and IL-5 mRNA expression by A23187-stimulated KU812 cells and basophils in response to cross-linkage of the IgE receptor. Fisetin reduced IL-4, IL-13, and IL-5 synthesis (inhibitory concentration of 50% [IC(50)] = 19.4, 17.7, and 17.4 micromol/L, respectively) but not IL-6 and IL-8 production by KU812 cells. In addition, fisetin inhibited IL-4 and IL-13 synthesis by anti-IgE antibody-stimulated human basophils (IC(50) = 5.1 and 6.2 micromol/L, respectively) and IL-4 synthesis by allergen-stimulated basophils from allergic patients (IC(50) = 4.8 micromol/L). Among the flavonoids examined, kaempferol and quercetin showed substantial inhibitory activities in cytokine expression but less so than those of fisetin. Fisetin inhibited nuclear localization of nuclear factor of activated T cells c2 by A23187-stimulated KU812 cells. These results provide evidence of a novel activity of the flavonoid fisetin that suppresses the expression of T(H)2-type cytokines (IL-4, IL-13, and IL-5) by basophils.

Antimalarial peroxides: the first intramolecular 1,2,4,5-tetraoxane

Directory of Open Access Journals (Sweden)

BOGDAN A. SOLAJA

2002-07-01

Full Text Available An intramolecular steroidal 1,2,4,5-tetraoxane has been synthesised in six steps starting from methyl 3-oxo-7a,12a-diacetoxy-5b-cholan-24-oate. The synthesised 1,2,4,5-tetraoxane has moderate in vitro antimalarial activity against P. falciparum strains (IC50 (D6 = 0.35 mg/mL; IC50 (W2 = 0.29 mg/mL.

Design, Synthesis and Evaluation of 3-(2-Aminoheterocycle-4-benzyloxyphenylbenzamide Derivatives as BACE-1 Inhibitors

Directory of Open Access Journals (Sweden)

Lushan Yu

2013-03-01

Full Text Available Three series of 3-(2-aminoheterocycle-4-benzyloxyphenylbenzamide derivatives, 2-aminooxazoles, 2-aminothiazoles, and 2-amino-6H-1,3,4-thiadizines were designed, synthesized and evaluated as β-secretase (BACE-1 inhibitors. Preliminary structure-activity relationships revealed that the existence of a 2-amino-6H-1,3,4-thiadizine moiety and α-naphthyl group were favorable for BACE-1 inhibition. Among the synthesized compounds, 5e exhibited the most potent BACE-1 inhibitory activity, with an IC50 value of 9.9 μΜ and it exhibited high brain uptake potential in Madin-Darby anine kidney cell lines (MDCK and a Madin-Darby canine kidney-multidrug resistance 1 (MDCK-MDR1 model.

Design, synthesis and evaluation of 3-(2-aminoheterocycle)-4-benzyloxyphenylbenzamide derivatives as BACE-1 inhibitors.

Science.gov (United States)

Shangguan, Shihao; Wang, Fei; Liao, Yong; Yu, Haiping; Li, Jia; Huang, Wenhai; Hu, Haihong; Yu, Lushan; Hu, Yongzhou; Sheng, Rong

2013-03-20

Three series of 3-(2-aminoheterocycle)-4-benzyloxyphenylbenzamide derivatives, 2-aminooxazoles, 2-aminothiazoles, and 2-amino-6H-1,3,4-thiadizines were designed, synthesized and evaluated as β-secretase (BACE-1) inhibitors. Preliminary structure-activity relationships revealed that the existence of a 2-amino-6H-1,3,4-thiadizine moiety and α-naphthyl group were favorable for BACE-1 inhibition. Among the synthesized compounds, 5e exhibited the most potent BACE-1 inhibitory activity, with an IC50 value of 9.9 μΜ and it exhibited high brain uptake potential in Madin-Darby anine kidney cell lines (MDCK) and a Madin-Darby canine kidney-multidrug resistance 1 (MDCK-MDR1) model.

Synthesis, structure, and physicochemical investigations of the new α Cu 0.50TiO(PO 4) oxyphosphate

Science.gov (United States)

Benmokhtar, S.; Belmal, H.; El Jazouli, A.; Chaminade, J. P.; Gravereau, P.; Pechev, S.; Grenier, J. C.; Villeneuve, G.; de Waal, D.

2007-02-01

The room-temperature crystal structure of a new Cu(II) oxyphosphate— α Cu 0.50IITiO(PO 4)—was determined from X-ray single crystals diffraction data, in the monoclinic system, space group P2 1/c. The refinement from 5561 independent reflections lead to the following parameters: a=7.5612(4)Å, b=7.0919(4)Å, c=7.4874(4)Å, β=122.25(1)°, Z=4, with the final R=0.0198, wR=0.0510. The structure of α Cu 0.50IITiO(PO 4) can be described as a TiOPO 4 framework constituted by chains of tilted corner-sharing [TiO 6] octahedra running parallel to the c-axis and cross linked by phosphate [PO 4] tetrahedra, where one-half of octahedral cavities created are occupied by Cu atoms. Ti atoms are displaced from the center of octahedra units in alternating long (2.308 Å) and short (1.722 Å) Ti-O(1) bonds along chains. Such O(1) atoms not linked to P atoms justify the oxyphosphate formulation α Cu 0.50TiO(PO 4). The divalent cations Cu 2+ occupy a Jahn-Teller distorted octahedron sharing two faces with two [TiO 6] octahedra. EPR and optical measurements are in good agreement with structural data. The X-ray diffraction results are supported by Raman and infrared spectroscopy studies that confirmed the existence of the infinite chains -Ti-O-Ti-O-Ti-. α Cu 0.50TiO(PO 4) shows a Curie-Weiss paramagnetic behavior in the temperature range 4-80 K.

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

Science.gov (United States)

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

2014-05-06

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

A Source Term for Wave Attenuation by Sea Ice in WAVEWATCH III (registered trademark): IC4

Science.gov (United States)

2017-06-07

blue and 4 locations in the ice: 1, 2, 5, and 10 km. Notice the steepening of the high frequency face and the shift of the peak to slightly lower...Term for Wave Attenuation by Sea Ice in WAVEWATCH III®: IC4 ClarenCe O. COllins iii W. eriCk rOgers Ocean Dynamics and Prediction Branch Oceanography...Wave model Sea ice Ocean surface waves Arctic Ocean WAVEWATCH III Spectral wave modeling Source terms Wave hindcasting 73-N2K2-07-5 Naval Research

Bacterial Peptide deformylase inhibition of cyano substituted biaryl analogs: Synthesis, in vitro biological evaluation, molecular docking study and in silico ADME prediction.

Science.gov (United States)

Khan, Firoz A Kalam; Patil, Rajendra H; Shinde, Devanand B; Sangshetti, Jaiprakash N

2016-08-15

Herein, we report the synthesis and screening of cyano substituted biaryl analogs 5(a-m) as Peptide deformylase (PDF) enzyme inhibitors. The compounds 5a (IC50 value=13.16μM), 5d (IC50 value=15.66μM) and 5j (IC50 value=19.16μM) had shown good PDF inhibition activity. The compounds 5a (MIC range=11.00-15.83μg/mL), 5b (MIC range=23.75-28.50μg/mL) and 5j (MIC range=7.66-16.91μg/mL) had also shown potent antibacterial activity when compared with ciprofloxacin (MIC range=25-50μg/mL). Thus, the active derivatives were not only potent PDF inhibitors but also efficient antibacterial agents. In order to gain more insight on the binding mode of the compounds with PDF, the synthesized compounds 5(a-m) were docked against PDF enzyme of Escherichia coli and compounds exhibited good binding properties. In silico ADME properties of synthesized compounds were also analyzed and showed potential to develop as good oral drug candidates. Copyright © 2016 Elsevier Ltd. All rights reserved.

Abundances of Planetary Nebulae IC 418, IC 2165 and NGC 5882

NARCIS (Netherlands)

Pottasch, [No Value; Bernard-Salas, J; Beintema, DA; Feibelman, WA

The ISO and IUE spectra of the elliptical nebulae NGC 5882, IC 418 and IC 2165 are presented. These spectra are combined with the spectra in the visual wavelength region to obtain a complete, extinction corrected, spectrum. The chemical composition of the nebulae is then calculated and compared to

Synthesis and biological evaluation of novel N-arylidenequinoline-3-carbohydrazides as potent β-glucuronidase inhibitors.

Science.gov (United States)

Taha, Muhammad; Sultan, Sadia; Nuzar, Herizal Ali; Rahim, Fazal; Imran, Syahrul; Ismail, Nor Hadiani; Naz, Humera; Ullah, Hayat

2016-08-15

Thirty N-arylidenequinoline-3-carbohydrazides (1-30) have been synthesized and evaluated against β-glucuronidase inhibitory potential. Twenty four analogs showed outstanding β-glucuronidase activity having IC50 values ranging between 2.11±0.05 and 46.14±0.95 than standard d-saccharic acid 1,4 lactone (IC50=48.4±1.25μM). Six analogs showed good β-glucuronidase activity having IC50 values ranging between 49.38±0.90 and 80.10±1.80. Structure activity relationship and the interaction of the active compounds and enzyme active site with the help of docking studies were established. Our study identifies novel series of potent β-glucuronidase inhibitors for further investigation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Synthesis and exploration of novel curcumin analogues as anti-malarial agents.

Science.gov (United States)

Mishra, Satyendra; Karmodiya, Krishanpal; Surolia, Namita; Surolia, Avadhesha

2008-03-15

Curcumin, a major yellow pigment and active component of turmeric, has been shown to possess anti-inflammatory and anti-cancer activities. Recent studies have indicated that curcumin inhibits chloroquine-sensitive (CQ-S) and chloroquine-resistant (CQ-R) Plasmodium falciparum growth in culture with an IC(50) of approximately 3.25 microM (MIC=13.2 microM) and IC(50) 4.21 microM (MIC=14.4 microM), respectively. In order to expand their potential as anti-malarials a series of novel curcumin derivatives were synthesized and evaluated for their ability to inhibit P. falciparum growth in culture. Several curcumin analogues examined show more effective inhibition of P. falciparum growth than curcumin. The most potent curcumin compounds 3, 6, and 11 were inhibitory for CQ-S P. falciparum at IC(50) of 0.48, 0.87, 0.92 microM and CQ-R P. falciparum at IC(50) of 0.45 microM, 0.89, 0.75 microM, respectively. Pyrazole analogue of curcumin (3) exhibited sevenfold higher anti-malarial potency against CQ-S and ninefold higher anti-malarial potency against CQ-R. Curcumin analogues described here represent a novel class of highly selective P. falciparum inhibitors and promising candidates for the design of novel anti-malarial agents.

Inhibitory Effects of Viscum coloratum Extract on IgE/Antigen-Activated Mast Cells and Mast Cell-Derived Inflammatory Mediator-Activated Chondrocytes

Directory of Open Access Journals (Sweden)

Jae-Myung Yoo

2016-12-01

Full Text Available The accumulation and infiltration of mast cells are found in osteoarthritic lesions in humans and rodents. Nonetheless, the roles of mast cells in osteoarthritis are almost unknown. Although Viscum coloratum has various beneficial actions, its effect on allergic and osteoarthritic responses is unknown. In this study, we established an in vitro model of mast cell-mediated osteoarthritis and investigated the effect of the ethanol extract of Viscum coloratum (VEE on IgE/antigen (IgE/Ag-activated mast cells and mast cell-derived inflammatory mediator (MDIM-stimulated chondrocytes. The anti-allergic effect of VEE was evaluated by degranulation, inflammatory mediators, and the FcεRI signaling cascade in IgE/Ag-activated RBL-2H3 cells. The anti-osteoarthritic action of VEE was evaluated by cell migration, and the expression, secretion, and activity of MMPs in MDIM-stimulated SW1353 cells. VEE significantly inhibited degranulation (IC50: 93.04 μg/mL, the production of IL-4 (IC50: 73.28 μg/mL, TNF-α (IC50: 50.59 μg/mL, PGD2 and LTC4, and activation of the FcεRI signaling cascade in IgE/Ag-activated RBL-2H3 cells. Moreover, VEE not only reduced cell migration but also inhibited the expression, secretion, and/or activity of MMP-1, MMP-3, or MMP-13 in MDIM-stimulated SW1353 cells. In conclusion, VEE possesses both anti-allergic and anti-osteoarthritic properties. Therefore, VEE could possibly be considered a new herbal drug for anti-allergic and anti-osteoarthritic therapy. Moreover, the in vitro model may be useful for the development of anti-osteoarthritic drugs.

Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands

Energy Technology Data Exchange (ETDEWEB)

Ghosh, Arun K.; Sean Fyvie, W.; Brindisi, Margherita; Steffey, Melinda; Agniswamy, Johnson; Wang, Yuan-Fang; Aoki, Manabu; Amano, Masayuki; Weber, Irene T.; Mitsuya, Hiroaki

2017-11-01

Design, synthesis, and evaluation of a new class of HIV-1 protease inhibitors containing diverse flexible macrocyclic P1'-P2' tethers are reported. Inhibitor 5a with a pyrrolidinone-derived macrocycle exhibited favorable enzyme inhibitory and antiviral activity (Ki = 13.2 nM, IC50 = 22 nM). Further incorporation of heteroatoms in the macrocyclic skeleton provided macrocyclic inhibitors 5m and 5o. These compounds showed excellent HIV-1 protease inhibitory (Ki = 62 pM and 14 pM, respectively) and antiviral activity (IC50 = 5.3 nM and 2.0 nM, respectively). Inhibitor 5o also remained highly potent against a DRV-resistant HIV-1 variant.

Differentiation stage-specific regulation of primitive human hematopoietic progenitor cycling by exogenous and endogenous inhibitors in an in vivo model.

Science.gov (United States)

Cashman, J D; Clark-Lewis, I; Eaves, A C; Eaves, C J

1999-12-01

Nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice transplanted with human cord blood or adult marrow cells and injected 6 weeks posttransplant with 2 daily doses of transforming growth factor-beta(1) (TGF-beta(1)), monocyte chemoattractant protein-1 (MCP-1), or a nonaggregating form of macrophage inflammatory protein-1alpha (MIP-1alpha) showed unique patterns of inhibition of human progenitor proliferation 1 day later. TGF-beta(1) was active on long-term culture initiating cells (LTC-IC) and on primitive erythroid and granulopoietic colony-forming cells (HPP-CFC), but had no effect on mature CFC. MCP-1 inhibited the cycling of both types of HPP-CFC but not LTC-IC. MIP-1alpha did not inhibit either LTC-IC or granulopoietic HPP-CFC but was active on erythroid HPP-CFC and mature granulopoietic CFC. All of these responses were independent of the source of human cells transplanted. LTC-IC of either human cord blood or adult marrow origin continue to proliferate in NOD/SCID mice for many weeks, although the turnover of all types of human CFC in mice transplanted with adult human marrow (but not cord blood) is downregulated after 6 weeks. Interestingly, administration of either MIP-1beta, an antagonist of both MIP-1alpha and MCP-1 or MCP-1(9-76), an antagonist of MCP-1 (and MCP-2 and MCP-3), into mice in which human marrow-derived CFC had become quiescent, caused the rapid reactivation of these progenitors in vivo. These results provide the first definition of stage-specific inhibitors of human hematopoietic progenitor cell cycling in vivo. In addition they show that endogenous chemokines can contribute to late graft failure, which can be reversed by the administration of specific antagonists.

Simplified design of IC amplifiers

CERN Document Server

Lenk, John

1996-01-01

Simplified Design of IC Amplifiers has something for everyone involved in electronics. No matter what skill level, this book shows how to design and experiment with IC amplifiers. For experimenters, students, and serious hobbyists, this book provides sufficient information to design and build IC amplifier circuits from 'scratch'. For working engineers who design amplifier circuits or select IC amplifiers, the book provides a variety of circuit configurations to make designing easier.Provides basics for all phases of practical design.Covers the most popular forms for amplif

Synthesis and biological activity of novel series of 4-methoxy, and 4,9-dimethoxy-5-substituted furo[2,3-g]-1,2,3-benzoxathiazine-7,7-dioxide derivatives.

Science.gov (United States)

El-Sawy, Eslam R; Ebaid, Manal S; Abo-Salem, Heba M; El-Hallouty, Salwa; Kassem, Emad M; Mandour, Adel H

2014-05-01

A novel series of 4-methoxy, and 4,9-dimethoxy-5-substituted furo[2,3-g]-1,2,3-benzoxathiazine-7,7-dioxide derivatives 3a,b, 10a-g and 11a-g were prepared in good yields via the reaction of 4-methoxy (1a) and 4,7-dimethoxy-5-acetyl-6-hydroxybenzofurans (1b) and their α,β-unsaturated keto derivatives 6a-g and 7a-g with chlorosulfonyl isocyanate (CSI). On the other hand, N-chlorosulfonyl carbamate derivatives 4a,b, 12a,b and 13a,b were prepared and allowed to react with piperidine to give the corresponding N-piperidinosulfonyl carbamate derivatives 5a,b, 14a,b and 15a,b, respectively. Sixteen new target compounds 3a,b, 10a-g, and 11a-g were tested for their DPPH radical-scavenging, and in vitro antiproliferative activity against A-549, MCF7 and HCT-116 cancer cell lines. Compounds 10a, 11c, 11e, and 11g showed moderate DPPH radical-scavenging activity compared to ascorbic acid at 100 μg/mL. 4,9-Dimethoxy-5-substituted styrylfuro[3,2-g]-1,2,3-benzoxathiazine-7,7-dioxides 11a, 11b, and 11c were found to be highly active against A-549 and HCT-116 cancer cell lines with IC50 values ranging from 0.02 to 0.08 μmol/mL compared to doxorubicin with IC50 = 0.04 and 0.06 μmol/mL, respectively.

Design, synthesis, and biological evaluation of prenylated chalcones as 5-LOX inhibitors.

Science.gov (United States)

Reddy, Nimmanapalli P; Aparoy, Polamarasetty; Reddy, T Chandra Mohan; Achari, Chandrani; Sridhar, P Ramu; Reddanna, Pallu

2010-08-15

Ten novel mono- and di-O-prenylated chalcone derivatives were designed on the basis of a homology derived molecular model of 5-lipoxygenase (5-LOX). The compounds were docked into 5-LOX active site and the binding characteristics were quantified using LUDI. To verify our theoretical assumption, the molecules were synthesized and tested for their 5-LOX inhibitory activities. The synthesis was carried out by Claisen-Schmidt condensation reaction of mono- and di-O-prenylated acetophenones with appropriate aldehydes. 5-LOX in vitro inhibition assay showed higher potency of di-O-prenylated chalcones than their mono-O-prenylated chalcone analogs. Compound 5e exhibited good inhibition with an IC(50) at 4 microM. The overall trend for the binding energies calculated and LUDI score was in good qualitative agreement with the experimental data. Further, the compound 5e showed potent anti-proliferative effects (GI(50) at 9 microM) on breast cancer cell line, MCF-7. Copyright 2010 Elsevier Ltd. All rights reserved.

26 CFR 1.50B-4 - Partnerships.

Science.gov (United States)

2010-04-01

... § 1.50A-3, or if the partnership fails to pay comparable wages and such failure is subject to the... 26 Internal Revenue 1 2010-04-01 2010-04-01 true Partnerships. 1.50B-4 Section 1.50B-4 Internal... Credit for Expenses of Work Incentive Programs § 1.50B-4 Partnerships. (a) General rule—(1) In general...

Synthesis and evaluation of calcium channel antagonist activity of new 1, 4-dihydropyridines containing phenylamineimidazolyl substitute in guinea-pig ileal smooth muscle

Directory of Open Access Journals (Sweden)

A Fassihi

2004-02-01

Full Text Available Background: 1,4-dihydropyridines are a class of drugs which are used in the treatment of some cardiovascular disorders. The prototype, Nifedipine, does not have optimal pharmacokinetic and pharmacodynamic properties. Several new derivatives of 1, 4-dihydropyridine have been produced and pharmacologically evaluated in order to find drugs with better pharmacological properties. Among them, those with a substituted heteroaromatic ring in the C4 position of the 1, 4-dihydropyridine ring, instead of the phenyl ring in Nifedipine, are most considered. In this study, eight novel derivatives of this class with “2-methylthio-1-(phenylaminoimidazole-5-yl” in the C4, C3 and C5 positions were prepared and evaluated as calcium channel antagonist agents. Methods: To prepare these compounds, Hantzsch method for the synthesis of 1, 4-dihydropyridine derivatives was deployed. An aldehyde was reacted with appropriate acetoacetate ester and ammonium acetate. This aldehyde was prepared in three steps. Cumulative doses were applied to determine the relaxing effect of the compounds on the longitudinal smooth muscle of male albino guinea pigs. Results: Chemical structures of the compounds were characterized by 1H nuclear magnetic resonance, infrared and mass spectroscopy. The IC50 of each compound was graphically determined from the concentration-response curves. Conclusions: Two compounds were more active than Nifedipine. Both had lipophilic ester groups with low steric hindrance that met the merits of a better receptor binding of 1, 4-dihydropyridines. These derivatives have high potential for further study. Keywords: 1, 4-dihydropyridine, Calcium channel antagonist, Phenylamineimidazolyl, Cardiovascular disorder

Synthesis and antileishmanial activity of antimony (V) complexes of hydroxypyranone and hydroxypyridinone ligands.

Science.gov (United States)

Sheikhmoradi, Vafa; Saberi, Sedigheh; Saghaei, Lotfollah; Pestehchian, Nader; Fassihi, Afshin

2018-04-01

A novel series of antimony (V) complexes with the hydroxypyranone and hydroxypyridinone ligands were synthesized and characterized by 1 HNMR, FT-IR and electron spin ionization mass spectroscopic (ESI-MS) techniques. The synthesis process involved protection of hydroxyl group followed by the reaction of the intermediate with primary amines and finally deprotection. All compounds were evaluated for in vitro activities against the amastigote and promastigote forms of Leishmania major . Most of the synthesized compounds exhibited good antileishmanial activity against both forms of L. major . IC 50 values of the most active compounds; 9d , 9d and 9e , after 24, 48 and 72 h against amastigote model were 15, 12.5 and 5.5 μg/mL, respectively. 9e , 11 and 9e inhibited the promastigote form of parasite after 24, 48 and 72 h with IC 50 values of 10, 2 and 1 μg/mL, respectively.

IC Treatment: Surgical Procedures

Science.gov (United States)

... Bowel Syndrome Lupus Pelvic Floor Dysfunction Pudendal Neuralgia Sjogren’s Syndrome Vulvodynia Newly Diagnosed Toolkit IC Awareness Toolkit Know ... Bowel Syndrome Lupus Pelvic Floor Dysfunction Pudendal Neuralgia Sjogren’s Syndrome Vulvodynia Newly Diagnosed Toolkit IC Awareness Toolkit Know ...

IC: Frequently Asked Questions

Science.gov (United States)

... Bowel Syndrome Lupus Pelvic Floor Dysfunction Pudendal Neuralgia Sjogren’s Syndrome Vulvodynia Newly Diagnosed Toolkit IC Awareness Toolkit Know ... Bowel Syndrome Lupus Pelvic Floor Dysfunction Pudendal Neuralgia Sjogren’s Syndrome Vulvodynia Newly Diagnosed Toolkit IC Awareness Toolkit Know ...

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

Science.gov (United States)

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

2017-08-01

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

Nanometer frequency synthesis beyond the phase-locked loop

CERN Document Server

Xiu, Liming

2012-01-01

This text presents a latest technology in frequency synthesis. The technology includes three key components: Time-Average-Frequency, Flying-Adder architecture, and Digital-to-Frequency converter. The coverage presents the case, through real application examples, that this Flying-Adder technology creates a new frontier for modern IC design. In so doing, it also discusses the weaknesses of current frequency synthesis techniques in dealing with certain problems in modern IC design. The result is a complete picture of this technology for professional design engineers, researchers, and advanced students.

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

Directory of Open Access Journals (Sweden)

Michalina Hebda

2016-03-01

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

Synthesis of chiral chloroquine and its analogues as antimalarial agents.

Science.gov (United States)

Sinha, Manish; Dola, Vasanth R; Soni, Awakash; Agarwal, Pooja; Srivastava, Kumkum; Haq, Wahajul; Puri, Sunil K; Katti, Seturam B

2014-11-01

In this investigation, we describe a new approach to chiral synthesis of chloroquine and its analogues. All tested compounds displayed potent activity against chloroquine sensitive as well as chloroquine resistant strains of Plasmodium falciparum in vitro and Plasmodium yoelii in vivo. Compounds S-13 b, S-13c, S-13 d and S-13 i displayed excellent in vitro antimalarial activity with an IC50 value of 56.82, 60.41, 21.82 and 7.94 nM, respectively, in the case of resistant strain. Furthermore, compounds S-13a, S-13c and S-13 d showed in vivo suppression of 100% parasitaemia on day 4 in the mouse model against Plasmodium yoelii when administered orally. These results underscore the application of synthetic methodology and need for further lead optimization. Copyright © 2014 Elsevier Ltd. All rights reserved.

A synthetic cryIC gene, encoding a Bacillus thuringiensis δ-endotoxin, confers Spodoptera resistance in alfalfa and tobacco

NARCIS (Netherlands)

Strizhov, N.; Keller, M.; Mathur, J.; Koncz-Kaiman, Z.; Bosch, D.; Prudovksy, E.; Schell, J.; Sneh, B.; Koncz, C.; Zilberstein, A.

1996-01-01

Spodoptera species, representing widespread polyphagous insect pests, are resistant to Bacillus thuringiensis δ-endotoxins used thus far as insecticides in transgenic plants. Here we describe the chemical synthesis of a cryIC gene by a novel template directed ligation–PCR method. This simple and

26 CFR 50.4 - Rates of tax.

Science.gov (United States)

2010-04-01

... 26 Internal Revenue 17 2010-04-01 2010-04-01 false Rates of tax. 50.4 Section 50.4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) MISCELLANEOUS EXCISE TAXES (CONTINUED) REGULATIONS RELATING TO THE TAX IMPOSED WITH RESPECT TO CERTAIN HYDRAULIC MINING § 50.4 Rates of...

Total synthesis of 4-F3t-neuroprostane and its 4-epimer

Czech Academy of Sciences Publication Activity Database

Auvinet, A. L.; Eignerová, Barbara; Guy, A.; Kotora, Martin; Durand, T.

2009-01-01

Roč. 50, č. 13 (2009), s. 1498-1500 ISSN 0040-4039 R&D Projects: GA MŠk 1M0508 Institutional research plan: CEZ:AV0Z40550506 Keywords : DPA * oxidative stress * neuroprostane * total synthesis Subject RIV: CC - Organic Chemistry Impact factor: 2.660, year: 2009

LD to IC

CERN Multimedia

Association du personnel

2010-01-01

LC to IC – Publication of posts: Following the publication of new LD to IC posts, we regret that a large number of post descriptions are not available in both CERN official languages, English and French. Consequently, the Staff Association has decided to provide assistance to those who need it with the translation of one or more posts of interest. To do this, please contact the Staff Association secretariat, tel. 72819 or 72761 or 74224.

Ganoboninketals A-C, Antiplasmodial 3,4-seco-27-Norlanostane Triterpenes from Ganoderma boninense Pat.

Science.gov (United States)

Ma, Ke; Ren, Jinwei; Han, Junjie; Bao, Li; Li, Li; Yao, Yijian; Sun, Chen; Zhou, Bing; Liu, Hongwei

2014-08-22

Three new nortriterpenes, ganoboninketals A-C (1-3), featuring rearranged 3,4-seco-27-norlanostane skeletons and highly complex polycyclic systems were isolated from the medicinal mushroom Ganoderma boninense. The structures of the new metabolites were established by spectroscopic methods. The absolute configurations in 1-3 were assigned by electronic circular dichroism (ECD) calculations. Compounds 1-3 showed antiplasmodial activity against Plasmodium falciparum with IC50 values of 4.0, 7.9, and 1.7 μM, respectively. Compounds 1 and 3 also displayed weak cytotoxicity against A549 cell line with IC50 values of 47.6 and 35.8 μM, respectively. Compound 2 showed weak cytotoxicity toward HeLa cell line with an IC50 value of 65.5 μM. Compounds 1-3 also presented NO inhibitory activity in the LPS-induced macrophages with IC50 values of 98.3, 24.3, and 60.9 μM, respectively.

Synthesis of novel octyl sinapate to enhance antioxidant capacity of rapeseed-linseed oil mixture.

Science.gov (United States)

Szydłowska-Czerniak, Aleksandra; Rabiej, Dobrochna; Krzemiński, Marek

2018-03-01

Lipophilisation allows the formation of new functionalised antioxidants having beneficial properties compared to natural hydrophilic phenolic acids. Therefore, this work focused on the synthesis of lipophilic antioxidants, such as a new octyl sinapate, octyl caffeate and octyl ferulate using the modified Fischer esterification of selected hydroxycinnamic acids with 1-octanol. The lipophilic octyl sinapate was obtained for the first time with satisfactory yield (83%) after purification by column chromatography. The identity of the synthesised phenolipids was confirmed by chromatographic and spectroscopic analyses. Antioxidant capacity of phenolipids was determined by DPPH (IC 50  = 35.87-52.24 μg mL -1 ) and ABTS (IC 50  = 39.45-48.72 μg mL -1 ) methods and compared with IC 50 values (7.37-35.30 μg mL -1 and 7.55-41.67 μg mL -1 , respectively) for well known antioxidants. The antioxidant capacity of rapeseed-linseed oil enriched with the purified esters was about two to 30 times higher in comparison with a non-supplemented oil. The novel octyl sinapate as well as octyl caffeate and octyl ferulate have antioxidant properties and lipophilic character, therefore they may be added to vegetable oils as potential antioxidants for tackling oxidative processes. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Synthesis and Free Radical Scavenging Activity of New Hydroxybenzylidene Hydrazines

Directory of Open Access Journals (Sweden)

Frantisek Sersen

2017-05-01

Full Text Available Hydroxybenzylidene hydrazines exhibit a wide spectrum of biological activities. Here, we report synthesis and free radical scavenging activity of nine new N-(hydroxybenzylidene-N′-[2,6-dinitro-4-(trifluoromethyl]phenylhydrazines. The chemical structures of these compounds were confirmed by 1H-NMR, 13C-NMR, 19F-NMR, IR spectroscopy, LC-MS, and elemental analysis. The prepared compounds were tested for their activity to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH, galvinoxyl radical (GOR, and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid (ABTS radicals. The free radical scavenging activity expressed as SC50 values of these compounds varied in a wide range, from a strong to no radical scavenging effect. The most effective radical scavengers were hydroxybenzylidene hydrazines containing three hydroxyl groups in the benzylidene part of their molecules. The prepared compounds were also tested for their activity to inhibit photosynthetic electron transport in spinach chloroplasts. IC50 values of these compounds varied in wide range, from an intermediate to no inhibitory effect.

Simultaneous detection of three lily viruses using Triplex IC-RT-PCR.

Science.gov (United States)

Zhang, Yubao; Wang, Yajun; Xie, Zhongkui; Yang, Guo; Guo, Zhihong; Wang, Le

2017-11-01

Viruses commonly infecting lily (Lilium spp.) include: Lily symptomless virus (LSV), Cucumber mosaic virus (CMV) and Lily mottle virus (LMoV). These viruses usually co-infect lilies causing severe economic losses in terms of quantity and quality of flower and bulb production around the world. Reliable and precise detection systems need to be developed for virus identification. We describe the development of a triplex immunocapture (IC) reverse transcription (RT) polymerase chain reaction (PCR) assay for the simultaneous detection of LSV, CMV and LMoV. The triplex IC-RT-PCR was compared with a quadruplex RT-PCR assay. Relative to the quadruplex RT-PCR, the specificity of the triplex IC-RT-PCR system for LSV, CMV and LMoV was 100% for field samples. The sensitivity of the triplex IC-RT-PCR system was 99.4%, 81.4% and 98.7% for LSV, CMV and LMoV, respectively. Agreement (κ) between the results obtained from the two tests was 0.968, 0.844 and 0.984 for LSV, CMV and LMoV, respectively. This is the first report of the simultaneous detection of LSV, CMV and LMoV in a triplex IC-RT-PCR assay. In particular we believe this convenient and reliable triplex IC-RT-PCR method could be used routinely for large-scale field surveys or crop health monitoring of lily. Copyright © 2017. Published by Elsevier B.V.

Xanthine oxidase inhibitors from Archidendron clypearia (Jack.) I.C. Nielsen: Results from systematic screening of Vietnamese medicinal plants

Institute of Scientific and Technical Information of China (English)

Nguyen Thuy Duong; Pham Duc Vinh; Phuong Thien Thuong; Nguyen Thi Hoai; Le Nguyen Thanh; Tran The Bach; Nguyen Hai Nam; Nguyen Hoang Anh

2017-01-01

Objective:To screen Vietnamese medicinal plants for xanthine oxidase (XO) inhibitory activity and to isolate XO inhibitor(s) from the most active plant.Methods: The plants materials were extracted by methanol. The active plant materials were fractionated using different organic solvents, includingn-hexane, ethyl acetate, andn-butanol. Bioassay-guided fractionation and column chromatography were used to isolate compounds. The compounds structures were elucidated by analysis of spectroscopic data, including IR, MS, and NMR. Results:Three hundreds and eleven methanol extracts (CME) belonging to 301 Vietnamese herbs were screened for XO inhibitory activity. Among these plants, 57 extracts displayed XO inhibitory activity at 100 μg/mL with inhibition rates of over 50%. The extracts of Archidendron clypearia,Smilax poilanei,Linociera ramiflora and Passiflora foetida exhibited the greatest potency with IC50 values below 30 μg/mL. Chemical study performed on the extract ofArchidendron clypearia resulted in the isolation of six compounds, including 1-octacosanol, docosenoic acid, daucosterol, methyl gallate, quercitrin and (?)-7-O-galloyltricetiflavan. The compound (?)-7-O-galloyltricetiflavan showed the most potent XO inhibitory activity with an IC50 value of 25.5 μmol/L.Conclusions:From this investigation, four Vietnamese medicinal plants were identified to have XO inhibitory effects with IC50 values of the methanol extracts below 30 μg/mL. Compound (?)-7-O-galloyltricetiflavan was identified as an XO inhibitor from Archidendron clypearia with IC50 value of 25.5 μmol/L.

The oiling of ICS

International Nuclear Information System (INIS)

Hunter, S.

1993-01-01

The incident command system (ICS) works for oil spills. It should be the industry standard and some will argue that it already is. But there are a number of temptations to fiddle with it. Fueling these inclinations is the fundamental difference between oil spills and natural disasters: Oil spills make the perpetrator fix the problem - under heavy oversight. Add to this difference the public outcry that attends oil spills and the dual role of government as both helper and prosecutor. From these conditions emerge adaptations of ICS which both weaken and strengthen it. The benefits of ICS are diminished by deputy incident commanders who block unified commanders from access to section chiefs, over-zealous crisis managers who displace command post decisions or its information office, separate press offices with party line slants, government law enforcement activity mixed into spill response, nonstandard operations terminology and structure involving open-quotes containment and clean upclose quotes or open-quotes salvage,close quotes and the commingling of public and private response funds. ICS's application to oil spill response is strengthened by the use of trained unified commanders, deputy incident commanders who operate as staff rather than line, crisis managers who support on-scene objectives, joint information centers, and heavy involvement of skilled, prepared environmental assessment teams in the planning section who generate priorities, strategies, and (operationally coordinated) tactics. Technically, not all these points constitute alterations of ICS, but most do and the others come close. This mixed bag of strengthening and weakening tweaks to oil spill ICS provides an opportunity to take a new look at this faithful friend to the crisis responder

Synthesis and Biological Evaluation of Benzochromenopyrimidinones as Cholinesterase Inhibitors and Potent Antioxidant, Non-Hepatotoxic Agents for Alzheimer’s Disease

Directory of Open Access Journals (Sweden)

Youssef Dgachi

2016-05-01

Full Text Available We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 μM, good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line.

Synthesis and anticancer evaluation of spermatinamine analogues

KAUST Repository

Moosa, Basem

2016-02-04

Spermatinamine was isolated from an Australian marine sponge, Pseudoceratina sp. as an inhibitor of isoprenylcystiene carboxyl methyltransferase (Icmt), an attractive and novel anticancer target. Herein, we report the synthesis of spermatinamine analogues and their cytotoxic evaluation against three human cancer cell lines i.e. cervix adenocarcinoma (HeLa), breast adenocarcinoma (MCF-7), and prostate carcinoma (DU145). Analogues 12, 14 and 15 were found to be the most potent against one or more cell lines with the IC50 values in the range of 5 - 10 μM. The obtained results suggested that longer polyamine linker along with aromatic oxime substitution provided the most potent analogue compounds against cancer cell lines.

Phenethyl ester and amide of Ferulic Acids: Synthesis and bioactivity against P388 Leukemia Murine Cells

Science.gov (United States)

Firdaus; Soekamto, N. H.; Seniwati; Islam, M. F.; Sultan

2018-03-01

Bioactivity of a compound is closely related to the molecular structure of the compound concerned, its strength being the quantitative relation of the strength of the activity of the group it possesses. The combining of moieties of the active compounds will produce more active compounds. Most phenolic compounds as well as compounds containing moiety phenethyl groups have potential activity as anticancer. Combining phenolic groups and phenethyl groups in a compound will result in compounds having strong anticancer bioactivity. This study aims to combine the feruloyl and phenethyl groups to form esters and amides by synthesize of phenethyl trans-3-(4-hydroxy-3-methoxyphenyl)acrylate (5) and trans-3-(4- hydroxy-3-methoxyphenyl)-N-phenethylacrylamide (6) from ferulic acid with phenethyl alcohol and phenethylamine, and to study their bioactivity as anticancer. The synthesis of both compounds was conducted via indirect reaction, including acetylation, chlorination, esterfication/amidation, and deacetylation. Structures of products were characterized by FTIR and NMR data, and their bioactivity assay of the compounds against P388 Leukemia Murine Cells was conducted by an MTT method. Results showed that the compound 5 was obtained as a yellow gel with the IC50 of 10.79 μg/mL (36.21 μΜ), and the compound 6 was a yellowish solid with a melting point of 118-120°C and the IC50 of 29.14 μg/mL (97.79 μΜ). These compounds were more active than the analog compounds.

SUPPLEMENTARY INFORMATION Synthesis and Molecular ...

Indian Academy of Sciences (India)

APOORVA MISRA

Effect of test compounds on growth pattern of E. coli and S. aureus……...19. S28: Binding mode ... cells after treatment with compound 6 at their respective IC50 ... l d e n s ity. (3. 2. 0 n m. ) 0. 4. 8. 12. 16. 20. 24. 0.0. 0.1. 0.2. 0.3. 0.4. 0.5. Control.

Heteropentanuclear Oxalato-Bridged nd–4f (n=4, 5) Metal Complexes with NO Ligand: Synthesis, Crystal Structures, Aqueous Stability and Antiproliferative Activity

KAUST Repository

Kuhn, Paul-Steffen

2015-08-10

A series of heteropentanuclear oxalate-bridged Ru(NO)-Ln (4d–4f) metal complexes of the general formula (nBu4N)5[Ln{RuCl3(μ-ox)(NO)}4], where Ln=Y (2), Gd (3), Tb (4), Dy (5) and ox=oxalate anion, were obtained by treatment of (nBu4N)2[RuCl3(ox)(NO)] (1) with the respective lanthanide salt in 4:1 molar ratio. The compounds were characterized by elemental analysis, IR spectroscopy, electrospray ionization (ESI) mass spectrometry, while 1, 2, and 5 were in addition analyzed by X-ray crystallography, 1 by Ru K-edge XAS and 1 and 2 by 13C NMR spectroscopy. X-ray diffraction showed that in 2 and 5 four complex anions [RuCl3(ox)(NO)]2− are coordinated to YIII and DyIII, respectively, with formation of [Ln{RuCl3(μ-ox)(NO)}4]5− (Ln=Y, Dy). While YIII is eight-coordinate in 2, DyIII is nine-coordinate in 5, with an additional coordination of an EtOH molecule. The negative charge is counterbalanced by five nBu4N+ ions present in the crystal structure. The stability of complexes 2 and 5 in aqueous medium was monitored by UV/Vis spectroscopy. The antiproliferative activity of ruthenium-lanthanide complexes 2–5 were assayed in two human cancer cell lines (HeLa and A549) and in a noncancerous cell line (MRC-5) and compared with those obtained for the previously reported Os(NO)-Ln (5d–4f) analogues (nBu4N)5[Ln{OsCl3(ox)(NO)}4] (Ln=Y (6), Gd (7), Tb (8), Dy (9)). Complexes 2–5 were found to be slightly more active than 1 in inhibiting the proliferation of HeLa and A549 cells, and significantly more cytotoxic than 5d–4f metal complexes 6–9 in terms of IC50 values. The highest antiproliferative activity with IC50 values of 20.0 and 22.4 μM was found for 4 in HeLa and A549 cell lines, respectively. These cytotoxicity results are in accord with the presented ICP-MS data, indicating five- to eightfold greater accumulation of ruthenium versus osmium in human A549 cancer cells.

Heteropentanuclear Oxalato-Bridged nd–4f (n=4, 5) Metal Complexes with NO Ligand: Synthesis, Crystal Structures, Aqueous Stability and Antiproliferative Activity

KAUST Repository

Kuhn, Paul-Steffen; Cremer, Laura; Gavriluta, Anatolie; Jovanović, Katarina K.; Filipović, Lana; Hummer, Alfred A.; Bü chel, Gabriel E.; Dojčinović, Biljana P.; Meier, Samuel M.; Rompel, Annette; Radulović, Siniša; Tommasino, Jean Bernard; Luneau, Dominique; Arion, Vladimir B.

2015-01-01

A series of heteropentanuclear oxalate-bridged Ru(NO)-Ln (4d–4f) metal complexes of the general formula (nBu4N)5[Ln{RuCl3(μ-ox)(NO)}4], where Ln=Y (2), Gd (3), Tb (4), Dy (5) and ox=oxalate anion, were obtained by treatment of (nBu4N)2[RuCl3(ox)(NO)] (1) with the respective lanthanide salt in 4:1 molar ratio. The compounds were characterized by elemental analysis, IR spectroscopy, electrospray ionization (ESI) mass spectrometry, while 1, 2, and 5 were in addition analyzed by X-ray crystallography, 1 by Ru K-edge XAS and 1 and 2 by 13C NMR spectroscopy. X-ray diffraction showed that in 2 and 5 four complex anions [RuCl3(ox)(NO)]2− are coordinated to YIII and DyIII, respectively, with formation of [Ln{RuCl3(μ-ox)(NO)}4]5− (Ln=Y, Dy). While YIII is eight-coordinate in 2, DyIII is nine-coordinate in 5, with an additional coordination of an EtOH molecule. The negative charge is counterbalanced by five nBu4N+ ions present in the crystal structure. The stability of complexes 2 and 5 in aqueous medium was monitored by UV/Vis spectroscopy. The antiproliferative activity of ruthenium-lanthanide complexes 2–5 were assayed in two human cancer cell lines (HeLa and A549) and in a noncancerous cell line (MRC-5) and compared with those obtained for the previously reported Os(NO)-Ln (5d–4f) analogues (nBu4N)5[Ln{OsCl3(ox)(NO)}4] (Ln=Y (6), Gd (7), Tb (8), Dy (9)). Complexes 2–5 were found to be slightly more active than 1 in inhibiting the proliferation of HeLa and A549 cells, and significantly more cytotoxic than 5d–4f metal complexes 6–9 in terms of IC50 values. The highest antiproliferative activity with IC50 values of 20.0 and 22.4 μM was found for 4 in HeLa and A549 cell lines, respectively. These cytotoxicity results are in accord with the presented ICP-MS data, indicating five- to eightfold greater accumulation of ruthenium versus osmium in human A549 cancer cells.

Synthesis, Characterization, and Anti-Cancer Activity of Some New N′-(2-Oxoindolin-3-ylidene-2-propylpentane hydrazide-hydrazones Derivatives

Directory of Open Access Journals (Sweden)

Ayman El-Faham

2015-08-01

Full Text Available Eight novel N′-(2-oxoindolin-3-ylidene-2-propylpentane hydrazide-hydrazone derivatives 4a–h were synthesized and fully characterized by IR, NMR (1H-NMR and 13C-NMR, elemental analysis, and X-ray crystallography. The cyto-toxicity and in vitro anti-cancer evaluation of the prepared compounds have been assessed against two different human tumour cell lines including human liver (HepG2 and leukaemia (Jurkat, as well as in normal cell lines derived from human embryonic kidney (HEK293 using MTT assay. The compounds 3e, 3f, 4a, 4c, and 4e revealed promising anti-cancer activities in tested human tumour cells lines (IC50 values between 3 and 7 μM as compared to the known anti-cancer drug 5-Fluorouracil (IC50 32–50 μM. Among the tested compounds, 4a showed specificity against leukaemia (Jurkat cells, with an IC50 value of 3.14 μM, but this compound was inactive in liver cancer and normal cell lines.

Synthesis of novel chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives via domino aldol-type/hetero Diels-Alder reaction and their cytotoxicity evaluation.

Science.gov (United States)

Madda, Jyothi; Venkatesham, Akkaladevi; Naveen Kumar, Bejjanki; Nagaiah, Kommu; Sujitha, Pombala; Ganesh Kumar, C; Rao, Tadikamalla Prabhakar; Jagadeesh Babu, Nanubolu

2014-09-15

New chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives have been synthesized by domino aldol-type reaction/hetero Diels-Alder reaction generated from o-quinone methide in situ from 7-O-prenyl derivatives of 8-formyl-2,3-disubstituted chromenones with resorcinols/naphthols in the presence of 20 mol% ethylenediamine diacetate (EDDA), triethylamine (2 mL) as co-catalyst in CH3CN under reflux conditions in good yields. The structures were established based on spectroscopic data, and further confirmed by X-ray diffraction analysis. The results showed that compounds 4h and 4j exhibited very potent cytotoxicity against human cervical cancer cell line (HeLa). Compound 4h displayed good inhibitory activity against both breast cancer cell lines, MDA-MB-231 and MCF-7. Further, the compound 4i exhibited good cytotoxicity against only MDA-MB-231, and compound 4j showed promising activity against human lung cancer cell line, A549 with IC50 value of 2.53±0.07 μM, which was comparable to the standard doxorubicin (IC50=1.21±0.1 μM). Copyright © 2014 Elsevier Ltd. All rights reserved.

Some new results on shock chemistry in IC 443

International Nuclear Information System (INIS)

DeNoyer, L.K.; Frerking, M.A.

1981-01-01

We have made new observations of CO, 13 CO, SiO, SO, H 2 CO, HCO + , N 2 H + , CS, OCS, HCN, and OH in the shocked clouds of IC 443. At position IC 443 B, we find (a) the shocked CO is optically thin, (b) the HCO + /CO abundance ratio is 4--9 x 10 -4 , a tenfold enhancement over normal interstellar clouds, (c) HCN/CO = 1--3 x 10 -4 and CS/CO = 2--3 x 10 -4 , consistent with abundances found in ordinary clouds, (d) no enhancements of SO or SiO as occur in Orion KL, (e) optically thin preshock OH, confirming a hundredfold enhancement of OH/CO in the shock, and (f) an OH main line anomaly, with T/sub ex/(1667)>T/sub ex/(1665) in the shocked region

Discovery of C-3 Tethered 2-oxo-benzo[1,4]oxazines as Potent Antioxidants: Bio-Inspired Based Design, Synthesis, Biological Evaluation, Cytotoxic, and in Silico Molecular Docking Studies

Directory of Open Access Journals (Sweden)

Vashundhra Sharma

2018-03-01

Full Text Available The discovery of C-3 tethered 2-oxo-benzo[1,4]oxazines as potent antioxidants is disclosed. All the analogs 20a-20ab have been synthesized via “on water” ultrasound-assisted irradiation conditions in excellent yields (upto 98%. All the compounds have been evaluated for their in vitro antioxidant activities using DPPH free radical scavenging assay as well as FRAP assay. The result showed promising antioxidant activities having IC50 values in the range of 4.74 ± 0.08 to 92.20 ± 1.54 μg/mL taking ascorbic acid (IC50 = 4.57 μg/mL as standard reference. In this study, compounds 20b and 20t, the most active compound of the series, showed IC50 values of 6.89 ± 0.07 μg/mL and 4.74 ± 0.08 μg/mL, respectively in comparison with ascorbic acid. In addition, the detailed SAR study shows that electron-withdrawing group increases antioxidant activity and vice versa. Furthermore, in the FRAP assay, eight compounds (20c, 20j, 20m, 20n, 20r, 20u, 20z, and 20aa were found more potent than standard reference BHT (C0.5FRAP = 546.0 ± 13.6 μM. The preliminary cytotoxic study reveals the non-toxic nature of active compounds 20b and 20t in non-cancerous 3T3 fibroblast cell lines in MTT assay up to 250 μg/mL concentration. The results were validated via carrying out in silico molecular docking studies of promising compounds 20a, 20b, and 20t in comparison with standard reference. To the best of our knowledge, this is the first detailed study of C-3 tethered 2-oxo-benzo[1,4]oxazines as potential antioxidant agents.

CO mapping of the nuclear region of NGC 6946 and IC 342 with Nobeyama millimeter array

Science.gov (United States)

Ishizuki, Sumio; Kawabe, Ryohei; Okumura, Sachiko K.; Morita, Koh-Ichiro; Ishiguro, Masato

1990-01-01

CO observations of nearby galaxies with nuclear active star forming regions (and starburst galaxies) with angular resolutions around 7 seconds revealed that molecular bars with a length of a few kiloparsecs have been formed in the central regions of the galaxies. The molecular bar is interpreted as part of shock waves induced by an oval or barred potential field. By shock dissipation or dissipative cloud-cloud collisions, the molecular gas gains an infall motion and the nuclear star formation activity is fueled. But the distribution and kinematics of the molecular gas in the nuclear regions, which are sites of active star formation, remain unknown. Higher angular resolutions are needed to investigate the gas in the nuclear regions. Researchers made aperture synthesis observations of the nuclear region of the late-type spiral galaxies NGC 6946 and IC 342 with resolutions of 7.6 seconds x 4.2 seconds (P.A. = 147 deg) and 2.4 seconds x 2.3 seconds (P.A. = 149 deg), respectively. The distances to NGC 6496 and IC 342 are assumed to be 5.5 Mpc and 3.9 Mpc, respectively. Researchers have found 100-300 pc nuclear gas disk and ring inside a few kpc molecular gas bars. Researchers present the results of the observations and propose a possible mechanism of active star formation in the nuclear region.

Grain refinement of AZ91D magnesium alloy by a new Mg–50%Al4C3 master alloy

International Nuclear Information System (INIS)

Liu, Shengfa; Chen, Yang; Han, Hui

2015-01-01

A novel and simple method for preparing Mg–50%Al 4 C 3 (hereafter in wt.%) master alloy has been developed by powder in-situ synthesis process under argon atmosphere. X-ray diffraction (XRD), scanning electron microscope (SEM) and energy dispersive X-ray spectroscopy (EDS) results show the existence of Al 4 C 3 particles in this master alloy. After adding 1.8% Mg–50%Al 4 C 3 master alloy, the average grain size of α-Mg decreased from 360 μm to 154 μm. Based on the DTA test results and calculation of the planar disregistry between Al 4 C 3 and α-Mg, Al 4 C 3 particles located in the central regions of magnesium grains can act as the heterogeneous nucleus of primary α-Mg phase

Docking, synthesis and antimalarial activity of novel 4-anilinoquinoline derivatives.

Science.gov (United States)

Vijayaraghavan, Shilpa; Mahajan, Supriya

2017-04-15

A series of 4-anilinoquinoline triazine derivatives were designed, synthesized and screened for in vivo antimalarial activity against a chloroquine-sensitive strain of Plasmodium berghei. The compounds were further subjected to in vitro antimalarial activity against chloroquine-resistant W2 strain of Plasmodium falciparum and β-haematin inhibition studies. All the compounds exhibited in vivo antimalarial activity better than that shown by the standard drug, chloroquine. Twelve out of fifteen compounds showed better inhibition than that of chloroquine against chloroquine-resistant W2 strain of Plasmodium falciparum. Ten compounds showed β-haematin inhibition, better than that of chloroquine, with IC 50 values in the range of 18-25µM. One compound, 3k, was found to be better than artemisinin against W2 strain of Plasmodium falciparum and also displayed the best β-haematin inhibitory activity, thereby becoming eligible to be explored as a potential lead for antimalarial chemotherapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Development of an ASD IC for the Micro Pixel Chamber

CERN Document Server

Orito, R; Kubo, H; Miuchi, K; Nagayoshi, T; Okada, Y; Takada, A; Takeda, A; Tanimori, T; Ueno, M

2004-01-01

A new amplifier-shaper-discriminator (ASD) chip was designed and manufactured for the Micro Pixel Chamber ($\\mu$-PIC). The design of this ASD IC is based on the ASD IC (TGC-ASD) for the Thin Gap Chamber in the LHC Atlas Experiment. The decay time constant of the preamplifier is 5-times longer than that of the TGC-ASD, and some other modifications have been made in order to improve the signal-to-noise ratio of the $\\mu$-PIC. The ASD IC uses SONY Analog Master Slice bipolar technology. The IC contains 4 channels in a QFP48 package. The decay time constant of the preamplifier is 80 ns and its gain is approximately 0.8 V/pC. The output from the preamplifier is received by a shaper (main-amplifier) with a gain of 7. A baseline restoration circuit is incorporated in the main-amplifier, and the current used for the baseline restoration is 5-times smaller than that of the TGC-ASD. The threshold voltage for the discriminator section is common to the 4 channels and their digital output level is LVDS-compatible. The ASD...

Vanillin Synthesis from 4-Hydroxybenzaldehyde

Science.gov (United States)

Taber, Douglass F.; Patel, Shweta; Hambleton, Travis M.; Winkel, Emma E.

2007-01-01

A regioselective, safe and efficient method for the synthesis of vanillin from 4-hydroxybenzaldehyde is being described. The vanillin derived from the process is cheap and can be used as a flavor or in the paper industry.

Physical IC debug ─ backside approach and nanoscale challenge

Directory of Open Access Journals (Sweden)

U. Kerst

2008-05-01

Full Text Available Physical analysis for IC functionality in submicron technologies requires access through chip backside. Based upon typical global backside preparation with 50–100 µm moderate silicon thickness remaining, a state of the art of the analysis techniques available for this purpose is presented and evaluated for functional analysis and layout pattern resolution potential. A circuit edit technique valid for nano technology ICs, is also presented that is based upon the formation of local trenches using the bottom of Shallow Trench Isolation (STI as endpoint for Focused Ion Beam (FIB milling. As a derivative from this process, a locally ultra thin silicon device can be processed, creating a back surface as work bench for breakthrough applications of nanoscale analysis techniques to a fully functional circuit through chip backside. Several applications demonstrate the power and potential of this new approach.

The Implications Related to Different IC, Different Projects and Different Thinking Addressing the Common Core of IC

DEFF Research Database (Denmark)

Lindgren, Peter; Saghaug, Kristin Margrethe

2009-01-01

challenge the development of IC: - The IC at the organizational level seems to diminish when innovation gets highly dispersed and is operated outside the core of the organization - The attractiveness of the organization to different ICA, which is one fundament to sustainable and successful innovation, seems...... to fall when the IC at the organizational core level diminishes The objective of this paper is therefore to understand 1) How the IC at the organizational core level may continue to be developed, when at the same time innovation is taking place in dispersed groups and projects. 2) How to motivate...... the different ICA´s to bring learning and knowledge back to the core with the purpose to develop IC at the organizational core level....

Enzymatic synthesis of arbutin undecylenic acid ester and its inhibitory effect on mushroom tyrosinase.

Science.gov (United States)

Tokiwa, Y; Kitagawa, M; Raku, T

2007-03-01

A novel tyrosinase inhibitor, an arbutin derivative having undecylenic acid at the 6-position of its glucose moiety, was enzymatically synthesized. Its inhibitory activity was studied in vitro by using catechol and phenol as substrates. The IC(50) value of the arbutin ester on tyrosinase using catechol (4 x 10(-4) M) was 1% of that when arbutin (4 x 10(-2) M) was used. Using phenol, IC(50) of the arbutin ester (3 x 10(-4) M) as substrate was 10% of that of arbutin (3 x 10(-3) M). These results suggest that the arbutin ester inhibits the latter part of the tyrosinase reaction, which consists of hydroxylation and oxidation.

Severe Acute Respiratory Syndrome-Coronavirus Papain-Like Novel Protease Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure and Biological Evaluation

Energy Technology Data Exchange (ETDEWEB)

Ghosh, Arun K.; Takayama, Jun; Rao, Kalapala Venkateswar; Ratia, Kiira; Chaudhuri, Rima; Mulhearn, Debbie C.; Lee, Hyun; Nichols, Daniel B.; Baliji, Surendranath; Baker, Susan C.; Johnson, Michael E.; Mesecar, Andrew D. (Purdue); (UC); (UIC)

2012-02-21

The design, synthesis, X-ray crystal structure, molecular modeling, and biological evaluation of a series of new generation SARS-CoV PLpro inhibitors are described. A new lead compound 3 (6577871) was identified via high-throughput screening of a diverse chemical library. Subsequently, we carried out lead optimization and structure-activity studies to provide a series of improved inhibitors that show potent PLpro inhibition and antiviral activity against SARS-CoV infected Vero E6 cells. Interestingly, the (S)-Me inhibitor 15h (enzyme IC{sub 50} = 0.56 {mu}M; antiviral EC{sub 50} = 9.1 {mu}M) and the corresponding (R)-Me 15g (IC{sub 50} = 0.32 {mu}M; antiviral EC{sub 50} = 9.1 {mu}M) are the most potent compounds in this series, with nearly equivalent enzymatic inhibition and antiviral activity. A protein-ligand X-ray structure of 15g-bound SARS-CoV PLpro and a corresponding model of 15h docked to PLpro provide intriguing molecular insight into the ligand-binding site interactions.

Synthesis, Characterization and in Vitro Antitumor Activity of Platinum(II Oxalato Complexes Involving 7-Azaindole Derivatives as Coligands

Directory of Open Access Journals (Sweden)

Pavel Štarha

2014-07-01

Full Text Available The platinum(II oxalato complexes [Pt(ox(naza2] (1–3 were synthesized and characterized by elemental analysis (C, H, N, multinuclear NMR spectroscopy (1H, 13C, 15N, 195Pt and electrospray ionization mass spectrometry (ESI-MS; naza = 4-chloro-7-azaindole (4Claza; 1, 3-bromo-7-azaindole (3Braza; 2 or 4-bromo-7-azaindole (4Braza; 3. The prepared substances were screened for their in vitro antitumor activity on the osteosarcoma (HOS and breast adenocarcinoma (MCF7 human cancer cell lines, where 2 showed moderate antitumor effect (IC50 = 27.5 μM, and 18.3 μM, respectively. The complex 2 was further tested on a panel of six others human cancer cell lines, including the malignant melanoma (G361, cervix carcinoma (HeLa, ovarian carcinoma (A2780, cisplatin-resistant ovarian carcinoma (A2780R, lung carcinoma (A549 and prostate adenocarcinoma (LNCaP. This substance was found to be moderate antitumor effective against G361 (IC50 = 17.3 μM, HeLa (IC50 = 31.8 μM and A2780 (IC50 = 19.2 μM cell lines. The complex 2 was also studied by NMR for its solution stability and by ESI-MS experiments for its ability to interact with biomolecules, such as cysteine, glutathione or guanosine 5'-monophosphate.

50 CFR 82.4 - Authority.

Science.gov (United States)

2010-10-01

... 50 Wildlife and Fisheries 6 2010-10-01 2010-10-01 false Authority. 82.4 Section 82.4 Wildlife and... PROTECTION ACT OF 1972) Introduction § 82.4 Authority. The Secretary of the Interior has delegated to the Director, Fish and Wildlife Service, his authority under the Marine Mammal Protection Act to enter into...

Synthesis and Biological Evaluation of Novel Benzimidazole Derivatives Bearing a Heterocyclic Ring at 4/5 Position

International Nuclear Information System (INIS)

Wubulikasimu, Reyila; Yang, Yanbing; Xue, Fei; Luo, Xianjin; Shao, Dongping; Li, Yuhuan; Gao, Rongmei; Ye, Weidong

2013-01-01

A series of novel benzimidazole derivatives bearing a heterocyclic ring as oxadiazole (21-32), thiadiazole (33-34), triazole (35-36) were synthesized and evaluated for their activities against Coxsackie virus B3 and B6 in Vero cells. Compounds 21-26, 31-36 with moieties of 2'-pyridyl, 3'-pyridyl and 4'-pyridyl at the 2-position and oxadiazoles, thiadiazole, or triazole substituent at the 4- or 5-position generally displayed activities against CVB3 and CVB6. Especially compound 24 (IC 50 = 1.08 μg/mL, SI = 61.7 against CVB3) was the promising candidate as lead compound for anti-enteroviral drug. It was observed in the incorporation of heterocyclic rings in benzimidazole at the 5-position could enhance their biological activities

Synthesis of Polyfunctionalized 4H-Pyrans

Directory of Open Access Journals (Sweden)

Manisha Bihani

2013-01-01

Full Text Available Amberlyst A21 catalyzed one-pot three-component coupling of aldehyde and malononitrile with active methylene compounds such as acetylacetone and ethyl acetoacetate for the synthesis of pharmaceutically important polyfunctionalized 4H-pyrans has been reported. Simple experimental procedure, no chromatographic purification, no hazardous organic solvents, easy recovery and reusability of the catalyst, and room temperature reaction conditions are some of the highlights of this protocol for the synthesis of pharmaceutically relevant focused libraries.

Synthesis of allocolchicinoids: a 50 year journey

International Nuclear Information System (INIS)

Sitnikov, N S; Fedorov, A Yu

2013-01-01

Published data on the stereo- and enantioselective synthesis of allocolchicinoids, which are of interest as antitumour agents, are summarized. The stereochemistry of these compounds is described. Two key approaches to their preparation are considered, namely, the synthesis from natural colchicine and total synthesis from commercially available reagents. Various total syntheses of N-acetylcolchicinol are performed using biaryl oxidative and reductive coupling, cyclopropanation–ring expansion and Nicholas reaction. The synthetic routes to allocolchicine are based on Diels–Alder cycloaddition, combination of metathesis and Diels–Alder reaction and direct catalytic CH-arylation. Analogues of the colchicine site ligands incorporating heteroaromatic rings are briefly considered; their structural features and methods of synthesis are discussed. The bibliography includes 144 references.

Irregular Dwarf Galaxy IC 1613

Science.gov (United States)

2005-01-01

Ultraviolet image (left) and visual image (right) of the irregular dwarf galaxy IC 1613. Low surface brightness galaxies, such as IC 1613, are more easily detected in the ultraviolet because of the low background levels compared to visual wavelengths.

Facile alkylation of 4-nitrobenzotriazole and its platelet aggregation inhibitory activity.

Science.gov (United States)

Singh, Dhandeep; Silakari, Om

2017-10-15

We explored the facile alkylation of 4-nitrobenzotriazole under basic conditions and the synthesized derivatives were tested for their potential ADP induced platelet aggregation inhibition activity in comparison with standard drug ticagrelor (selective P2Y12 inhibitor). The nitro group at 4-position is highly activating toward alkylation reactions (under strong basic conditions) and resulted in formation of degradation product like 3-nitrobenzene-1,2-diamine which make isolation of alkyl products very difficult. We optimized the reaction under mild basic condition (potassium carbonate and DMF) which is devoid of any degradation product. This is perhaps the first report of 4-nitrobenzotriazole derivatives possessing platelet aggregation inhibitory activity. Generally activity increases with increase in length of alkyl chain and 1-alkyl positional isomers were found to be more potent than 2-alkyl isomers. The benzoyl derivative was found to be the most potent [compound 22; (4-Nitro-1H-benzotriazol-1-yl)(phenyl)methanone; IC 50 =0.65±0.10mM] which may be attributed to electronegative oxygen atom and aromatic ring. Benzyl derivatives [compound 20; 1-Benzyl-4-nitro-1H-benzotriazole; IC 50 =0.81±0.08mM, compound 21; 2-Benzyl-4-nitro-2H-benzotriazole; IC 50 =0.82±0.19mM] and sulfonyl derivative [compound 23; 1-[(4-Methylphenyl)sulfonyl]-4-nitro-1H-benzotriazole; IC 50 =0.82±0.19mM] are also found to be highly active. Furthermore, all compounds possess P2Y12 binding affinity as confirmed by VASP/P2Y12 phosphorylation assay. Copyright © 2017. Published by Elsevier Ltd.

Facile and green synthesis of mesoporous Co3O4 nanocubes and their applications for supercapacitors

Science.gov (United States)

Liu, Xiangmei; Long, Qing; Jiang, Chunhui; Zhan, Beibei; Li, Chen; Liu, Shujuan; Zhao, Qiang; Huang, Wei; Dong, Xiaochen

2013-06-01

Nanostructured Co3O4 materials attracted significant attention due to their exceptional electrochemical (pseudo-capacitive) properties. However, rigorous preparation conditions are needed to control the size (especially nanosize), morphology and size distribution of the products obtained by conventional methods. Herein, we describe a novel one step shape-controlled synthesis of uniform Co3O4 nanocubes with a size of 50 nm with the existence of mesoporous carbon nanorods (meso-CNRs). In this synthesis process, meso-CNRs not only act as a heat receiver to directly obtain Co3O4 eliminating the high-temperature post-calcination, but also control the morphology of the resulting Co3O4 to form nanocubes with uniform distribution. More strikingly, mesoporous Co3O4 nanocubes are obtained by further thermal treatment. The structure and morphology of the samples were characterized by scanning electron microscopy, transmission electron microscopy and X-ray diffraction. A possible formation mechanism of mesoporous Co3O4 nanocubes is proposed here. Electrochemical tests have revealed that the prepared mesoporous Co3O4 nanocubes demonstrate a remarkable performance in supercapacitor applications due to the porous structure, which endows fast ion and electron transfer.Nanostructured Co3O4 materials attracted significant attention due to their exceptional electrochemical (pseudo-capacitive) properties. However, rigorous preparation conditions are needed to control the size (especially nanosize), morphology and size distribution of the products obtained by conventional methods. Herein, we describe a novel one step shape-controlled synthesis of uniform Co3O4 nanocubes with a size of 50 nm with the existence of mesoporous carbon nanorods (meso-CNRs). In this synthesis process, meso-CNRs not only act as a heat receiver to directly obtain Co3O4 eliminating the high-temperature post-calcination, but also control the morphology of the resulting Co3O4 to form nanocubes with uniform

Precipitation method for barium metaborate (BaB2O4) synthesis from borax solution

International Nuclear Information System (INIS)

Akşener, Eymen; Figen, Aysel Kantürk; Pişkin, Sabriye

2013-01-01

In this study, barium metaborate (BaB 2 O 4 , BMB) synthesis from the borax solution was carried out. BMB currently is used in production of ceramic glazes, luminophors, oxide cathodes as well as additives to pigments for aqueous emulsion paints and also β−BaB 2 O 4 single crystals are the best candidate for fabrication of solid-state UV lasers operating at a wavelength of 200 nm due to excellent nonlinear optical properties. In the present study, synthesis was carried out from the borax solution (Na 2 B 4 O 7⋅ 10H 2 O, BDH) and barium chloride (BaCI 2⋅ 2H 2 O, Ba) in the glass-batch reactor with stirring. The effect of, times (5-15 min), molar ratio [stoich.ration (1.0:2.0), 1.25:2.0, 1.5:2.0, 2.5:2:0, 3.0:2.0, 3.5:2.0,4.0:2.0, 5.0:2.0] and also crystallization time (2-6 hour) on the BMB yield (%) was investigated at 80 °C reaction temperature. It is found that, BMB precipitation synthesis with 90 % yield can be performed from 0.50 molar ration (BDH:Ba), under 80 °C, 15 minute, and 6 hours crystallization time. The structural properties of BMB powders were characterized by using XRD, FT-IR and DTA-TG instrumental analysis technique

Precipitation method for barium metaborate (BaB2O4) synthesis from borax solution

Science.gov (United States)

Akşener, Eymen; Figen, Aysel Kantürk; Pişkin, Sabriye

2013-12-01

In this study, barium metaborate (BaB2O4, BMB) synthesis from the borax solution was carried out. BMB currently is used in production of ceramic glazes, luminophors, oxide cathodes as well as additives to pigments for aqueous emulsion paints and also β-BaB2O4 single crystals are the best candidate for fabrication of solid-state UV lasers operating at a wavelength of 200 nm due to excellent nonlinear optical properties. In the present study, synthesis was carried out from the borax solution (Na2B4O7ṡ10H2O, BDH) and barium chloride (BaCI2ṡ2H2O, Ba) in the glass-batch reactor with stirring. The effect of, times (5-15 min), molar ratio [stoich.ration (1.0:2.0), 1.25:2.0, 1.5:2.0, 2.5:2:0, 3.0:2.0, 3.5:2.0,4.0:2.0, 5.0:2.0] and also crystallization time (2-6 hour) on the BMB yield (%) was investigated at 80 °C reaction temperature. It is found that, BMB precipitation synthesis with 90 % yield can be performed from 0.50 molar ration (BDH:Ba), under 80 °C, 15 minute, and 6 hours crystallization time. The structural properties of BMB powders were characterized by using XRD, FT-IR and DTA-TG instrumental analysis technique.

Design and synthesis of novel N-benzylidenesulfonohydrazide inhibitors of MurC and MurD as potential antibacterial agents.

Science.gov (United States)

Frlan, Rok; Kovac, Andreja; Blanot, Didier; Gobec, Stanislav; Pecar, Slavko; Obreza, Ales

2008-01-11

A series of novel N-benzylidenesulfonohydrazide compounds were designed and synthesized as inhibitors of UDP-N-acetylmuramic acid: L-alanine ligase (MurC) and UDP-N-acetylmuramoyl-L-alanine: D-glutamate ligase (MurD) from E. coli, involved in the biosynthesis of bacterial cell-walls. Some compounds possessed inhibitory activity against both enzymes with IC(50) values as low as 30 microM. In addition, a new, one-pot synthesis of amidobenzaldehydes is reported.

Electronic States of IC60BA and PC71BM

International Nuclear Information System (INIS)

Sheng Chun-Qi; Wang Peng; Shen Ying; Li Wen-Jie; Li Hong-Nian; Zhang Wen-Hua; Zhu Jun-Fa; Lai Guo-Qiao

2013-01-01

We investigate the electronic states of IC 60 BA and PC 71 BM using first-principles calculations and photoelectron spectroscopy (PES) measurements. The energy level structures for all possible isomers are reported and compared with those of C 60 , C 70 and PC 61 BM. The attachment of the side chains can raise the LUMO energies and decrease the HOMO-LUMO gaps, and thus helps to increase the power-conversion efficiency of bulk heterojunction solar cells. In the PES studies, we prepared IC 60 BA and PC 71 BM films on Si:H(111) substrates to construct adsorbate/substrate interfaces describable with the integer charge-transfer (ICT) model. Successful measurements then revealed that one of the most important material properties for an electron acceptor, the energy of the negative integer charge-transfer state (E ICT− ), is 4.31 eV below the vacuum level for PC 71 BM. The E ICT− of IC 60 BA is smaller than 4.14 eV

Human eosinophils express, relative to other circulating leukocytes, large amounts of secretory 14-kD phospholipase A2

NARCIS (Netherlands)

Blom, M.; Tool, A. T.; Wever, P. C.; Wolbink, G. J.; Brouwer, M. C. [=Maria Clara; Calafat, J.; Egesten, A.; Knol, E. F.; Hack, C. E.; Roos, D.; Verhoeven, A. J.

1998-01-01

Human eosinophils perform several functions dependent on phospholipase A2 (PLA2) activity, most notably the synthesis of platelet-activating factor (PAF) and leukotriene C4 (LTC4). Several forms of PLA2 have been identified in mammalian cells. In the present study, the 14-kD, secretory form of PLA2

Xanthine oxidase inhibitors from Archidendron clypearia (Jack.) I.C. Nielsen: Results from systematic screening of Vietnamese medicinal plants.

Science.gov (United States)

Duong, Nguyen Thuy; Vinh, Pham Duc; Thuong, Phuong Thien; Hoai, Nguyen Thi; Thanh, Le Nguyen; Bach, Tran The; Nam, Nguyen Hai; Anh, Nguyen Hoang

2017-06-01

To screen Vietnamese medicinal plants for xanthine oxidase (XO) inhibitory activity and to isolate XO inhibitor(s) from the most active plant. The plants materials were extracted by methanol. The active plant materials were fractionated using different organic solvents, including n-hexane, ethyl acetate, and n-butanol. Bioassay-guided fractionation and column chromatography were used to isolate compounds. The compounds structures were elucidated by analysis of spectroscopic data, including IR, MS, and NMR. Three hundreds and eleven methanol extracts (CME) belonging to 301 Vietnamese herbs were screened for XO inhibitory activity. Among these plants, 57 extracts displayed XO inhibitory activity at 100 μg/mL with inhibition rates of over 50%. The extracts of Archidendron clypearia (A. clypearia), Smilax poilanei, Linociera ramiflora and Passiflora foetida exhibited the greatest potency with IC 50 values below 30 μg/mL. Chemical study performed on the extract of A. clypearia resulted in the isolation of six compounds, including 1-octacosanol, docosenoic acid, daucosterol, methyl gallate, quercitrin and (-)-7-O-galloyltricetiflavan. The compound (-)-7-O-galloyltricetiflavan showed the most potent XO inhibitory activity with an IC 50 value of 25.5 μmol/L. From this investigation, four Vietnamese medicinal plants were identified to have XO inhibitory effects with IC 50 values of the methanol extracts below 30 μg/mL. Compound (-)-7-O- galloyltricetiflavan was identified as an XO inhibitor from A. clypearia with IC 50 value of 25.5 μmol/L. Copyright © 2017 Hainan Medical University. Production and hosting by Elsevier B.V. All rights reserved.

Substituted N-Benzylpyrazine-2-carboxamides: Synthesis and Biological Evaluation

Directory of Open Access Journals (Sweden)

Katarína Kráľová

2012-11-01

Full Text Available A series of twelve amides was synthesized via aminolysis of substituted pyrazinecarboxylic acid chlorides with substituted benzylamines. Compounds were characterized with analytical data and assayed in vitro for their antimycobacterial, antifungal, antibacterial and photosynthesis-inhibiting activity. 5-tert-Butyl-6-chloro-N-(4-methoxybenzylpyrazine-2-carboxamide (12 has shown the highest antimycobacterial activity against Mycobacterium tuberculosis (MIC = 6.25 µg/mL, as well as against other mycobacterial strains. The highest antifungal activity against Trichophyton mentagrophytes, the most susceptible fungal strain tested, was found for 5-chloro-N-(3-trifluoromethylbenzyl-pyrazine-2-carboxamide (2, MIC = 15.62 µmol/L. None of the studied compounds exhibited any activity against the tested bacterial strains. Except for 5-tert-butyl-6-chloro-N-benzylpyrazine-2-carboxamide (9, IC50 = 7.4 µmol/L and 5-tert-butyl-6-chloro-N-(4-chlorobenzylpyrazine-2-carboxamide (11, IC50 = 13.4 µmol/L, only moderate or weak photosynthesis-inhibiting activity in spinach chloroplasts (Spinacia oleracea L. was detected.

A SPECTROSCOPICALLY NORMAL TYPE Ic SUPERNOVA FROM A VERY MASSIVE PROGENITOR

International Nuclear Information System (INIS)

Valenti, Stefano; Pastorello, Andrea; Benetti, Stefano; Cappellaro, Enrico; Tomasella, Lina; Turatto, Massimo; Taubenberger, Stefan; Aramyan, Levon; Botticella, Maria Teresa; Fraser, Morgan; Smartt, Stephen J.; Magill, Lindsay; Kotak, Rubina; Wright, Darryl E.; Elias-Rosa, Nancy; Ergon, Mattias; Sollerman, Jesper; Magnier, Eugene; Price, Paul A.

2012-01-01

We present observations of the Type Ic supernova (SN Ic) 2011bm spanning a period of about one year. The data establish that SN 2011bm is a spectroscopically normal SN Ic with moderately low ejecta velocities and with a very slow spectroscopic and photometric evolution (more than twice as slow as SN 1998bw). The Pan-STARRS1 retrospective detection shows that the rise time from explosion to peak was ∼40 days in the R band. Through an analysis of the light curve and the spectral sequence, we estimate a kinetic energy of ∼7-17 foe and a total ejected mass of ∼7-17 M ☉ , 5-10 M ☉ of which is oxygen and 0.6-0.7 M ☉ is 56 Ni. The physical parameters obtained for SN 2011bm suggest that its progenitor was a massive star of initial mass 30-50 M ☉ . The profile of the forbidden oxygen lines in the nebular spectra shows no evidence of a bi-polar geometry in the ejected material.

SENYAWA ASAM 2- METILESTER-1-H-PIROL-4-KARBOKSILAT DALAM EKSTRAK ETIL ASETAT BUAH SALAK VARIETAS BONGKOK SEBAGAI ANTIOKSIDAN DAN ANTIHYPERURICEMIA [Studies on 2-Methylester-1-H-Pyrolle-4-Carboxylic Acid Compound in Ethylacetate Extract of Snake Fruit Variety Bongkok as Antioxidant and Anthyperuricemic

Directory of Open Access Journals (Sweden)

Leni Herliani Afrianti 1*

2010-06-01

Full Text Available The aim of the study was to determine the antioxidant and antihyperuricemia activity of ethyl acetate extract of snake fruit (Salacca edulis Reinw. var. Bongkok. The research methods used in this study comprised of three stages. First stage, the isolation processes, consist ed of maceration, fractionation, and purification using several techniques of chromatography. The chemical structures of the isolated compounds were determined based on UV, IR, 1-D NMR, and 2-D NMR spectral data. The ethyl acetate extract of snake fruit var. Bongkok isolated was a new compound 2-methylester-1-H-pyrolle-4- carboxylic acid. In the second stage the antioxidant activity of the extract and the isolated compounds were measured by 1,1 diphenol (DPPH method. The antioxidant activity of the extracts and the isolated compounds were expressed as IC50, The ethyl acetate extracts at concentrations of 0.2, 2, 20, 200, 400, and 2000 µg/mL showed inhibition of 9.67, 4.47, 41.89, 96.06, 82.54, and 90.60 % respectively, with an IC50 of 1.6 µg/mL. Ascorbic acid standards at the same concentration range showed an IC50 of 0.54 µg/mL. Meanwhile, at the same concentrations the 2-methylester-1-H-pyrolle-4-carboxylic acid showed free radical inhibition of 17.48, 21.48, 18.14, 31.87, and 62.34 % respectively, with an IC50 of 3.27 µg/mL. During the third stage, the antihyperuricemic properties of the extracts and the isolated compound were examinated in vitro using inhibition of xanthin oxidase method. The ethyl acetate extracts at concentrations of 0.01, 0.02, 0.2, 2, and 2000 µg/mL showed xanthin oxidase inhibition of 49.24, 49.58, 50.28 and 52.26 % respectively, with an IC50 of 24.75 µg/mL. At the same concentrations, the 2-methylester-1-H-pyrolle-4- carboxylic acid, showed xanthin oxidase inhibition of 27.7, 30.5, 37.3, 50.27 and 50.55 % respectively, with an IC50 of 48.86 µg/mL. Allopurinol as a standard drug showed an IC50 of 0.92 µg/mL.

Effect of irradiation on unscheduled DNA synthesis induced by 4-nitroquinoline in tracheal epithelium of rats

International Nuclear Information System (INIS)

Hahn, F.F.; Kennedy, R.; Brooks, A.L.

1986-01-01

Unscheduled DNA synthesis (UDS) was determined in rat epithelium by autoradiographic techniques to determine the influence of prior irradiation on the ability of the cells to repair mutagenic damage induced by 4-nitroquionoline (4NQO). UDS was stimulated by in vitro exposure to 4NPO. However, prior whole-body irradiation of rats with either 50 or 300 rad did not alter the UDS induced by 4NQO. The results of this study do not support the hypothesis that irradiation can induce DNA repair enzymes in respiratory tract epithelium. 5 references, 3 figures

Visualization research on spray atomization, evaporation and combustion processes of ethanol–diesel blend under LTC conditions

International Nuclear Information System (INIS)

Huang, Sheng; Deng, Peng; Huang, Ronghua; Wang, Zhaowen; Ma, Yinjie; Dai, Hui

2015-01-01

Highlights: • Spray combustion of E20 diesel in LTC condition shows a U-shape flame structure. • The chasing behavior of fuel spray exists near the spray axis. • Fuel ignition doesn’t initiate at the spray tip but in peripheral regions behind it. • An improper chamber structure may lead to a long post-combustion duration. - Abstract: Utilization of ethanol in diesel engines has been widely studied by means of engine experiments and emission detection. However, pertinent studies on the spray combustion process of ethanol–diesel blends are scarce. In order to verify the effect of ethanol in modern diesel engines, an experiment is conducted to visualize the spray combustion process of ethanol–diesel blend under LTC conditions. Stages including atomization, evaporation and combustion, are investigated individually to realize synergistic analysis. Meanwhile, considering the long time scale of combustion after fuel injection finishes, characteristics during and after injection period are both targeted in this paper. Moreover, measurement of macroscopic characteristics, such as spray tip penetration, spray spreading cone angle and flame lift off length, provides a quantitative profile of the spray structure. Results show that, evaporation, different from atomization, has little influence on spray penetration, but promotes the spray spreading angle and spray projected area. So does combustion, which enlarges the spray projected area further. Ignition takes place on the periphery behind the spray tip, then quickly extends to the whole head of the spray and forms a U-shape diffusion structure. After the injection period, the residual spray tail develops into wavelike structures due to absence of subsequent entrainment force. Also, the penetration speed falls greatly to an extent much slower than flame propagation, which frees the flame from the lift-off effect. Subsequently, the flame propagates upstream towards the nozzle orifice. After consumed all fuel in

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

Science.gov (United States)

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

2016-06-01

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

Non-clinical efficacy and safety of HyVac4:IC31 vaccine administered in a BCG prime-boost regimen.

Science.gov (United States)

Skeiky, Yasir A W; Dietrich, Jes; Lasco, Todd M; Stagliano, Katherine; Dheenadhayalan, Veerabadran; Goetz, Margaret Ann; Cantarero, Luis; Basaraba, Randall J; Bang, Peter; Kromann, Ingrid; McMclain, J Bruce; Sadoff, Jerald C; Andersen, Peter

2010-01-22

Despite the extensive success with the introduction of M. bovis Bacille Calmette-Guérin (BCG), tuberculosis (TB) remains a major global epidemic infecting between 8 and 9 million people annually with an estimated 1.7 million deaths each year. However, because of its demonstrated effectiveness against some of the most severe forms of childhood TB, it is now realized that BCG vaccination of newborns is unlikely to be replaced. Therefore, BCG or an improved BCG will continue to be used as a prime TB vaccine and there is a need to develop effective boost vaccines that would enhance and prolong the protective immunity induced by BCG prime immunization. We report on a heterologous booster approach using two highly immunogenic TB antigens comprising Ag85B and TB10.4 (HyVac4) delivered as a fusion molecule and formulated in the proprietary adjuvant IC31. This vaccine was found to be immunogenic and demonstrated greater protection in the more stringent guinea pig model of pulmonary tuberculosis than BCG alone when used in a prime/boost regimen. Significant difference in lung involvement was observed for all animals in the HyVac4 boosted group compared to BCG alone regardless of time to death or sacrifice. A vaccine toxicology study of the HyVac4:IC31 regimen was performed and it was judged safe to advance the vaccine into clinical trials. Therefore, all non-clinical data supports the suitability of HyVac4 as a safe, immunogenic, and effective vaccination in a prime-boost regimen with BCG.

The mibefradil derivative NNC55-0396, a specific T-type calcium channel antagonist, exhibits less CYP3A4 inhibition than mibefradil.

Science.gov (United States)

Bui, Peter H; Quesada, Arnulfo; Handforth, Adrian; Hankinson, Oliver

2008-07-01

A novel mibefradil derivative, NNC55-0396, designed to be hydrolysis-resistant, was shown to be a selective T-type Ca(2+) channel inhibitor without L-type Ca(2+) channel efficacy. However, its effects on cytochromes P450 (P450s) have not previously been examined. We investigated the inhibitory effects of NNC55-0396 toward seven major recombinant human P450s--CYP3A4, CYP2D6, CYP1A2, CYP2C9, CYP2C8, CYPC19, and CYP2E1--and compared its effects with those of mibefradil and its hydrolyzed metabolite, Ro40-5966. Our results show that CYP3A4 and CYP2D6 are the two P450s most affected by mibefradil, Ro40-5966, and NNC55-0396. Mibefradil (IC(50) = 33 +/- 3 nM, K(i) = 23 +/- 0.5 nM) and Ro40-5966 (IC(50) = 30 +/- 7.8 nM, K(i) = 21 +/- 2.8 nM) have a 9- to 10-fold greater inhibitory activity toward recombinant CYP3A4 benzyloxy-4-trifluoromethylcoumarin-O-debenzylation activity than NNC55-0396 (IC(50) = 300 +/- 30 nM, K(i) = 210 +/- 6 nM). More dramatically, mibefradil (IC(50) = 566 +/- 71 nM, K(i) = 202 +/- 39 nM) shows 19-fold higher inhibition of CYP3A-associated testosterone 6beta-hydroxylase activity in human liver microsomes compared with NNC55-0396 (IC(50) = 11 +/- 1.1 microM, K(i) = 3.9 +/- 0.4 microM). Loss of testosterone 6beta-hydroxylase activity by recombinant CYP3A4 was shown to be time- and concentration-dependent with both compounds. However, NNC55-0396 (K(I) = 3.87 microM, K(inact) = 0.061/min) is a much less potent mechanism-based inhibitor than mibefradil (K(I) = 83 nM, K(inact) = 0.048/min). In contrast, NNC55-0396 (IC(50) = 29 +/- 1.2 nM, K(i) = 2.8 +/- 0.3 nM) and Ro40-5966 (IC(50) = 46 +/- 11 nM, K(i) = 4.5 +/- 0.02 nM) have a 3- to 4-fold greater inhibitory activity toward recombinant CYP2D6 than mibefradil (IC(50) = 129 +/- 21 nM, K(i) = 12.7 +/- 0.9 nM). Our results suggest that NNC55-0396 could be a more favorable T-type Ca(2+) antagonist than its parent compound, mibefradil, which was withdrawn from the market because of strong inhibition of CYP3A4.

Linalool, a Piper aduncum essential oil component, has selective activity against Trypanosoma cruzi trypomastigote forms at 4°C.

Science.gov (United States)

Villamizar, Luz Helena; Cardoso, Maria das Graças; Andrade, Juliana de; Teixeira, Maria Luisa; Soares, Maurilio José

2017-02-01

Recent studies showed that essential oils from different pepper species (Piper spp.) have promising leishmanicidal and trypanocidal activities. In search for natural compounds against Trypanosoma cruzi, different forms of the parasite were incubated for 24 h at 28ºC or 4ºC with Piper aduncum essential oil (PaEO) or its main constituents linalool and nerolidol. PaEO chemical composition was obtained by GC-MS. Drug activity assays were based on cell counting, MTT data or infection index values. The effect of PaEO on the T. cruzi cell cycle and mitochondrial membrane potential was evaluated by flow cytometry. PaEO was effective against cell-derived (IC50/24 h: 2.8 μg/mL) and metacyclic (IC50/24 h: 12.1 μg/mL) trypomastigotes, as well as intracellular amastigotes (IC50/24 h: 9 μg/mL). At 4ºC - the temperature of red blood cells (RBCs) storage in blood banks - cell-derived trypomastigotes were more sensitive to PaEO (IC50/24 h = 3.8 μg/mL) than to gentian violet (IC50/24 h = 24.7 mg/mL). Cytotoxicity assays using Vero cells (37ºC) and RBCs (4ºC) showed that PaEO has increased selectivity for cell-derived trypomastigotes. Flow cytometry analysis showed that PaEO does not affect the cell cycle of T. cruzi epimastigotes, but decreases their mitochondrial membrane potential. GC-MS data identified nerolidol and linalool as major components of PaEO, and linalool had trypanocidal effect (IC50/24 h: 306 ng/mL) at 4ºC. The trypanocidal effect of PaEO is likely due to the presence of linalool, which may represent an interesting candidate for use in the treatment of potentially contaminated RBCs bags at low temperature.

Linalool, a Piper aduncum essential oil component, has selective activity against Trypanosoma cruzi trypomastigote forms at 4°C

Directory of Open Access Journals (Sweden)

Luz Helena Villamizar

Full Text Available BACKGROUND Recent studies showed that essential oils from different pepper species (Piper spp. have promising leishmanicidal and trypanocidal activities. OBJECTIVES In search for natural compounds against Trypanosoma cruzi, different forms of the parasite were incubated for 24 h at 28ºC or 4ºC with Piper aduncum essential oil (PaEO or its main constituents linalool and nerolidol. METHODS PaEO chemical composition was obtained by GC-MS. Drug activity assays were based on cell counting, MTT data or infection index values. The effect of PaEO on the T. cruzi cell cycle and mitochondrial membrane potential was evaluated by flow cytometry. FINDINGS PaEO was effective against cell-derived (IC50/24 h: 2.8 μg/mL and metacyclic (IC50/24 h: 12.1 μg/mL trypomastigotes, as well as intracellular amastigotes (IC50/24 h: 9 μg/mL. At 4ºC - the temperature of red blood cells (RBCs storage in blood banks - cell-derived trypomastigotes were more sensitive to PaEO (IC50/24 h = 3.8 μg/mL than to gentian violet (IC50/24 h = 24.7 mg/mL. Cytotoxicity assays using Vero cells (37ºC and RBCs (4ºC showed that PaEO has increased selectivity for cell-derived trypomastigotes. Flow cytometry analysis showed that PaEO does not affect the cell cycle of T. cruzi epimastigotes, but decreases their mitochondrial membrane potential. GC-MS data identified nerolidol and linalool as major components of PaEO, and linalool had trypanocidal effect (IC50/24 h: 306 ng/mL at 4ºC. MAIN CONCLUSION The trypanocidal effect of PaEO is likely due to the presence of linalool, which may represent an interesting candidate for use in the treatment of potentially contaminated RBCs bags at low temperature.

Dillapiole as antileishmanial agent: discovery, cytotoxic activity and preliminary SAR studies of dillapiole analogues.

Science.gov (United States)

Parise-Filho, Roberto; Pasqualoto, Kerly Fernanda Mesquita; Magri, Fátima Maria Motter; Ferreira, Adilson Kleber; da Silva, Bárbara Athayde Vaz Galvão; Damião, Mariana Celestina Frojuello Costa Bernstorff; Tavares, Maurício Temotheo; Azevedo, Ricardo Alexandre; Auada, Aline Vivian Vatti; Polli, Michelle Carneiro; Brandt, Carlos Alberto

2012-12-01

In this paper, the isolation of dillapiole (1) from Piper aduncum was reported as well as the semi-synthesis of two phenylpropanoid derivatives [di-hydrodillapiole (2), isodillapiole (3)], via reduction and isomerization reactions. Also, the compounds' molecular properties (structural, electronic, hydrophobic, and steric) were calculated and investigated to establish some preliminary structure-activity relationships (SAR). Compounds were evaluated for in vitro antileishmanial activity and cytotoxic effects on fibroblast cells. Compound 1 presented inhibitory activity against Leishmania amazonensis (IC(50)  = 69.3 µM) and Leishmania brasiliensis (IC(50)  = 59.4 µM) and induced cytotoxic effects on fibroblast cells mainly in high concentrations. Compounds 2 (IC(50)  = 99.9 µM for L. amazonensis and IC(50)  = 90.5 µM for L. braziliensis) and 3 (IC(50)  = 122.9 µM for L. amazonensis and IC(50)  = 109.8 µM for L. brasiliensis) were less active than dillapiole (1). Regarding the molecular properties, the conformational arrangement of the side chain, electronic features, and the hydrophilic/hydrophobic balance seem to be relevant for explaining the antileishmanial activity of dillapiole and its analogues. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Diclofenac 1,3,4-Oxadiazole Derivatives; Biology-Oriented Drug Synthesis (BIODS) in Search of Better Non-Steroidal, Non-Acid Antiinflammatory Agents.

Science.gov (United States)

Shah, Shazia; Arshia; Kazmi, Nida Siraj; Jabeen, Almas; Faheem, Aisha; Dastagir, Nida; Ahmed, Tariq; Khan, Khalid Mohammed; Ahmed, Shakil; Raza, Abeer; Perveen, Shahnaz

2018-03-21

Inflammation is defined as the response of immune system cells to damaged or injured tissues The major symptoms of inflammation include increased blood flow, cellular influx, edema, elevated cellular metabolism, reactive oxygen species (ROS) nitric oxide (NO) and vasodilation. This normally protective mechanism against harmful agents when this normal mechanism becomes dysregulated that can cause serious illnesses including ulcerative colitis, Crohn's disease, rheumatoid arthritis, osteoarthritis, sepsis, and chronic pulmonary inflammation . In this study synthetic transformations on diclofenac were carried out in search of better non-steroidal antiinflammatory drugs (NSAIDs), non-acidic, antiinflammatory agents. For this purpose diclofenac derivatives (2-20) were synthesized from diclofenac (1). All derivatives (2-20) and parent diclofenac (1) were evaluated for their antiinflammatory effect using different parameters including suppression of intracellular reactive oxygen species (ROS), produced by whole blood phagocytes, produced by neutrophils, and inhibition of nitric oxide (NO) production from J774.2 macrophages. Most active compound also evaluated for cytotoxicity activity. Diclofenac (1) inhibited the ROS with an IC50 of 3.9 ± 2.8, 1.2 ± 0.0 μg/mL respectively and inhibited NO with an IC50 of 30.01 ± 0.01 μg/mL. Among its derivatives 4, 5, 11, 16, and 20, showed better antiinflammatory potential. The compound 5 was found to be the most potent inhibitor of intracellular ROS as well as NO with an IC50 values of 1.9 ± 0.9, 1.7 ± 0.4 μg/mL respectively and 7.13 ± 1.0 μg/mL, respectively, and showed good inhibitory activity than parent diclofenac. The most active compounds were tested for their toxic effect on NIH-3T3 cells where all compounds were found to be non-toxic compared to the standard cytotoxic drug cyclohexamide. Five derivatives were found to be active. Compound 5 was found to be the most potent inhibitor of ROS and NO compared to parent

Wafer level 3-D ICs process technology

CERN Document Server

Tan, Chuan Seng; Reif, L Rafael

2009-01-01

This book focuses on foundry-based process technology that enables the fabrication of 3-D ICs. The core of the book discusses the technology platform for pre-packaging wafer lever 3-D ICs. However, this book does not include a detailed discussion of 3-D ICs design and 3-D packaging. This is an edited book based on chapters contributed by various experts in the field of wafer-level 3-D ICs process technology. They are from academia, research labs and industry.

Synthesis of Novel β-Keto-Enol Derivatives Tethered Pyrazole, Pyridine and Furan as New Potential Antifungal and Anti-Breast Cancer Agents

Directory of Open Access Journals (Sweden)

Smaail Radi

2015-11-01

Full Text Available Recently, a new generation of highly promising inhibitors bearing β-keto-enol functionality has emerged. Reported herein is the first synthesis and use of novel designed drugs based on the β-keto-enol group embedded with heterocyclic moieties such as pyrazole, pyridine, and furan, prepared in a one-step procedure by mixed Claisen condensation. All the newly synthesized compounds were characterized by FT-IR, 1H-NMR, 13C-NMR, ESI/LC-MS, elemental analysis, and evaluated for their in vitro antiproliferative activity against breast cancer (MDA-MB241 human cell lines and fungal strains (Fusarium oxysporum f.sp albedinis FAO. Three of the synthesized compounds showed potent activity against fungal strains with IC50 values in the range of 0.055–0.092 µM. The results revealed that these compounds showed better IC50 values while compared with positive controls.

Late Protein Synthesis-Dependent Phases in CTA Long-Term Memory: BDNF Requirement

Science.gov (United States)

Martínez-Moreno, Araceli; Rodríguez-Durán, Luis F.; Escobar, Martha L.

2011-01-01

It has been proposed that long-term memory (LTM) persistence requires a late protein synthesis-dependent phase, even many hours after memory acquisition. Brain-derived neurotrophic factor (BDNF) is an essential protein synthesis product that has emerged as one of the most potent molecular mediators for long-term synaptic plasticity. Studies in the rat hippocampus have been shown that BDNF is capable to rescue the late-phase of long-term potentiation as well as the hippocampus-related LTM when protein synthesis was inhibited. Our previous studies on the insular cortex (IC), a region of the temporal cortex implicated in the acquisition and storage of conditioned taste aversion (CTA), have demonstrated that intracortical delivery of BDNF reverses the deficit in CTA memory caused by the inhibition of IC protein synthesis due to anisomycin administration during early acquisition. In this work, we first analyze whether CTA memory storage is protein synthesis-dependent in different time windows. We observed that CTA memory become sensible to protein synthesis inhibition 5 and 7 h after acquisition. Then, we explore the effect of BDNF delivery (2 μg/2 μl per side) in the IC during those late protein synthesis-dependent phases. Our results show that BDNF reverses the CTA memory deficit produced by protein synthesis inhibition in both phases. These findings support the notion that recurrent rounds of consolidation-like events take place in the neocortex for maintenance of CTA memory trace and that BDNF is an essential component of these processes. PMID:21960964

Late protein synthesis-dependent phases in CTA long-term memory: BDNF requirement

Directory of Open Access Journals (Sweden)

Araceli eMartínez-Moreno

2011-09-01

Full Text Available It has been proposed that long-term memory persistence requires a late protein synthesis-dependent phase, even many hours after memory acquisition. Brain-derived neurotrophic factor (BDNF is an essential protein synthesis product that has emerged as one of the most potent molecular mediators for long-term synaptic plasticity. Studies in the rat hippocampus have been shown that BDNF is capable to rescue the late-phase of long-term potentiation as well as the hippocampus-related long-term memory when protein synthesis was inhibited. Our previous studies on the insular cortex (IC, a region of the temporal cortex implicated in the acquisition and storage of conditioned taste aversion (CTA, have demonstrated that intracortical delivery of BDNF reverses the deficit in CTA memory caused by the inhibition of IC protein synthesis due to anisomycin administration during early acquisition. In this work, we first analyze whether CTA memory storage is protein synthesis dependent in different time-windows. We observed that CTA memory become sensible to protein synthesis inhibition 5 and 7 hours after acquisition. Then, we explore the effect of BDNF delivery (2 μg/2 μl per side in the IC during those late protein synthesis-dependent phases. Our results show that BDNF reverses the CTA memory deficit produced by protein synthesis inhibition in both phases. These findings support the notion that recurrent rounds of consolidation-like events take place in the neocortex for maintenance of CTA memory trace and that BDNF is an essential component of these processes.

Late Protein Synthesis-Dependent Phases in CTA Long-Term Memory: BDNF Requirement.

Science.gov (United States)

Martínez-Moreno, Araceli; Rodríguez-Durán, Luis F; Escobar, Martha L

2011-01-01

It has been proposed that long-term memory (LTM) persistence requires a late protein synthesis-dependent phase, even many hours after memory acquisition. Brain-derived neurotrophic factor (BDNF) is an essential protein synthesis product that has emerged as one of the most potent molecular mediators for long-term synaptic plasticity. Studies in the rat hippocampus have been shown that BDNF is capable to rescue the late-phase of long-term potentiation as well as the hippocampus-related LTM when protein synthesis was inhibited. Our previous studies on the insular cortex (IC), a region of the temporal cortex implicated in the acquisition and storage of conditioned taste aversion (CTA), have demonstrated that intracortical delivery of BDNF reverses the deficit in CTA memory caused by the inhibition of IC protein synthesis due to anisomycin administration during early acquisition. In this work, we first analyze whether CTA memory storage is protein synthesis-dependent in different time windows. We observed that CTA memory become sensible to protein synthesis inhibition 5 and 7 h after acquisition. Then, we explore the effect of BDNF delivery (2 μg/2 μl per side) in the IC during those late protein synthesis-dependent phases. Our results show that BDNF reverses the CTA memory deficit produced by protein synthesis inhibition in both phases. These findings support the notion that recurrent rounds of consolidation-like events take place in the neocortex for maintenance of CTA memory trace and that BDNF is an essential component of these processes.

Synthesis and properties of novel 4,5-diaminonaphthalimides

International Nuclear Information System (INIS)

Morris, I.P.

1999-07-01

This thesis presents work carried out into the synthesis and properties of Novel 4,5-diaminonaphthalimides. Previous work had identified that these compounds could be synthesised through a short reaction sequence but a very limited number of examples had been produced. With some modifications, the structure of 4,5-diaminonaphthalimides suggests a number of applications. The diamine functionality suggests the formation of complexes and if chiral amines were used asymmetric synthesis is a possibility. Naphthalimides are known to intercalate into DNA and so compounds of this nature may have interesting anti-cancer activity. Finally diaminonaphthalimides are strongly fluorescent and this in combination with the chelation potential of the diamine functionality may afford ion and molecular sensors. The first section of this thesis reviews these areas of research and demonstrates how diaminonaphthalimides might contribute to these areas. The second section describes the synthesis of 4,5-diaminonaphthalimides and illustrates the variety of compounds that may be synthesised. In addition this section explores the applications to fluorescence sensing and asymmetric synthesis. 4,5-Diaminonaphthalimides are shown to undergo chelation enhanced quenching (CHEQ) and chelation enhanced fluorescence (CHEF) with various transition metal ions. The precise features are shown to be dependent on the metal ion present. The mass spectroscopic results discussed in this section show 4,5-diaminonaphthalimides to be a new class of supramolecular compound as they show pre-assembly around alkali earth metal ions. 4,5-Diaminonaphthalimides were also used as catalysts in asymmetric reactions where they show some catalytic activity in the addition of diethylzinc to benzaldehyde. (author)

Stereoselective synthesis of L-[4-13C]carnitine

International Nuclear Information System (INIS)

Unkefer, C.J.; Ehler, D.S.

1991-01-01

The stereoselective synthesis of L-[4- 13 C]carnitine was achieved in 5 steps. The label was introduced from K 13 CN into an easily separated diastereomeric pair of 3-deoxy-D-[1- 13 C]aldohexoses. Reductive amination of the labeled aldohexose yielded the corresponding D-1-(dimethylamino)[1- 13 C]alditol which was oxidized in two steps and alkylated with iodomethane to yield L-[4- 13 C]carnitine. The stereochemical integrity at C-2 of the 3-deoxy-D-[1- 13 C]glucose precursor was maintained throughout the synthesis of L-[4- 13 C]carnitine. (author)

Synthesis of 4-Halogenated 3-Fluoro-6-methoxyquinolines: Key Building Blocks for the Synthesis of Antibiotics

DEFF Research Database (Denmark)

Flagstad, Thomas; Petersen, Mette Terp; Hinnerfeldt, Daniel Michael

2014-01-01

A practical and scalable 4-step route is presented for the synthesis of 4-bromo-3-fluoro-6-methoxyoquinoline and 3-fluoro-4-iodo-6-methoxyoquinoline from readily available 2,4-dichloro-3-fluoroquinoline with an overall yield of 81-85%. Halogenated quinoline building blocks have found much use in ...... in antimicrobial drug discovery, and the method reported here would be useful for the synthesis of these compounds. © Georg Thieme Verlag....

Aphadilactones A-D, four diterpenoid dimers with DGAT inhibitory and antimalarial activities from a Meliaceae plant.

Science.gov (United States)

Liu, Jia; He, Xiu-Feng; Wang, Gai-Hong; Merino, Emilio F; Yang, Sheng-Ping; Zhu, Rong-Xiu; Gan, Li-She; Zhang, Hua; Cassera, Maria B; Wang, He-Yao; Kingston, David G I; Yue, Jian-Min

2014-01-17

Aphadilactones A-D (1-4), four diastereoisomers possessing an unprecedented carbon skeleton, were isolated from the Meliaceae plant Aphanamixis grandifolia. Their challenging structures and absolute configurations were determined by a combination of spectroscopic data, chemical degradation, fragment synthesis, experimental CD spectra, and ECD calculations. Aphadilactone C (3) with the 5S,11S,5'S,11'S configuration showed potent and selective inhibition against the diacylglycerol O-acyltransferase-1 (DGAT-1) enzyme (IC50 = 0.46 ± 0.09 μM, selectivity index > 217) and is the strongest natural DGAT-1 inhibitor discovered to date. In addition, compounds 1-4 showed significant antimalarial activities with IC50 values of 190 ± 60, 1350 ± 150, 170 ± 10, and 120 ± 50 nM, respectively.

Design, synthesis, biological evaluation and docking study of 5-oxo-4,5-dihydropyrano[3,2-c]chromene derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors.

Science.gov (United States)

Khoobi, Mehdi; Alipour, Masoumeh; Sakhteman, Amirhossein; Nadri, Hamid; Moradi, Alireza; Ghandi, Mehdi; Emami, Saeed; Foroumadi, Alireza; Shafiee, Abbas

2013-10-01

A series of fused coumarins namely 5-oxo-4,5-dihydropyrano[3,2-c]chromenes linked to N-benzylpyridinium scaffold were synthesized and evaluated as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. The 1-(4-fluorobenzyl)pyridinium derivative 6g showed the most potent anti-AChE activity (IC50 value=0.038 μM) and the highest AChE/BuChE selectivity (SI>48). The docking study permitted us to rationalize the observed structure-affinity relationships and to detect possible binding modes. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Synthesis and Antiplasmodial Activity of Betulinic Acid and Ursolic Acid Analogues

Directory of Open Access Journals (Sweden)

Simone C. B. Gnoatto

2012-10-01

Full Text Available More than 40% of the World population is at risk of contracting malaria, which affects primarily poor populations in tropical and subtropical areas. Antimalarial pharmacotherapy has utilised plant-derived products such as quinine and artemisinin as well as their derivatives. However, worldwide use of these antimalarials has caused the spread of resistant parasites, resulting in increased malaria morbidity and mortality. Considering that the literature has demonstrated the antimalarial potential of triterpenes, specially betulinic acid (1 and ursolic acid (2, this study investigated the antimalarial activity against P. falciparum chloroquine-sensitive 3D7 strain of some new derivatives of 1 and 2 with modifications at C-3 and C-28. The antiplasmodial study employed flow cytometry and spectrofluorimetric analyses using YOYO-1, dihydroethidium and Fluo4/AM for staining. Among the six analogues obtained, compounds 1c and 2c showed excellent activity (IC50 = 220 and 175 nM, respectively while 1a and b demonstrated good activity (IC50 = 4 and 5 μM, respectively. After cytotoxicity evaluation against HEK293T cells, 1a was not toxic, while 1c and 2c showed IC50 of 4 μM and a selectivity index (SI value of 18 and 23, respectively. Moreover, compound 2c, which presents the best antiplasmodial activity, is involved in the calcium-regulated pathway(s.

Discovery of 2-(4-Substituted-piperidin/piperazine-1-yl-N-(5-cyclopropyl-1H-pyrazol-3-yl-quinazoline-2,4-diamines as PAK4 Inhibitors with Potent A549 Cell Proliferation, Migration, and Invasion Inhibition Activity

Directory of Open Access Journals (Sweden)

Tianxiao Wu

2018-02-01

Full Text Available A series of novel 2,4-diaminoquinazoline derivatives were designed, synthesized, and evaluated as p21-activated kinase 4 (PAK4 inhibitors. All compounds showed significant inhibitory activity against PAK4 (half-maximal inhibitory concentration IC50 < 1 μM. Among them, compounds 8d and 9c demonstrated the most potent inhibitory activity against PAK4 (IC50 = 0.060 μM and 0.068 μM, respectively. Furthermore, we observed that compounds 8d and 9c displayed potent antiproliferative activity against the A549 cell line and inhibited cell cycle distribution, migration, and invasion of this cell line. In addition, molecular docking analysis was performed to predict the possible binding mode of compound 8d. This series of compounds has the potential for further development as PAK4 inhibitors for anticancer activity.

Development of a Monoclonal Antibody-Based icELISA for the Detection of Ustiloxin B in Rice False Smut Balls and Rice Grains

Directory of Open Access Journals (Sweden)

Xiaoxiang Fu

2015-08-01

Full Text Available Rice false smut is an emerging and economically-important rice disease caused by infection by the fungal pathogen Villosiclava virens. Ustiloxin B is an antimitotic cyclopeptide mycotoxin isolated from the rice false smut balls that formed in the pathogen-infected rice spikelets. A monoclonal antibody (mAb designated as mAb 1B5A10 was generated with ustiloxin B—ovalbumin conjugate. A highly-sensitive and specific indirect competitive enzyme-linked immunosorbent assay (icELISA was then developed. The median inhibitory concentration (IC50 of the icELISA was 18.0 ng/mL for the detection of ustiloxin B; the limit of detection was 0.6 ng/mL, and the calibration range was from 2.5 to 107.4 ng/mL. The LOD/LOQ values of the developed ELISA used for the determination of ustiloxin B in rice false smut balls and rice grains were 12/50 μg/g and 30/125 ng/g, respectively. The mAb 1B5A10 cross-reacted with ustiloxin A at 13.9% relative to ustiloxin B. Average recoveries of ustiloxin B ranged from 91.3% to 105.1% for rice false smut balls at spiking levels of 0.2 to 3.2 mg/g and from 92.6% to 103.5% for rice grains at spiking levels of 100 to 5000 ng/g. Comparison of ustiloxin B content in rice false smut balls and rice grains detected by both icELISA and high performance liquid chromatography (HPLC demonstrated that the developed icELISA can be employed as an effective and accurate method for the detection of ustiloxin B in rice false smut balls, as well as rice food and feed samples.

Synthesis, characterization and hemolysis studies of Zn{sub (1−x)}Ca{sub x}Fe{sub 2}O{sub 4} ferrites synthesized by sol-gel for hyperthermia treatment applications

Energy Technology Data Exchange (ETDEWEB)

Jasso-Terán, Rosario Argentina, E-mail: arg.jasso@gmail.com; Cortés-Hernández, Dora Alicia; Sánchez-Fuentes, Héctor Javier; Reyes-Rodríguez, Pamela Yajaira; León-Prado, Laura Elena de; Escobedo-Bocardo, José Concepción; Almanza-Robles, José Manuel

2017-04-01

The synthesis of Zn{sub (1−x)}Ca{sub x}Fe{sub 2}O{sub 4} nanoparticles, x=0, 0.25, 0.50, 0.75 and 1.0, was performed by sol-gel method followed by a heat treatment at 400 °C for 30 min. These ferrites showed nanometric sizes and nearly superparamagnetic behavior. The Zn{sub 0.50}Ca{sub 0.50}Fe{sub 2}O{sub 4} and CaFe{sub 2}O{sub 4} ferrites presented a size within the range of 12–14 nm and appropriate heating ability for hyperthermia applications. Hemolysis testing demonstrated that Zn{sub 0.50}Ca{sub 0.50}Fe{sub 2}O{sub 4} ferrite was not cytotoxic when using 10 mg of ferrite/mL of solution. According to the results obtained, Zn{sub 0.50}Ca{sub 0.50}Fe{sub 2}O{sub 4} is a potential material for cancer treatment by magnetic hyperthermia therapy. - Highlights: • The synthesis of Zn{sub (1−x)}Ca{sub x}Fe{sub 2}O{sub 4} ferrites was performed by sol-gel method. • CaFe{sub 2}O{sub 4} and Zn{sub 0.50}Ca{sub 0.}50Fe{sub 2}O{sub 4} ferrites showed heating ability. • The Zn{sub 0.50}Ca{sub 0.50}Fe{sub 2}O{sub 4} ferrite demonstrated to be no hemolytic.

Synthesis and evaluation of the antioxidative potential of minoxidil-polyamine conjugates.

Science.gov (United States)

Hadjipavlou-Litina, Dimitra; Magoulas, George E; Bariamis, Stavros E; Tsimali, Zinovia; Avgoustakis, Konstantinos; Kontogiorgis, Christos A; Athanassopoulos, Constantinos M; Papaioannou, Dionissios

2013-07-01

A series of conjugates (MNX-CO-PA) of minoxidil (MNX) with the polyamines (PAs) putrescine (PUT), spermidine (SPD) and spermine (SPM) as well as dopamine were produced through activation of MNX with N,N'-carbonyldiimidazole, followed by reaction with dopamine or selectively protected PAs and acid-mediated deprotection. These conjugates together with conjugates of the general type MNX-PA or PA-MNX-PA, readily produced using literature protocols, were tested as antioxidants. The most potent inhibitors of lipid peroxidation were the conjugates MNX-SPM (2, 94%), SPM-MNX-SPM (4, 94%) and MNX-N(4)-SPD (7, 91%) and MNX (91%). The most powerful lipoxygenase (LOX) inhibitors were MNX (IC50 = 20 μM) and the conjugates MNX-N(8)-SPD (9, IC50 = 22.1 μM), MNX-CO-dopamine (11, IC50 = 28 μM) and MNX-N(1)-SPD (8, IC50 = 30 μM). The most interesting conjugates 2, MNX-CO-PUT (5), 8 and 11 as well as MNX were generally found to exhibit weaker (22-36.5%) or no (conjugate 8) anti-inflammatory activity than indomethacin (47%) with the exception of MNX which showed almost equal potency (49%) to indomethacin. The cytocompatibility of conjugates and MNX at the highest concentration of 100 μM showed a survival percentage of 87-107%, with the exception of conjugates with SPM (compound 2) and MNX-CO-SPM (6), which showed considerable cytotoxicity (survival percentage 8-14%). Molecular docking studies were carried on conjugate 9 and the parent compound MNX and were found to be in accordance with our experimental biological results. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Design, synthesis and biological evaluation of benzo[e][1,2,4]triazin-7(1H)-one and [1,2,4]-triazino[5,6,1-jk]carbazol-6-one derivatives as dual inhibitors of beta-amyloid aggregation and acetyl/butyryl cholinesterase.

Science.gov (United States)

Catto, Marco; Berezin, Andrey A; Lo Re, Daniele; Loizou, Georgia; Demetriades, Marina; De Stradis, Angelo; Campagna, Francesco; Koutentis, Panayiotis A; Carotti, Angelo

2012-12-01

Alzheimer's disease (AD) onset and progression are associated with the dysregulation of multiple and complex physiological processes and a successful therapeutic approach should therefore address more than one target. Two new chemical entities, the easily accessible heterocyclic scaffolds 1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one (benzotriazinone I) and 2-phenyl-6H-[1,2,4]triazino[5,6,1-jk]carbazol-6-one (triazafluoranthenone II), were explored for their multitarget-directed inhibition of beta-amyloid (Aβ) fibrillization and acetyl- (AChE) and/or butyryl- (BChE) cholinesterase, three valuable targets for AD therapy. Introduction of appropriate amine substituents at positions 6 and 5 on scaffold I and II, respectively, allowed the preparation of a series of compounds that were tested as Aβ(1-40) aggregation and cholinesterase inhibitors. Potent inhibitors of Aβ self-aggregation were discovered and among them benzotriazinone 7 exhibited an outstanding IC(50) equal to 0.37 μM. Compounds bearing a basic amine linked to the heterocyclic scaffold through a linear alkyl chain of varying length also afforded good ChE inhibitors. In particular, benzotriazinone 24 and triazafluoranthenone 38 were endowed with an interesting multiple activity, the former displaying IC(50) values of 1.4, 1.5 and 1.9 μM on Aβ aggregation and AChE and BChE inhibition, respectively, and the latter showing IC(50) values of 1.4 and an outstanding 0.025 μM in the Aβ aggregation and BChE inhibition, respectively. Benzotriazinone 24 and triazafluoranthenone 29, selected owing to their suitable aqueous solubility and Aβ aggregation inhibition, were submitted to a time course kinetic assay followed with thioflavin T (ThT) spectrofluorimetry, circular dichroism (CD) and transmission electron microscopy (TEM). Experimental data indicated that 24 acted at a low concentration ratio (10 μM 24 vs. 50 μM Aβ), stabilizing the unstructured Aβ peptide and inhibiting fibrillogenesis, and that 29

Insulin treatment promotes tyrosine phosphorylation of PKR and inhibits polyIC induced PKR threonine phosphorylation.

Science.gov (United States)

Swetha, Medchalmi; Ramaiah, Kolluru V A

2015-11-01

Tyrosine phosphorylation of insulin receptor beta (IRβ) in insulin treated HepG2 cells is inversely correlated to ser(51) phosphorylation in the alpha-subunit of eukaryotic initiation factor 2 (eIF2α) that regulates protein synthesis. Insulin stimulates interaction between IRβ and PKR, double stranded RNA-dependent protein kinase, also known as EIF2AK2, and phosphorylation of tyrosine residues in PKR, as analyzed by immunoprecipitation and pull down assays using anti-IRβ and anti-phosphotyrosine antibodies, recombinant IRβ and immunopurified PKR. Further polyIC or synthetic double stranded RNA-induced threonine phosphorylation or activation of immunopurified and cellular PKR is suppressed in the presence of insulin treated purified IRβ and cell extracts. Acute, but not chronic, insulin treatment enhances tyrosine phosphorylation of IRβ, its interaction with PKR and tyrosine phosphorylation of PKR. In contrast, lipopolysaccharide that stimulates threonine phosphorylation of PKR and eIF2α phosphorylation and AG 1024, an inhibitor of the tyrosine kinase activity of IRβ, reduces PKR association with the receptor, IRβ in HepG2 cells. These findings therefore may suggest that tyrosine phosphorylated PKR plays a role in the regulation of insulin induced protein synthesis and in maintaining insulin sensitivity, whereas, suppression of polyIC-mediated threonine phosphorylation of PKR by insulin compromises its ability to fight against virus infection in host cells. Copyright © 2015 Elsevier Inc. All rights reserved.

SEM probe of IC radiation sensitivity

Science.gov (United States)

Gauthier, M. K.; Stanley, A. G.

1979-01-01

Scanning Electron Microscope (SEM) used to irradiate single integrated circuit (IC) subcomponent to test for radiation sensitivity can localize area of IC less than .03 by .03 mm for determination of exact location of radiation sensitive section.

Dicty_cDB: FC-IC0102 [Dicty_cDB

Lifescience Database Archive (English)

Full Text Available FC-IC (Link to library) FC-IC0102 (Link to dictyBase) - - - Contig-U16527-1 FC-IC01...02F (Link to Original site) FC-IC0102F 434 - - - - - - Show FC-IC0102 Library FC-IC (Link to library) Clone ...ID FC-IC0102 (Link to dictyBase) Atlas ID - NBRP ID - dictyBase ID - Link to Contig Contig-U16527-1 Original site URL http://dict... (bits) Value N AB088483 |AB088483.1 Dictyostelium discoideum gene for gamete and mating-type specific prote...oducing significant alignments: (bits) Value AB088483_1( AB088483 |pid:none) Dictyostelium discoideum gmsA g

Flexible synthesis of poison-frog alkaloids of the 5,8-disubstituted indolizidine-class. II: Synthesis of (--209B, (--231C, (--233D, (--235B", (--221I, and an epimer of 193E and pharmacological effects at neuronal nicotinic acetylcholine receptors

Directory of Open Access Journals (Sweden)

Garraffo H Martin

2007-09-01

Full Text Available Abstract Background The 5,8-disubstituted indolizidines constitute the largest class of poison-frog alkaloids. Some alkaloids have been shown to act as noncompetitive blockers at nicotinic acetylcholine receptors but the proposed structures and the biological activities of most of the 5,8-disubstituted indolizidines have not been determined because of limited supplies of the natural products. We have therefore conducted experiments to confirm proposed structures and determine biological activities using synthetic compounds. Recently, we reported that one of this class of alkaloids, (--235B', acts as a noncompetitive antagonist for α4β2 nicotinic receptors, and its sensitivity is comparable to that of the classical competitive antagonist for this receptor, dihydro-β-erythroidine. Results The enantioselective syntheses of (--209B, (--231C, (--233D, (--235B", (--221I, and what proved to be an epimer of natural 193E, starting from common chiral lactams have been achieved. When we performed electrophysiological recordings to examine the effects of the synthetic alkaloids on two major subtypes of nicotinic receptors (α4β2 and α7 expressed in Xenopus laevis oocytes, (--231C effectively blocked α4β2 receptor responses (IC50 value, 1.5 μM with a 7.0-fold higher potency than for blockade of α7 receptor responses. In contrast, synthetic (--221I and (--epi-193E were more potent in blocking α7 receptor responses (IC50 value, 4.4 μM and 9.1 μM, respectively than α4β2 receptor responses (5.3-fold and 2.0-fold, respectively. Conclusion We achieved the total synthesis of (--209B, (--231C, (--233D, (--235B", (--221I, and an epimer of 193E starting from common chiral lactams, and the absolute stereochemistry of natural (--233D was determined. Furthermore, the relative stereochemistry of (--231C and (--221I was also determined. The present asymmetric synthesis of the proposed structure for 193E revealed that the C-8 configuration of natural 193E

Improved Synthesis of 4-Cyanotryptophan and Other Tryptophan Analogues in Aqueous Solvent Using Variants of TrpB from Thermotoga maritima.

Science.gov (United States)

Boville, Christina E; Romney, David K; Almhjell, Patrick J; Sieben, Michaela; Arnold, Frances H

2018-04-27

The use of enzymes has become increasingly widespread in synthesis as chemists strive to reduce their reliance on organic solvents in favor of more environmentally benign aqueous media. With this in mind, we previously endeavored to engineer the tryptophan synthase β-subunit (TrpB) for production of noncanonical amino acids that had previously been synthesized through multistep routes involving water-sensitive reagents. This enzymatic platform proved effective for the synthesis of analogues of the amino acid tryptophan (Trp), which are frequently used in pharmaceutical synthesis as well as chemical biology. However, certain valuable compounds, such as the blue fluorescent amino acid 4-cyanotryptophan (4-CN-Trp), could only be made in low yield, even at elevated temperature (75 °C). Here, we describe the engineering of TrpB from Thermotoga maritima that improved synthesis of 4-CN-Trp from 24% to 78% yield. Remarkably, although the final enzyme maintains high thermostability ( T 50 = 93 °C), its temperature profile is shifted such that high reactivity is observed at ∼37 °C (76% yield), creating the possibility for in vivo 4-CN-Trp production. The improvements are not specific to 4-CN-Trp; a boost in activity at lower temperature is also demonstrated for other Trp analogues.

Multicomponent synthesis of 4,4-dimethyl sterol analogues and their effect on eukaryotic cells.

Science.gov (United States)

Alonso, Fernando; Cirigliano, Adriana M; Dávola, María Eugenia; Cabrera, Gabriela M; García Liñares, Guadalupe E; Labriola, Carlos; Barquero, Andrea A; Ramírez, Javier A

2014-06-01

Most sterols, such as cholesterol and ergosterol, become functional only after the removal of the two methyl groups at C-4 from their biosynthetic precursors. Nevertheless, some findings suggest that 4,4-dimethyl sterols might be involved in specific physiological processes. In this paper we present the synthesis of a collection of analogues of 4,4-dimethyl sterols with a diamide side chain and a preliminary analysis of their in vitro activity on selected biological systems. The key step for the synthesis involves an Ugi condensation, a versatile multicomponent reaction. Some of the new compounds showed antifungal and cytotoxic activity. Copyright © 2014 Elsevier Inc. All rights reserved.

CTAB-assisted ultrasonic synthesis, characterization and photocatalytic properties of WO{sub 3}

Energy Technology Data Exchange (ETDEWEB)

Sánchez-Martínez, D., E-mail: dansanm@gmail.com; Gomez-Solis, C.; Torres-Martinez, Leticia M.

2015-01-15

Highlights: • WO{sub 3} 2D nanostructures were synthesized by ultrasound method assisted with CTAB. • WO{sub 3} morphology was mainly of rectangular nanoplates with a thickness of ∼50 nm. • The highest surface area value of WO{sub 3} was obtained to lowest concentration of CTAB. • WO{sub 3} activity was attributed to morphology, surface area and the addition of CTAB. • WO{sub 3} nanoplates were able to causing almost complete mineralization of rhB and IC. - Abstract: WO{sub 3} 2D nanostructures have been prepared by ultrasound synthesis method assisted with CTAB using different molar ratios. The formation of monoclinic crystal structure of WO{sub 3} was confirmed by X-ray powder diffraction (XRD). The characterization of the WO{sub 3} samples was complemented by analysis of scanning electron microscopy (SEM), which revealed morphology mainly of rectangular nanoplates with a thickness of around 50 nm and length of 100–500 nm. Infrared spectroscopy (FT-IR) was used to confirm the elimination of the CTAB in the synthesized samples. The specific surface area was determinate by the BET method and by means of diffuse reflectance spectroscopy (DRS) it was determinate the band-gap energy (E{sub g}) of the WO{sub 3} samples. The photocatalytic activity of the WO{sub 3} oxide was evaluated in the degradation reactions of rhodamine B (rhB) and indigo carmine (IC) under Xenon lamp irradiation. The highest photocatalytic activity was observed in the samples containing low concentration of CTAB with morphology of rectangular nanoplates and with higher surface area value than commercial WO{sub 3}. Photodegradation of rhB and IC were followed by means of UV–vis absorption spectra. The mineralization degree of organic dyes by WO{sub 3} photocatalyst was determined by total organic carbon analysis (TOC) reaching percentages of mineralization of 92% for rhB and 50% for IC after 96 h of lamp irradiation.

Inhibitory Effects of Commonly Used Herbal Extracts on UDP-Glucuronosyltransferase 1A4, 1A6, and 1A9 Enzyme Activities

Science.gov (United States)

Mohamed, Mohamed-Eslam F.

2011-01-01

The aim of this study was to investigate the effect of commonly used botanicals on UDP-glucuronosyltransferase (UGT) 1A4, UGT1A6, and UGT1A9 activities in human liver microsomes. The extracts screened were black cohosh, cranberry, echinacea, garlic, ginkgo, ginseng, milk thistle, saw palmetto, and valerian in addition to the green tea catechin epigallocatechin gallate (EGCG). Formation of trifluoperazine glucuronide, serotonin glucuronide, and mycophenolic acid phenolic glucuronide was used as an index reaction for UGT1A4, UGT1A6, and UGT1A9 activities, respectively, in human liver microsomes. Inhibition potency was expressed as the concentration of the inhibitor at 50% activity (IC50) and the volume in which the dose could be diluted to generate an IC50-equivalent concentration [volume/dose index (VDI)]. Potential inhibitors were EGCG for UGT1A4, milk thistle for both UGT1A6 and UGT1A9, saw palmetto for UGT1A6, and cranberry for UGT1A9. EGCG inhibited UGT1A4 with an IC50 value of (mean ± S.E.) 33.8 ± 3.1 μg/ml. Milk thistle inhibited both UGT1A6 and UGT1A9 with IC50 values of 59.5 ± 3.6 and 33.6 ± 3.1 μg/ml, respectively. Saw palmetto and cranberry weakly inhibited UGT1A6 and UGT1A9, respectively, with IC50 values >100 μg/ml. For each inhibition, VDI was calculated to determine the potential of achieving IC50-equivalent concentrations in vivo. VDI values for inhibitors indicate a potential for inhibition of first-pass glucuronidation of UGT1A4, UGT1A6, and UGT1A9 substrates. These results highlight the possibility of herb-drug interactions through modulation of UGT enzyme activities. Further clinical studies are warranted to investigate the in vivo extent of the observed interactions. PMID:21632963

Dynamical Competition of IC-Industry Clustering from Taiwan to China

Science.gov (United States)

Tsai, Bi-Huei; Tsai, Kuo-Hui

2009-08-01

Most studies employ qualitative approach to explore the industrial clusters; however, few research has objectively quantified the evolutions of industry clustering. The purpose of this paper is to quantitatively analyze clustering among IC design, IC manufacturing as well as IC packaging and testing industries by using the foreign direct investment (FDI) data. The Lotka-Volterra system equations are first adopted here to capture the competition or cooperation among such three industries, thus explaining their clustering inclinations. The results indicate that the evolution of FDI into China for IC design industry significantly inspire the subsequent FDI of IC manufacturing as well as IC packaging and testing industries. Since IC design industry lie in the upstream stage of IC production, the middle-stream IC manufacturing and downstream IC packing and testing enterprises tend to cluster together with IC design firms, in order to sustain a steady business. Finally, Taiwan IC industry's FDI amount into China is predicted to cumulatively increase, which supports the industrial clustering tendency for Taiwan IC industry. Particularly, the FDI prediction of Lotka-Volterra model performs superior to that of the conventional Bass model after the forecast accuracy of these two models are compared. The prediction ability is dramatically improved as the industrial mutualism among each IC production stage is taken into account.

Efficient synthesis of (+/-)-4-methyloctanoic acid, aggregation pheromone of rhinoceros beetles of the genus Oryctes (Coleoptera: Dynastidae, Scarabaeidae).

Science.gov (United States)

Ragoussis, Valentine; Giannikopoulos, Alexandros; Skoka, Efthymia; Grivas, Panagiotis

2007-06-27

(+/-)-4-Methyloctanoic acid and its ethyl ester are aggregation pheromones of many rhinoceros beetles of the genus Oryctes and are investigated for the control of these pests by olfactory trapping. A simple, economical, and high-yield (>50%) synthesis of (+/-)-4-methyloctanoic acid and its ethyl ester is presented starting from n-hexanal. The key step in this sequence is an orthoester Claisen rearrangement for the elongation of the carbon chain by two.

ASD IC for the thin gap chambers in the LHC Atlas experiment

International Nuclear Information System (INIS)

Sasaki, Osamu; Yoshida, Mitsuhiro

1999-01-01

An amplifier-shaper-discriminator (ASD) chip was designed and built for Thin Gap Chambers in the forward muon trigger system of the LHC Atlas experiment. The ASD IC uses SONY Analog Master Slice bipolar technology. The IC contains 4 channels in a QFP48 package. The gain of its first stage (preamplifier) is approximately 0.8V/pC and output from the preamplifier is received by a shaper (main-amplifier) with a gain of 7. The baseline restoration circuit is incorporated in the main-amplifier. The threshold voltage for discriminator section is common to the 4 channels and their digital output level is LVDS-compatible. The IC also has analog output of the preamplifier. The equivalent noise charge at input capacitance of 150 pF is around 7,500 electrons. The power dissipation with LDVS outputs (100 Omega load) is 59mW/ch

ASD IC for the thin gap chambers in the LHC ATLAS experiment

CERN Document Server

Sasaki, O

1998-01-01

An amplifier-shaper-discriminator (ASD) chip was designed and built for Thin Gap Chambers in the forward muon trigger system of the LHC ATLAS experiment. The ASD IC uses SONY Analog Master Slice bipolar technology. The IC contains 4 $9 channels in a QFP48 package. The gain of its first stage (preamplifier) is approximately 0.8 V/pC and output from the preamplifier is received by a shaper (main-amplifier) with a gain of 7. The baseline restoration circuit is $9 incorporated in the main-amplifier. The threshold voltage for the discriminator section is common to the 4 channels and their digital output level is LVDS-compatible. The IC also has analog output for the preamplifier. The equivalent $9 noise charge at input capacitance of 150 pF is around 7500 electrons. The power dissipation with LDVS outputs (100 Omega load) is 59 mW/ch. (8 refs).

ASD IC for the thin gap chambers in the LHC ATLAS Experiment

CERN Document Server

Sasaki, O

1999-01-01

An amplifier-shaper-discriminator (ASD) chip was designed and built for Thin Gap Chambers in the forward muon trigger system of the LHC Atlas experiment. The ASD IC uses SONY Analog Master Slice bipolar technology. The IC contains 4 channels in a QFP48 package. The gain of its first stage (preamplifier) is approximately 0.8 V/pC and output from the preamplifier is received by a shaper (main-amplifier) with a gain of 7. The baseline restoration circuit is incorporated in the main-amplifier. The threshold voltage for discriminator section is common to the 4 channels and their digital output level is LVDS- compatible. The IC also has analog output of the preamplifier. The equivalent noise charge at input capacitance of 150 pF is around 7500 electrons. The power dissipation with LDVS outputs (100 Omega load) is 59 mW/ch.

Sulfonamide-Linked Ciprofloxacin, Sulfadiazine and Amantadine Derivatives as a Novel Class of Inhibitors of Jack Bean Urease; Synthesis, Kinetic Mechanism and Molecular Docking.

Science.gov (United States)

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

2017-08-16

Sulfonamide derivatives serve as an important building blocks in the drug design discovery and development (4D) process. Ciprofloxacin-, sulfadiazine- and amantadine-based sulfonamides were synthesized as potent inhibitors of jack bean urease and free radical scavengers. Molecular diversity was explored and electronic factors were also examined. All 24 synthesized compounds exhibited excellent potential against urease enzyme. Compound 3e (IC 50 = 0.081 ± 0.003 µM), 6a (IC 50 = 0.0022 ± 0.0002 µM), 9e (IC 50 = 0.0250 ± 0.0007 µM) and 12d (IC 50 = 0.0266 ± 0.0021 µM) were found to be the lead compounds compared to standard (thiourea, IC 50 = 17.814 ± 0.096 µM). Molecular docking studies were performed to delineate the binding affinity of the molecules and a kinetic mechanism of enzyme inhibition was propounded. Compounds 3e , 6a and 12d exhibited a mixed type of inhibition, while derivative 9e revealed a non-competitive mode of inhibition. Compounds 12a , 12b , 12d , 12e and 12f showed excellent radical scavenging potency in comparison to the reference drug vitamin C.

Laser-Assisted Synthesis of Mn0.50Zn0.50Fe2O4 Nanomaterial: Characterization and In Vitro Inhibition Activity towards Bacillus subtilis Biofilm

Directory of Open Access Journals (Sweden)

Shaukat Ali Shahid

2015-01-01

Full Text Available There is growing interest in the development of novel nanomaterials with potential antimicrobial activity and lesser toxicity. In the current research work, Mn0.5Zn0.5Fe2O4 nanoparticles were synthesized via a novel coprecipitation cum laser ablation technique yielding fine spinal structured material. The synthesized nanomaterial was structurally characterized by X-ray diffraction technique which confirmed the formation and the crystalline nature of Mn0.50Zn0.50Fe2O4 nanomaterial. The crystallite size determined by Debye-Scherrer’s formula was found to be ~12 nm. The formation of nanoparticles was evidenced by scanning electron microscopy. Energy dispersive X-ray analysis (EDXA was performed for elemental analysis. The synthesized nanomaterial was interestingly found to be an effective antimicrobial agent and inhibited the growth of Bacillus subtilis biofilm formation. The 5 µg of Mn0.5Zn0.5Fe2O4 nanomaterial dissolved in 1 mL of DMSO showed excellent biofilm inhibitory activity 91.23% ± 1.87 against Bacillus subtilis.

Synthesis, antitumour and antioxidant activities of novel α,β-unsaturated ketones and related heterocyclic analogues: EGFR inhibition and molecular modelling study.

Science.gov (United States)

El-Husseiny, Walaa M; El-Sayed, Magda A-A; Abdel-Aziz, Naglaa I; El-Azab, Adel S; Ahmed, Esam R; Abdel-Aziz, Alaa A-M

2018-12-01

New α,β-unsaturated ketones 4a,b; 5a-c; and 6a,b; as well as 4-H pyran 7; pyrazoline 8a,b; isoxazoline 9; pyridine 10-11; and quinoline-4-carboxylic acid 12a,b derivatives were synthesized and evaluated for in vitro antitumour activity against HepG2, MCF-7, HeLa, and PC-3 cancer cell lines. Antioxidant activity was investigated by the ability of these compounds to scavenge the 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTS •+ ). Compounds 6a, 6b, 7, and 8b exhibited potent antitumour activities against all tested cell lines with [IC 50 ] ≅5.5-18.1 µΜ), in addition to significantly high ABTS •+ scavenging activities. In vitro EGFR kinase assay for 6a, 6b, 7, and 8b as the most potent antitumour compounds showed that; compounds 6b, and 7 exhibited worthy EGFR inhibition activity with IC 50 values of 0.56 and 1.6 µM, respectively, while compounds 6a and 8b showed good inhibition activity with IC 50 values of 4.66 and 2.16 µM, respectively, compared with sorafenib reference drug (IC 50  = 1.28 µM). Molecular modelling studies for compounds 6b, 7, and 8b were conducted to exhibit the binding mode towards EGFR kinase, which showed similar interaction with erlotinib.

Prediction of fracture toughness K/sub Ic/ of steel from Charpy impact test results

Energy Technology Data Exchange (ETDEWEB)

Iwadate, Tadao; Tanaka, Yasuhiko; Takemata, Hiroyuki; Terashima, Shuhei

1986-08-01

This paper presents a method to predict the fracture toughness K/sub Ic/ and/or K/sub Id/ of steels using their Charpy impact test results and tensile properties. The fracture toughness, Charpy impact and tensile properties of 2 1/4 Cr-1Mo, ASTM A508 Cl.1, A508 Cl.2 A508 Cl.3 and A533 Gr.B Cl.1 steels were measured and analysed on the basis of the excess temperature (test temperature minus FATT) and Rolfe-Novak correlation. The relationship between K/sub Ic//K/sub Ic-us/ and the excess temperature, where K/sub Ic-us/ is the upper-shelf fracture toughness K/sub Ic/ predicted by Rolfe-Novak correlation, discloses that the K/sub Ic/ transition curves of several steels are representable by only one trend curve of K/sub Ic//K/sub Ic-us/ or K/sub Id//K/sub Id-us/ versus excess temperature relation. This curve is denoted as a ''master curve''. By using this curve, the fracture toughness of steel can be predicted using Charpy impact and tensile test results. By taking account of the scattering of both the fracture toughness and Charpy impact test results, the confidence limits of the master curve were also determined. Another approach to develop more general procedure of predicting the fracture toughness K/sub Ic/ is also discussed.

Submicron InP DHBT technology for high-speed high-swing mixed-signal ICs

DEFF Research Database (Denmark)

Godin, Jean; Nodjiadjim, V.; Riet, Muriel

2008-01-01

We report on the development of a submicron InP DHBT technology, optimized for the fabrication of 50-GHz-clock mixed signal ICs. In-depth study of device geometry and structure has allowed to get the needed performances and yield. Special attention has been paid to critical thermal behavior. Vari...... applications of interest....

Synthesis, crystal structures, fluorescence and xanthine oxidase inhibitory activity of pyrazole-based 1,3,4-oxadiazole derivatives

Science.gov (United States)

Qi, De-Qiang; Yu, Chuan-Ming; You, Jin-Zong; Yang, Guang-Hui; Wang, Xue-Jie; Zhang, Yi-Ping

2015-11-01

A series of pyrazole-based 1,3,4-oxadiazole derivatives were rationally designed and synthesized in good yields by following a convenient route. All the newly synthesized molecules were fully characterized by IR, 1H NMR and elemental analysis. Eight compounds were structurally determined by single crystal X-ray diffraction analysis. The fluorescence properties of all the compounds were investigated in dimethyl sulfoxide media. In addition, these newly synthesized compounds were evaluated for in vitro inhibitory activity against commercial enzyme xanthine oxidase (XO) by measuring the formation of uric acid from xanthine. Among the compounds synthesized and tested, 3d and 3e were found to be moderate inhibitory activity against commercial XO with IC50 = 72.4 μM and 75.6 μM. The studies gave a new insight in further optimization of pyrazole-based 1,3,4-oxadiazole derivatives with excellent fluorescence properties and XO inhibitory activity.

In Vitro Antiplasmodial Activity and Cytotoxic Effect of (Z-2-Benzylidene-4, 6-Dimethoxybenzofuran-3(2H-One Derivatives

Directory of Open Access Journals (Sweden)

Ali RAMAZANI

2016-10-01

Full Text Available Background: Aurones are naturally occurring compounds that belong to flavenoids family and have antiplasmodial effects. This study investigated some new aurones derivatives against chloroquine sensitive Plasmodium falciparum. Here we report the synthesis, in vitro antiplasmodial activity and cytotoxic evaluation of 11 compound from derivatives of (Z-2- benzylidene-4, 6-dimethoxybenzofuran-3(2H-one.Methods: The cytotoxic evaluations of active compounds were performed with MTT (3-[4, 5-dimethylthiazol-2-yl]-2, 5 diphenyltetrazolium bromide assay on human breast cancer cell lines; MCF7 and T47D.Results: From 11 compounds M3, M6 and M7 compounds showed good antiplasmodial effect against chloroquine-sensitive 3D strain of P. falciparum with IC50 (50% inhibitory concentration values of 7.82, 7.27 and 2.3 µM respectively. No noticeable toxicity was‌ observed with these compounds when tested against tested cell lines. Conclusion: The replacement of the 4 and 5 positions at ring B of aurone derivatives, with propoxy and bromide (Br respectively was revealed highly advantageous for their antiplasmodial effect.

Design, Synthesis and Docking Studies of Flavokawain B Type Chalcones and Their Cytotoxic Effects on MCF-7 and MDA-MB-231 Cell Lines

Directory of Open Access Journals (Sweden)

Addila Abu Bakar

2018-03-01

Full Text Available Flavokawain B (1 is a natural chalcone extracted from the roots of Piper methysticum, and has been proven to be a potential cytotoxic compound. Using the partial structure of flavokawain B (FKB, about 23 analogs have been synthesized. Among them, compounds 8, 13 and 23 were found in new FKB derivatives. All compounds were evaluated for their cytotoxic properties against two breast cancer cell lines, MCF-7 and MDA-MB-231, thus establishing the structure–activity relationship. The FKB derivatives 16 (IC50 = 6.50 ± 0.40 and 4.12 ± 0.20 μg/mL, 15 (IC50 = 5.50 ± 0.35 and 6.50 ± 1.40 μg/mL and 13 (IC50 = 7.12 ± 0.80 and 4.04 ± 0.30 μg/mL exhibited potential cytotoxic effects on the MCF-7 and MDA-MB-231 cell lines. However, the methoxy group substituted in position three and four in compound 2 (IC50 = 8.90 ± 0.60 and 6.80 ± 0.35 μg/mL and 22 (IC50 = 8.80 ± 0.35 and 14.16 ± 1.10 μg/mL exhibited good cytotoxicity. The lead compound FKB (1 showed potential cytotoxicity (IC50 = 7.70 ± 0.30 and 5.90 ± 0.30 μg/mL against two proposed breast cancer cell lines. It is evident that the FKB skeleton is unique for anticancer agents, additionally, the presence of halogens (Cl and F in position 2 and 3 also improved the cytotoxicity in FKB series. These findings could help to improve the future drug discovery process to treat breast cancer. A molecular dynamics study of active compounds revealed stable interactions within the active site of Janus kinase. The structures of all compounds were determined by 1H-NMR, EI-MS, IR and UV and X-ray crystallographic spectroscopy techniques.

IC Associated Conditions

Science.gov (United States)

... Bowel Syndrome Lupus Pelvic Floor Dysfunction Pudendal Neuralgia Sjogren’s Syndrome Vulvodynia Newly Diagnosed Toolkit IC Awareness Toolkit Know ... Bowel Syndrome Lupus Pelvic Floor Dysfunction Pudendal Neuralgia Sjogren’s Syndrome Vulvodynia Click to learn more about these and ...

Synthesis of Chromonylthiazolidines and Their Cytotoxicity to Human Cancer Cell Lines

Directory of Open Access Journals (Sweden)

Hoang Le Tuan Anh

2015-01-01

Full Text Available Nine new chromonylthiazolidine derivatives were successfully semi-synthesized from paeonol. All of the compounds, including starting materials, the intermediate compound and products, were evaluated for their cytotoxic effects toward eight human cancer cell lines. The synthesized chromonylthiazolidines displayed weak cytotoxic effects against the tested cancer cell lines, but selective cytotoxic effects were observed. Compounds 3a and 3b showed the most selective cytotoxic effects against human epidermoid carcinoma (IC50 44.1 ± 3.6 μg/mL and breast cancer (IC50 32.8 ± 1.4 μg/mL cell lines, respectively. The results suggest that chromoylthiazolidines are potential low-cost, and selective anticancer agents.

Regioselective Synthesis of 3-Amino-4-arylisoxazol-5(4H)-ones

Energy Technology Data Exchange (ETDEWEB)

Shin, Dong Won; Lee, Ihl Young Choi; Lim, Hee Jong [Korea Research Institute of Chemical Technology, Daejeon (Korea, Republic of)

2010-11-15

We have demonstrated a new and efficient method for the synthesis of 3-substituted aminoisoxazoles from readily available thiocarbamoyl esters. Mercury (II) chloride appeared to be a Lewis acid of choice among the metals tested in this cyclodesulfurization reaction. Application of this method for the synthesis of substituted aminopyrazoles is now under investigation in our laboratory. 3-Aminoisoxazol-5(4H)-one is an important building block of many biologically active compounds including antimicrobial and antioxidant, K channel opener, and kinase inhibitors. Besides, it could be transformed to fused heterocyclic compounds such as indoles, imidazopyridines, and isoxazolopyrimidines. Condensation reaction of α-cyanoacetate with hydroxylamine was a well known method to access either 3-aminoisoxazol-5(4H)-one or isomeric 5-aminoisoxazol-3(4H)-one depending upon condition. For instance, reaction under the neutral condition provided 3-aminoisoxazolone isomer via acetamidoxime intermediate, whereas 5-aminoisoxazolone isomer was obtained under the alkaline condition.

Regioselective Synthesis of 3-Amino-4-arylisoxazol-5(4H)-ones

International Nuclear Information System (INIS)

Shin, Dong Won; Lee, Ihl Young Choi; Lim, Hee Jong

2010-01-01

We have demonstrated a new and efficient method for the synthesis of 3-substituted aminoisoxazoles from readily available thiocarbamoyl esters. Mercury (II) chloride appeared to be a Lewis acid of choice among the metals tested in this cyclodesulfurization reaction. Application of this method for the synthesis of substituted aminopyrazoles is now under investigation in our laboratory. 3-Aminoisoxazol-5(4H)-one is an important building block of many biologically active compounds including antimicrobial and antioxidant, K channel opener, and kinase inhibitors. Besides, it could be transformed to fused heterocyclic compounds such as indoles, imidazopyridines, and isoxazolopyrimidines. Condensation reaction of α-cyanoacetate with hydroxylamine was a well known method to access either 3-aminoisoxazol-5(4H)-one or isomeric 5-aminoisoxazol-3(4H)-one depending upon condition. For instance, reaction under the neutral condition provided 3-aminoisoxazolone isomer via acetamidoxime intermediate, whereas 5-aminoisoxazolone isomer was obtained under the alkaline condition

Synthesis and anti-HIV activity of novel 3-substituted phenyl-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]isoxazole analogues.

Science.gov (United States)

Ali, Mohamed A; Ismail, Rusli; Choon, Tan S; Yoon, Yeong K; Wei, Ang C; Pandian, Suresh; Samy, Jeyabalan G; De Clercq, Eric; Pannecouque, Christophe

2011-01-01

A series of novel 3-(substituted phenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]isoxazole analogues were synthesized by the reaction of 5,6-dimethoxy-2-[(E)-1-phenylmethylidene]-1-indanone with hydroxylamine hydrochloride. The title compounds were tested for their in vitro anti-HIV activity. Among the compounds, (4g) showed a promising anti-HIV activity in the in vitro testing against IIIB and ROD strains. The IC50 of both IIIB and ROD were found to be 9.05 microM and > 125 microM, respectively.

Synthesis and Characterization of (Z-5-Arylmethylidene-rhodanines with Photosynthesis-Inhibiting Properties

Directory of Open Access Journals (Sweden)

Josef Jampilek

2011-06-01

Full Text Available A series of rhodanine derivatives was prepared. The synthetic approach, analytical and spectroscopic data of all synthesized compounds are presented. Lipophilicity of all the discussed rhodanine derivatives was analyzed using the RP-HPLC method. The compounds were tested for their ability to inhibit photosynthetic electron transport (PET in spinach (Spinacia oleracea L. chloroplasts and reduce chlorophyll content in freshwater alga Chlorella vulgaris. Structure-activity relationships between the chemical structure, physical properties and biological activities of the evaluated compounds are discussed. For majority of the tested compounds the lipophilicity of the compound and not electronic properties of the R1 substituent were decisive for PET-inhibiting activity. The most potent PET inhibitor was (5Z-5-(4-bromobenzylidene-2-thioxo-1,3-thiazolidin-4-one (IC50 = 3.0 μmol/L and the highest antialgal activity was exhibited by (5Z-5-(4-chlorobenzylidene-2-thioxo-1,3-thiazolidin-4-one (IC50 = 1.3 μmol/L.

31 CFR 50.4 - Mandatory participation in Program.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Mandatory participation in Program. 50.4 Section 50.4 Money and Finance: Treasury Office of the Secretary of the Treasury TERRORISM RISK... definition of an insurer under the Act is required to participate in the Program. ...

An Optical and Infrared Photometric Study of the Young Open Cluster IC 1805 in the Giant H II Region W4 †

Science.gov (United States)

Sung, Hwankyung; Bessell, Michael S.; Chun, Moo-Young; Yi, Jonghyuk; Nazé, Y.; Lim, Beomdu; Karimov, R.; Rauw, G.; Park, Byeong-Gon; Hur, Hyeonoh

2017-05-01

We present deep wide-field optical CCD photometry and mid-infrared Spitzer/IRAC and MIPS 24 μm data for about 100,000 stars in the young open cluster IC 1805. The members of IC 1805 were selected from their location in the various color-color and color-magnitude diagrams, and the presence of Hα emission, mid-infrared excess emission, and X-ray emission. The reddening law toward IC 1805 is nearly normal (R V = 3.05 ± 0.06). However, the distance modulus of the cluster is estimated to be 11.9 ± 0.2 mag (d=2.4+/- 0.2 kpc) from the reddening-free color-magnitude diagrams, which is larger than the distance to the nearby massive star-forming region W3(OH) measured from the radio VLBA astrometry. We also determined the age of IC 1805 ({τ }{MSTO}=3.5 Myr). In addition, we critically compared the age and mass scale from two pre-main-sequence evolution models. The initial mass function with a Salpeter-type slope of Γ = -1.3 ± 0.2 was obtained and the total mass of IC 1805 was estimated to be about 2700 ± 200 {M}⊙ . Finally, we found our distance determination to be statistically consistent with the Tycho-Gaia Astrometric Solution Data Release 1, within the errors. The proper motion of the B-type stars shows an elongated distribution along the Galactic plane, which could be explained by some of the B-type stars being formed in small clouds dispersed by previous episodes of star formation or supernova explosions. The optical imaging data in this article were gathered with two facilities: the AZT-22 1.5 m telescope at Maidanak Astronomical Observatory in Uzbekistan and the Canada-France-Hawaii Telescope (CFHT), which is operated by the National Research Council of Canada, the Institut National des Sciences de l’Univers of the Centre National de la Recherche Scientifique of France, and the University of Hawaii.

Synthesis of 1, 4-Dioxan-2-one from 1, 3-Dioxolane and Carbon Monoxide over Cation-exchange Resin Catalyst

OpenAIRE

Takagi, Hiroyuki; Oumi, Yasunori; Uozumi, Toshiya; Masuda, Takashi; Sano, Tsuneji

2001-01-01

The possibility of the synthesis of 1, 4-dioxan-2-one (p-dioxanon) by carbonylation of 1, 3-dioxolane (cyclic ether) over Nafion® NR-50 cation-exchange resin catalyst was investigated. 1, 4-Dioxan-2-one, one of the cyclic esterethers used as a monomer of polyester, was obtained by depolymerization of polyester oligomers. The maximum yield (40%) of 1, 4-dioxan-2-one was achieved under reaction conditions of 25MPa initial PCO, 120°C reaction temperature and 4h reaction time.

Single-mode 850-nm vertical-cavity surface-emitting lasers with Zn-diffusion and oxide-relief apertures for > 50 Gbit/sec OOK and 4-PAM transmission

Science.gov (United States)

Shi, Jin-Wei; Wei, Chia-Chien; Chen, Jyehong; Ledentsov, N. N.; Yang, Ying-Jay

2017-02-01

Vertical-cavity surface-emitting lasers (VCSELs) has become the most important light source in the booming market of short-reach (targeted at 56 Gbit/sec data rate per channel (CEI-56G) with the total data rate up to 400 Gbit/sec. However, the serious modal dispersion of multi-mode fiber (MMF), limited speed of VCSEL, and its high resistance (> 150 Ω) seriously limits the >50 Gbit/sec linking distance (50 Gbit/sec transmission due to that it can save one-half of the required bandwidth. Nevertheless, a 4.7 dB optical power penalty and the linearity of transmitter would become issues in the 4-PAM linking performance. Besides, in the modern OI system, the optics transreceiver module must be packaged as close as possible with the integrated circuits (ICs). The heat generated from ICs will become an issue in speed of VSCEL. Here, we review our recent work about 850 nm VCSEL, which has unique Zn-diffusion/oxide-relief apertures and special p- doping active layer with strong wavelength detuning to further enhance its modulation speed and high-temperature (85°C) performances. Single-mode (SM) devices with high-speed ( 26 GHz), reasonable resistance ( 70 Ω) and moderate output power ( 1.5 mW) can be achieved. Error-free 54 Gbit/sec OOK transmission through 1km MMF has been realized by using such SM device with signal processing techniques. Besides, the volterra nonlinear equalizer has been applied in our 4-PAM 64 Gbit/sec transmission through 2-km OM4 MMF, which significantly enhance the linearity of device and outperforms fed forward equalization (FFE) technique. Record high bit-rate distance product of 128.km is confirmed for optical-interconnect applications.

Synthesis and antitumoral activity of novel 3-(2-substituted-1,3,4-oxadiazol-5-yl) and 3-(5-substituted-1,2,4-triazol-3-yl) beta-carboline derivatives.

Science.gov (United States)

Formagio, Anelise S Nazari; Tonin, Lilian T Düsman; Foglio, Mary Ann; Madjarof, Christiana; de Carvalho, João Ernesto; da Costa, Willian Ferreira; Cardoso, Flávia P; Sarragiotto, Maria Helena

2008-11-15

Several novel 1-substituted-phenyl beta-carbolines bearing the 2-substituted-1,3,4-oxadiazol-5-yl and 5-substituted-1,2,4-triazol-3-yl groups at C-3 were synthesized and evaluated for their in vitro anticancer activity. The assay results pointed thirteen compounds with growth inhibition effect (GI(50)<100 microM) for all eight different types of human cancer cell lines tested. The beta-carbolines 7a and 7h, bearing the 3-(2-metylthio-1,3,4-oxadiazol-5-yl) group, displayed high selectivity and potent anticancer activity against ovarian cell line with GI(50) values lying in the nanomolar concentration range (GI(50)=10 nM for both compounds). The 1-(N,N-dimethylaminophenyl)-3-(5-thioxo-1,2,4-triazol-3-yl) beta-carboline (8g) was the most active compound, showing particular effectiveness on lung (GI(50)=0.06 microM), ovarian and renal cell lines. The potent anticancer activity presented for synthesized compounds 7a, 7h, and 8g, together with their easiness of synthesis, makes these compounds promising anticancer agents.

Benzimidazole condensed ring systems 10 (1). Synthesis and cytotoxic activity of some pyrido[1,2-a]benzimidazoles.

Science.gov (United States)

Badawey, E S; Kappe, T

1995-01-01

As a part of research project on the synthesis of a number of pyrido[1,2-a]benzimidazole derivatives with possible antineoplastic activity and as a result of the interesting antineoplastic activity recorded for one such compounds (NSC 649900), some new pyrido[1,2-a]benzimidazoles were prepared and evaluated for such activity. Compound (11, NSC 660334) exhibited a moderate in vitro antineoplastic activity especially against most of the leukemia cell lines, while compound (10, VM30309) showed a good cytotoxic activity against Artina salina larvae (IC50 = 1.75 micrograms/ml).

Synthesis of 3-Methyl-1-morpholin-4-ylmethyl-2,6-diphenylpiperidin-4-one

Directory of Open Access Journals (Sweden)

Bathey R. Venkatraman

2009-09-01

Full Text Available This paper describes the synthesis of 3-methyl-1-morpholin-4-ylmethyl-2,6-diphenylpiperidin-4-one from 3-methyl-2,6-diphenylpiperidin-4-one. The synthesized compound was characterized by FT-IR, 1H NMR, EI-MS and elemental analysis.

Synthesis, characterization and biological evaluation of ruthenium flavanol complexes against breast cancer

Science.gov (United States)

Singh, Ashok Kumar; Saxena, Gunjan; Sahabjada; Arshad, M.

2017-06-01

Four Ru(II) DMSO complexes (M1R-M4R) having substituted flavones viz. 3-Hydroxy-2-(4-methoxyphenyl)-4H-chromen-4-one (HL1), 3-Hydroxy-2-(4-nitrophenyl)-4H-chromen-4-one (HL2), 3-Hydroxy-2-(4-dimethylaminophenyl)-4H-chromen-4-one (HL3) and 3-Hydroxy-2-(4-chlorophenyl)-4H-chromen-4-one (HL4) were synthesized and characterized by elemental analysis, IR, UV-Vis, 1H NMR spectroscopies and ESI-MS. The molecular structures of the complexes were investigated by integrated spectroscopic and computational techniques (DFT). Both ligands as well as their complexes were screened for anticancer activities against breast cancer cell lines MCF-7. Cytotoxicity was assayed by MTT [3-(4, 5-dimethyl thiazol-2-yl)-2, 5-diphenyl tetrazolium bromide] assay. All ligands and their complexes exhibited significant cytotoxic potential of 5-40 μM concentration at incubation period of 24 h. The cell cytotoxicity increased significantly in a concentration-dependent manner. In this series of compounds, HL2 (IC50 17.2 μM) and its complex M2R (IC50 16 μM) induced the highest cytotoxicity.

Design, synthesis and fungicidal evaluation of novel pyraclostrobin analogues.

Science.gov (United States)

Wang, Lili; Zhao, Shuangshuang; Kong, Xiaotian; Cao, Lingling; Tian, Sheng; Ye, Yonghao; Qiao, Chunhua

2018-02-15

A series of novel pyraclostrobin derivatives were designed and prepared as antifungal agents. Their antifungal activities were tested in vitro with five important phytopathogenic fungi, namely, Batrylis cinerea, Phytophthora capsici, Fusarium sulphureum, Gloeosporium pestis and Sclerotinia sclerotiorum using the mycelium growth inhibition method. Among these compounds, 5s displayed IC 50 value of 0.57 μg/mL against Batrylis cinerea and 5k-II displayed IC 50 value of 0.43 μg/mL against Sclerotinia sclerotiorum, which were close to that of the positive control pyraclostrobin (0.18 μg/mL and 0.15 μg/mL). Other compounds 5f, 5k-II, 5j, 5m and 5s also exhibited strong antifungal activity. Further enzymatic assay demonstrated compound 5s inhibited porcine bc 1 complex with IC 50 value of 0.95 μM. The statistical results from an integrated computational pipeline demonstrated the predicted total binding free energy for compound 5s is the highest. Consequently, compound 5s with the biphenyl-4-methoxyl side chain could serve as a new motif as inhibitors of bc 1 complex and deserve to be further investigated. Copyright © 2018 Elsevier Ltd. All rights reserved.

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

Science.gov (United States)

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

2017-01-27

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

Synthesis and Cytotoxic Evaluation of a Series of 2-Amino-Naphthoquinones against Human Cancer Cells

Directory of Open Access Journals (Sweden)

Thiago A. P. de Moraes

2014-08-01

Full Text Available The cytotoxicity of a series of aminonaphthoquinones resulting from the reaction of suitable aminoacids with 1,4-naphthoquinone was assayed against SF-295 (glioblastoma, MDAMB-435 (breast, HCT-8 (colon, HCT-116 (colon, HL-60 (leukemia, OVCAR-8 (ovarian, NCI-H358M (bronchoalveolar lung carcinoma and PC3-M (prostate cancer cells and also against PBMC (peripheral blood mononuclear cells. The results demonstrated that all the synthetic aminonaphthoquinones had relevant cytotoxic activity against all human cancer lines used in this experiment. Five of the compounds showed high cytotoxicity and selectivity against all cancer cell lines tested (IC50 = 0.49 to 3.89 µg·mL−1. The title compounds were less toxic to PBMC, since IC50 was 1.5 to eighteen times higher (IC50 = 5.51 to 17.61 µg·mL−1 than values shown by tumour cell lines. The mechanism of cell growth inhibition and structure–activity relationships remains as a target for future investigations.

Improved CVD Techniques for Depositing Passivation Layers of ICs

Science.gov (United States)

1975-10-01

Halted PhilcoT xong, 43 o Flex b ru.an I ery t92." PrutptEnt,"e Electro nic -News; p. 34 --(M a~y 20, 1974). 355. 4t3fAtil, No 2(estbgru sey SpesHg-o e...and No. 4, 78 (1974). *J. G. Biddle Co., Plymouth Meeting, PA 19462. 222 NARROW AND WIDE INTERFERENCE CONTOUR 2 4 6 IC PE LLET Bonding pad oxide area

Inflammatory effects induced by selected limonene oxidation products: 4-OPA, IPOH, 4-AMCH in human bronchial (16HBE14o-) and alveolar (A549) epithelial cell lines.

Science.gov (United States)

Lipsa, Dorelia; Leva, Paolo; Barrero-Moreno, Josefa; Coelhan, Mehmet

2016-11-16

Limonene, a monoterpene abundantly present in most of the consumer products (due to its pleasant citrus smell), easily undergoes ozonolysis leading to several limonene oxidation products (LOPs) such as 4-acetyl-1-methylcyclohexene (4-AMCH), 4-oxopentanal (4-OPA) and 3-isopropenyl-6-oxoheptanal (IPOH). Toxicological studies have indicated that human exposure to limonene and ozone can cause adverse airway effects. However, little attention has been paid to the potential health impact of specific LOPs, in particular of IPOH, 4-OPA and 4-AMCH. This study evaluates the cytotoxic effects of the selected LOPs on human bronchial epithelial (16HBE14o-) and alveolar epithelial (A549) cell lines by generating concentration-response curves using the neutral red uptake assay and analyzing the inflammatory response with a series of cytokines/chemokines. The cellular viability was mostly reduced by 4-OPA [IC 50 =1.6mM (A549) and 1.45mM (16HBE14o-)] when compared to IPOH [IC 50 =3.5mM (A549) and 3.4mM (16HBE14o-)] and 4-AMCH [IC 50 could not be calculated]. As a result from the inflammatory response, IPOH [50μM] induced an increase of both IL-6 and IL-8 secretion in A549 (1.5-fold change) and in 16HBE14o- (2.8- and 7-fold change respectively). 4-OPA [50μM] treatment of A549 increased IL-6 (1.4-times) and IL-8 (1.3-times) levels, while in 16HBE14o- had an opposite effect. A549 treated with 4-AMCH [50μM] elevate both IL-6 and IL-8 levels by 1.2-times, while in 16HBE14o- had an opposite effect. Based on our results, lung cellular injury characterized by inflammatory cytokine release was observed for both cell lines treated with the selected chemicals at concentrations that did not affect their cellular viability. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Synthesis, Structural Characterization, and Antitumor Activity of a Ca(II Coordination Polymer Based on 1,6-Naphthalenedisulfonate and 4,4′-Bipyridyl

Directory of Open Access Journals (Sweden)

Xishi Tai

2013-08-01

Full Text Available A novel Ca(II coordination polymer, [CaL(4,4′-bipyridyl(H2O4]n (L = 1,6-naphthalenedisulfonate, was synthesized by reaction of calcium perchlorate with 1,6-naphthalenedisulfonic acid disodium salt and 4,4′-bipyridyl in CH3CH2OH/H2O. It was characterized by elemental analysis, IR, molar conductivity and thermogravimetric analysis. X-ray crystallography reveals that the Ca(II coordination polymer belongs to the orthorhombic system, with space group P212121. The geometry of the Ca(II ion is a distorted CaNO6 pengonal bipyramid, arising from its coordination by four water molecules, one nitrogen atom of 4,4′-bipyridyl molecule, and two oxygen atoms from two L ligands. The complex molecules form a helical chain by self-assembly. The antitumor activity of 1,6-naphthalenedisulfonic acid disodium salt and the Ca(II coordination polymer against human hepatoma smmc-7721 cell line and human lung adenocarcinoma A549 cell line reveals that the Ca(II coordination polymer inhibits cell growth of human lung adenocarcinoma A549 cell line with IC50 value of 27 μg/mL, and is more resistive to human lung adenocarcinoma A549 cell line as compared to 1,6-naphthalenedisulfonic acid disodium salt.

Chemistry of Renieramycins. Part 14: Total Synthesis of Renieramycin I and Practical Synthesis of Cribrostatin 4 (Renieramycin H

Directory of Open Access Journals (Sweden)

Masashi Yokoya

2015-08-01

Full Text Available The first total synthesis of (±-renieramycin I, which was isolated from the Indian bright blue sponge Haliclona cribricutis, is described. The key step is the selenium oxide oxidation of pentacyclic bis-p-quinone derivative (3 stereo- and regioselectively. We also report a large-scale synthesis of cribrostatin 4 (renieramycin H via the C3-C4 double bond formation in an early stage based on the Avendaño’s protocol, from readily available 1-acetyl-3-(3-methyl-2,4,5-trimethylphenylmethyl-piperazine-2,5-dione (8 in 18 steps (8.3% overall yield. The synthesis provides unambiguous evidence supporting the original structure of renieramycin I.

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

Science.gov (United States)

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

2012-06-01

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

Design, synthesis and antibreast cancer MCF-7 cells biological evaluation of heterocyclic analogs of resveratrol.

Science.gov (United States)

Du, Cheng; Dong, Ming-Hui; Ren, Yu-Jie; Jin, Lu; Xu, Cheng

2017-09-01

A new series of resveratrol heterocyclic analogs (4a-m) were designed and synthesized, and their inhibitiory effects on MCF-7 cells were evaluated to investigate structure-activity relationship. The effects of these analogs on human breast cancer MCF-7 cells were also determined. Results showed that MCF-7 cells could be inhibited more potently by these analogs than by resveratrol (IC 50  = 80.0 μM). Among the analogs, compounds 4c, 4e, and 4k showed a significantly higher activity (IC 50  = 42.7, 48.1, and 43.4 μM) than resveratrol. Furthermore, the derivatives without additional heterocyclic structure in the 4'-OH position exhibited a more potent activity than that with addition heterocyclic structure. In addition, docking simulation was performed to adequately position compound 4c in a human F 1 -ATPase active site to determine a probable binding model. These heterocyclic analogs could be effective candidates for the chemoprevention of human breast cancer.

Precipitation method for barium metaborate (BaB{sub 2}O{sub 4}) synthesis from borax solution

Energy Technology Data Exchange (ETDEWEB)

Akşener, Eymen; Figen, Aysel Kantürk; Pişkin, Sabriye [Yildiz Technical University, Chem. Eng. Dept., Davutpasa Campus, 34210, Istanbul (Turkey)

2013-12-16

In this study, barium metaborate (BaB{sub 2}O{sub 4}, BMB) synthesis from the borax solution was carried out. BMB currently is used in production of ceramic glazes, luminophors, oxide cathodes as well as additives to pigments for aqueous emulsion paints and also β−BaB{sub 2}O{sub 4} single crystals are the best candidate for fabrication of solid-state UV lasers operating at a wavelength of 200 nm due to excellent nonlinear optical properties. In the present study, synthesis was carried out from the borax solution (Na{sub 2}B{sub 4}O{sub 7⋅}10H{sub 2}O, BDH) and barium chloride (BaCI{sub 2⋅}2H{sub 2}O, Ba) in the glass-batch reactor with stirring. The effect of, times (5-15 min), molar ratio [stoich.ration (1.0:2.0), 1.25:2.0, 1.5:2.0, 2.5:2:0, 3.0:2.0, 3.5:2.0,4.0:2.0, 5.0:2.0] and also crystallization time (2-6 hour) on the BMB yield (%) was investigated at 80 °C reaction temperature. It is found that, BMB precipitation synthesis with 90 % yield can be performed from 0.50 molar ration (BDH:Ba), under 80 °C, 15 minute, and 6 hours crystallization time. The structural properties of BMB powders were characterized by using XRD, FT-IR and DTA-TG instrumental analysis technique.

Conceptualising Intellectual Capital (IC) as Language Game and Power

DEFF Research Database (Denmark)

Jørgensen, Kenneth Mølbjerg

2006-01-01

Intellectual Capital (IC) can be viewed as knowledge about knowledge, knowledge creation and how such processes might be leveraged into value. Developing a critical understanding of IC requires a historical and contextual understanding of how IC has emerged and how IC is used. This paper, drawing...... this process of social construction. The paper concludes by proposing some methodological guidelines for conducting critical genealogical research on intellectual capital....

Compounds acting against HIV: Imidazo[1,2-a]pyridines as non-nucleoside reverse transcriptase inhibitors (NNRTIs)

CSIR Research Space (South Africa)

Bode, M

2010-09-01

Full Text Available .6 µM N N NH Cl Res Act = 3% IC50 = 2 µM MAGI IC50 = 0.2 µM N N NH Cl Res Act = 5% IC50 = 3.5 µM MAGI IC50 = 0.18 µM N N NH Cl Res Act = 13% IC50 = 8 µM MAGI IC50 = 0.6 µM N N NH Cl Cl Res Act = 4% IC50 = 1.5 µM MAGI IC50... 2010 www.csir.co.za N N NH N N NH Cl N N NH Cl CN IC50= 4.4 uM (RT) IC50= 0.16 uM (PBMC) IC50= 0.41 uM (MAGI) cf . Nevirapine IC50=0.67 uM (RT) IC50=0.033 uM (PBMC) IC50= 29 uM (RT) IC50= 41 uM (PBMC) cf...

Design, Synthesis and Evaluation of 2,5-Diketopiperazines as Inhibitors of the MDM2-p53 Interaction.

Directory of Open Access Journals (Sweden)

Mariell Pettersson

Full Text Available The transcription factor p53 is the main tumour suppressor in cells and many cancer types have p53 mutations resulting in a loss of its function. In tumours that retain wild-type p53 function, p53 activity is down-regulated by MDM2 (human murine double minute 2 via a direct protein-protein interaction. We have designed and synthesised two series of 2,5-diketopiperazines as inhibitors of the MDM2-p53 interaction. The first set was designed to directly mimic the α-helical region of the p53 peptide, containing key residues in the i, i+4 and i+7 positions of a natural α-helix. Conformational analysis indicated that 1,3,6-trisubstituted 2,5-diketopiperazines were able to place substituents in the same spatial orientation as an α-helix template. The key step of the synthesis involved the cyclisation of substituted dipeptides. The other set of tetrasubstituted 2,5-diketopiperazines were designed based on structure-based docking studies and the Ugi multicomponent reaction was used for the synthesis. This latter set comprised the most potent inhibitors which displayed micromolar IC50-values in a biochemical fluorescence polarisation assay.

Electrochemical oxidation of 4-morpholinoaniline in aqueous solutions: Synthesis of a new trimer of 4-morpholinoaniline

International Nuclear Information System (INIS)

Esmaili, Roya; Nematollahi, Davood

2011-01-01

Research highlights: → Electrochemical study of 4-morpholinoaniline in various pHs. → Electrochemical trimerization of 4-morpholinoaniline in aqueous solution. → Green method for the synthesis of '4-morpholinoaniline-trimer'. → Potential-pH diagram for 4-morpholinoaniline. - Abstract: Electrochemical oxidation of 4-morpholinoaniline has been studied in various pHs using cyclic voltammetry and controlled-potential coulometry. The electrochemical trimerization of 4-morpholinoaniline is described and its mechanism has been studied in aqueous solution. This method provides a green, reagent-less, and environmentally friendly procedure with high atom economy, for the synthesis of '4-morpholinoaniline-trimer' using a carbon electrode in an undivided cell in good yield and purity.

Defining the minimal structural requirements for partial agonism at the type I myo-inositol 1,4,5-trisphosphate receptor.

Science.gov (United States)

Wilcox, R A; Fauq, A; Kozikowski, A P; Nahorski, S R

1997-02-03

The novel synthetic analogues D-3-fluoro-myo-inositol 1,5-bisphosphate-4-phosphorothioate, [3F-Ins(1,5)P2-4PS], D-3-fluoro-myo-inositol 1,4-bisphosphate-5-phosphorothioate [3F-Ins(1,4)P2-5PS], and D-3-fluoro-myo-inositol 1-phosphate-4,5-bisphosphorothioate [3F-Ins(1)P-(4,5)PS2] were utilised to define the structure-activity relationships which could produce partial agonism at the Ca2+ mobilising myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] receptor. Based on prior structure-activity data we hypothesised that the minimal structural requirements for lns(1,4,5)P3 receptor partial agonism, were phosphorothioate substitution of the crucial vicinal 4,5-bisphosphate pair accompanied by another structural perturbation, such fluorination of 3-position of the myo-inositol ring. All the analogues fully displaced [3H]Ins(1,4,5)P3 from a single Ins(1,4,5)P3 binding site in pig cerebellar membranes [3F-Ins(1,5)P2-4PS (1C50 = 26 nM), 3F-Ins(1,4)P2-5PS (IC50 = 80 nM) and 3F-Ins(1)P-(4,5)PS2 (IC50 = 109 nM) cf. Ins(1,4,5)P3 (IC50 = 11 nM)]. In contrast, 3F-Ins(1,5)P2-4PS (IC50 = 424 nM) and 3F-Ins(1,4)P2-5PS (IC50 = 3579 nM) were weak full agonists at the Ca2+ mobilising Ins(1,4,5)P3 receptor of permeabilised SH-SY5Y neuroblastoma cells, being respectively 4- and 36-fold less potent than Ins(1,4,5)P3 (EC50 = 99 nM). While 3F-Ins(1)P-(4,5)PS2 (EC50 = 11345 nM) was a partial agonist releasing only 64.3 +/- 1.9% of the Ins(1,4,5)P3-sensitive intracellular Ca2+ pools. 3F-Ins(1)P-(4,5)PS2 was unique among the Ins(1,4,5)P3 receptor partial agonists so far identified in having a relatively high affinity for the Ins(1,4,5)P3 binding site, accompanied by a significant loss of intrinsic activity for Ca2+ mobilisation. This improved affinity was probably due to the retention of the 1-position phosphate, which enhances interaction with the Ins-(1,4,5)P3 receptor. 3F-Ins(1)P-(4,5)PS2 may be an important lead compound for the development of efficient Ins(1,4,5)P3 receptor antagonists.

Bacterial Peptide Deformylase Inhibition of Tetrazole-Substituted Biaryl Acid Analogs: Synthesis, Biological Evaluations, and Molecular Docking Study.

Science.gov (United States)

Khan, Firoz A Kalam; Patil, Rajendra H; Patil, Manjiri; Arote, Rohidas; Shinde, Devanand B; Sangshetti, Jaiprakash N

2016-12-01

The synthesis and screening of tetrazole-substituted biaryl acid analogs 7a-l as bacterial peptide deformylase (PDF) enzyme inhibitors is reported. The compounds 7e (IC 50 value = 5.50 μM) and 7g (IC 50 value = 7.25 μM) showed good PDF inhibition activity. The compounds 7e (MIC range = 10.75-11.66 μg/mL) and 7g (MIC range = 8.91-12.83 μg/mL) also showed potent antibacterial activity when compared with the standard ciprofloxacin (MIC range = 25-50 μg/mL). Thus, the active derivatives were not only potent PDF enzyme inhibitors but also efficient antibacterial agents. In order to gain more insight into the binding mode of the compounds with the PDF enzyme, the most active compounds 7e and 7g, the moderately active compound 7k, and the least active compound 7h were docked against the PDF enzyme of Escherichia coli. The docking study of the most active compounds 7e and 7g against the PDF enzyme exhibited good binding properties. Hence, we believe our synthesized compounds 7a-l could serve as reservoir for bacterial PDF inhibitor development. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Radiochemical synthesis of 3-(4-[18F] Fluorophenyl)-8-hydroxy-1, 2, 3, 4-tetrahydrochromeno [3, 4-c] pyridin-5-one: A putative dopamine D$4 receptor PET imaging agent

International Nuclear Information System (INIS)

Li, G.C.; Yin, D.Z.; Wang, M.W.; Cheng, D.F.; Wang, Y.X.

2005-01-01

Introduction: The dopamine D 4 receptor has lately received increasing interest since it has been hypothesized to be involved in the pathology and pharmacotherapy of schizophrenia. While this receptor is expressed in lower density in various extrastriatal brain regions and its distribution is still unclear due to the lack of suitable imaging agent and its level change in schizophrenia is controversial. Herein, based on the structure-activity analysis of chromeno[3, 4-c]pyridine- 5-ones as potential dopamine D 4 receptor ligands, a putative D 4 subtype positron emission tomography (PET) radioligand, 3-(4-[ 18 F]fluorophenyl)-8-hydroxy-1, 2, 3, 4-tetrahydrochromeno [3, 4-c]pyridin-5-one ([ 18 F]FHTP), was designed and synthesized. Methods: The radiochemical synthesis route was shown in Figure 1. [ 18 F]Fluoride was produced with a Cyclone-30 (IBA, Belgium) by 18 O(p, n) 18 F reaction using enriched 18 O-H 2 O and eluted from a Dowex 1-X8 anion-exchange column with aqueous potassium carbonate (20 mg/mL). 4-[ 18 F]Fluorobenzaldehyde was prepared according to the method reported by Alan A. Wilson and et al.. Then, 8-hydroxy-1, 2, 3, 4-tetrahydrochromeno [3, 4-c]pyridin-5-one, sodium cyanoborohydride, methanol and acetic acid were added to the dry residue, The mixture was then sealed and heated at 120 degree C for 12 min. At the end of the reaction, the mixture was cooled, diluted with ethyl acetate and washed with water. The extracted organic layer was passed through a small anhydrous magnesium sulfate column. After removal of the solvents in the mixture at 50 degree C under a stream of nitrogen, the obtained residue was redissolved in methanol and purified with a semi-preparative HPLC system, then the desired product was collected. Results: The radiochemical synthesis of [ 18 F]FHTP took around 110 min at EOS with an overall radiochemical yield 19% (decay-corrected) and its radiochemical purity was higher than 95%. Conclusion: A presumed dopamine D 4 receptor PET

Purification, crystallization and preliminary X-ray analysis of aminoglycoside-2′′-phosphotransferase-Ic [APH(2′′)-Ic] from Enterococcus gallinarum

International Nuclear Information System (INIS)

Byrnes, Laura J.; Badarau, Adriana; Vakulenko, Sergei B.; Smith, Clyde A.

2008-01-01

APH(2′′)-Ic is an enzyme that is responsible for high-level gentamicin resistance in E. gallinarum isolates. Crystals of the wild-type enzyme and three mutants have been prepared and a complete X-ray diffraction data set was collected to 2.15 Å resolution from an F108L crystal. Bacterial resistance to aminoglycoside antibiotics is primarily the result of deactivation of the drugs. Three families of enzymes are responsible for this activity, with one such family being the aminoglycoside phosphotransferases (APHs). The gene encoding one of these enzymes, aminoglycoside-2′′-phosphotransferase-Ic [APH(2′′)-Ic] from Enterococcus gallinarum, has been cloned and the wild-type protein (comprising 308 amino-acid residues) and three mutants that showed elevated minimum inhibitory concentrations towards gentamicin (F108L, H258L and a double mutant F108L/H258L) were expressed in Escherichia coli and subsequently purified. All APH(2′′)-Ic variants were crystallized in the presence of 14–20%(w/v) PEG 4000, 0.25 M MgCl 2 , 0.1 M Tris–HCl pH 8.5 and 1 mM Mg 2 GTP. The crystals belong to the monoclinic space group C2, with one molecule in the asymmetric unit. The approximate unit-cell parameters are a = 82.4, b = 54.2, c = 77.0 Å, β = 108.8°. X-ray diffraction data were collected to approximately 2.15 Å resolution from an F108L crystal at beamline BL9-2 at SSRL, Stanford, California, USA

Inhibitory Effects of Resveratrol Analogs on Mushroom Tyrosinase Activity

Directory of Open Access Journals (Sweden)

Nádia Rezende Barbosa Raposo

2012-10-01

Full Text Available Skin pigmentation disorders typically involve an overproduction or uneven distribution of melanin, which results in skin spots. Resveratrol can inhibit tyrosinase, the active enzyme in the synthesis of melanin, but it does not inhibit the synthesis of melanin to an extent that enables its use alone as a skin whitening agent in pharmaceutical formulations, so its use as a coadjuvant in treatment of hyperpigmentation is suggested. Six resveratrol analogs were tested for tyrosinase inhibitory activity in vitro. Among the analogs tested, compound D was the most powerful tyrosinase inhibitor (IC50 = 28.66 µg/mL, two times more active than resveratrol (IC50 = 57.05 µg/mL, followed by the analogs A, E, B, F and C, respectively. This demonstrated that the hydroxylation at C4' on the phenolic ring was the molecular modification with most importance for the observed activity.

Cymantrenyl-Nucleobases: Synthesis, Anticancer, Antitrypanosomal and Antimicrobial Activity Studies

Directory of Open Access Journals (Sweden)

Artur Jabłoński

2017-12-01

Full Text Available The synthesis of four cymantrene-5-fluorouracil derivatives (1–4 and two cymantrene-adenine derivatives (5 and 6 is reported. All of the compounds were characterized by spectroscopic methods and the crystal structure of two derivatives (1 and 6, together with the previously described cymantrene-adenine compound C was determined by X-ray crystallography. While the compounds 1 and 6 crystallized in the triclinic P-1 space group, compound C crystallized in the monoclinic P21/m space group. The newly synthesized compounds 1–6 were tested together with the two previously described cymantrene derivatives B and C for their in vitro antiproliferative activity against seven cancer cell lines (MCF-7, MCF-7/DX, MDA-MB-231, SKOV-3, A549, HepG2m and U-87-MG, five bacterial strains Staphylococcus aureus (methicillin-sensitive, methicillin-resistant and vancomycin-intermediate strains, Staphylococcus epidermidis, and Escherichia coli, including clinical isolates of S. aureus and S. epidermidis, as well as against the protozoan parasite Trypanosoma brucei. The most cytotoxic compounds were derivatives 2 and C for A549 and SKOV-3 cancer cell lines, respectively, with 50% growth inhibition (IC50 values of about 7 µM. The anticancer activity of the cymantrene compounds was determined to be due to their ability to induce oxidative stress and to trigger apoptosis and autophagy in cancer cells. Three derivatives (1, 4 and 5 displayed promising antitrypanosomal activity, with GI50 values in the low micromolar range (3–4 µM. The introduction of the 5-fluorouracil moiety in 1 enhanced the trypanocidal activity when compared to the activity previously reported for the corresponding uracil derivative. The antibacterial activity of cymantrene compounds 1 and C was within the range of 8–64 µg/mL and seemed to be the result of induced cell shrinking.

Synthesis of 6-Methyl-9-n-propyldibenzothiophene-4-ol

Energy Technology Data Exchange (ETDEWEB)

Eisenbraun, E.J.

1991-04-27

The material covered here can be divided into 3 parts: large-scale synthesis of 200+ grams of distilled 1,4-diethyl-2-[(2'- methoxyphenyl)thio]benzene, synthesis of sulfones both as starting materials for chemical cyclization reactions and as solid derivatives for identification purposes, and continued investigation of the cyclization to dibenzothiophenes both by chemical and photochemical means. 5 refs, figs.

VizieR Online Data Catalog: Optical & Spitzer photometry in IC 1805 (Sung+, 2017)

Science.gov (United States)

Sung, H.; Bessell, M. S.; Chun, M.-Y.; Yi, J.; Naze, Y.; Lim, B.; Karimov, R.; Rauw, G.; Park, B.-G.; Hur, H.

2017-06-01

For a study of the IMF and the star-formation history of the young open cluster IC 1805, we obtained deep wide-field VRI and Hα images of IC 1805 using the CFH12K mosaic CCD camera of the CFHT on 2002 January 6 and 7. We also observed several regions in IC 1805, for a study of the reddening and massive star content, using the SITe 2000x800 CCD (Maidanak 2k CCD) and standard UBVRI filters of the AZT-22 1.5m telescope at the Maidanak Astronomical Observatory in Uzbekistan on 2003 August 18 and 2004 december 25,30. Later, we obtained additional images of the central region of IC 1805 with the Fairchild 486 CCD (SNUCam) and UBVI and Hα filters of the AZT-22 telescope on 2007 October 7 and 2009 January 19. The Spitzer mapping observations were performed on 2006 September 20 under program ID 20052 (PI: S. Wolff). For complete photometry of stars in the CFH12K FOV in 3.6 and 4.5um, we also downloaded and reduced the GLIMPSE360 data (AOR: 38753280, 38763264, 38769408, 38799104, 38798592, 38784512, PI: B. A. Whitney). MIPS scans of IC 1805 were obtained on 2005 August 31 and 2005 September 2 (PID 3234, PI: J. S. Greeves). The Chandra X-ray Observatory Observations of IC 1805 (ObsID: 7033, PI: L. Townley) were made on 2006 November 25. The total exposure time was about 79ks. The properties of 647 X-ray sources were published in Townsley+ (2014,J/ApJS/213/1). We searched for the optical and MIR counterparts of these X-ray sources with a matching radius of up to 1.5". (4 data files).

Synthesis and Selective Functionalization of [1,2,4]Triazolo[4,3-a]pyrazines

DEFF Research Database (Denmark)

Demmer, Charles Sylvain; Jorgensen, Morten; Kehler, Jan

2015-01-01

A new tactic for the synthesis and selective functionalization of [1,2,4]triazolo[4,3-a]pyrazines has been developed using an oxidative cyclization as key step. Furthermore, novel strategies for introducing diverse substituents in all positions of the heterocycle were identified....

Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer’s disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids

Directory of Open Access Journals (Sweden)

Bautista-Aguilera OM

2014-10-01

Full Text Available Oscar M Bautista-Aguilera,1,* Gerard Esteban,2,* Mourad Chioua,1 Katarina Nikolic,3 Danica Agbaba,3 Ignacio Moraleda,4 Isabel Iriepa,4 Elena Soriano,5 Abdelouahid Samadi,1 Mercedes Unzeta,2 José Marco-Contelles1 1Laboratory of Medicinal Chemistry (Institute of General Organic Chemistry [IQOG], National Research Council [CSIC], Madrid, Spain; 2Department of Biochemistry and Molecular Biology, Institute of Neurosciences, Autonomous Barcelona University, Barcelona, Spain; 3Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia; 4Department of Organic Chemistry, Faculty of Pharmacy, University of Alcalá, Ctra Barcelona, Alcalá de Henares, Spain; 5Synthesis, and Structure of Organic Compounds (SEPCO (IQOG, CSIC, Madrid, Spain *These authors have equally contributed to this work Abstract: The design, synthesis, and biochemical evaluation of donepezil-pyridyl hybrids (DPHs as multipotent cholinesterase (ChE and monoamine oxidase (MAO inhibitors for the potential treatment of Alzheimer’s disease (AD is reported. The 3D-quantitative structure-activity relationship study was used to define 3D-pharmacophores for inhibition of MAO A/B, acetylcholinesterase (AChE, and butyrylcholinesterase (BuChE enzymes and to design DPHs as novel multi-target drug candidates with potential impact in the therapy of AD. DPH14 (­Electrophorus electricus AChE [EeAChE]: half maximal inhibitory concentration [IC50] =1.1±0.3 nM; equine butyrylcholinesterase [eqBuChE]: IC50 =600±80 nM was 318-fold more potent for the inhibition of AChE, and 1.3-fold less potent for the inhibition of BuChE than the reference compound ASS234. DPH14 is a potent human recombinant BuChE (hBuChE inhibitor, in the same range as DPH12 or DPH16, but 13.1-fold less potent than DPH15 for the inhibition of human recombinant AChE (hAChE. Compared with donepezil, DPH14 is almost equipotent for the inhibition of hAChE, and 8.8-fold more potent for h

Synthesis and in silico studies of novel sulfonamides having oxadiazole ring: As β-glucuronidase inhibitors.

Science.gov (United States)

Taha, Muhammad; Baharudin, Mohd Syukri; Ismail, Nor Hadiani; Selvaraj, Manikandan; Salar, Uzma; Alkadi, Khaled A A; Khan, Khalid Mohammed

2017-04-01

Novel sulfonamides having oxadiazole ring were synthesized by multistep reaction and evaluated to check in vitro β-glucuronidase inhibitory activity. Luckily, except compound 13, all compounds were found to demonstrate good inhibitory activity in the range of IC 50 =2.40±0.01-58.06±1.60μM when compared to the standard d-saccharic acid 1,4-lactone (IC 50 =48.4±1.25μM). Structure activity relationship was also presented. However, in order to ensure the SAR as well as the molecular interactions of compounds with the active site of enzyme, molecular docking studies on most active compounds 19, 16, 4 and 6 was carried out. All derivatives were fully characterized by 1 H NMR, 13 C NMR and EI-MS spectroscopic techniques. CHN analysis was also presented. Copyright © 2017 Elsevier Inc. All rights reserved.

Synthesis and Comparison of In Vitro Leishmanicidal Activity of 5-(Nitroheteroaryl-1, 3, 4-Thiadiazols Containing Cyclic Amine of Piperidin-4-ol at C-2 with Acyclic Amine Analogues against Iranian Strain of Leishmania major (MRHO/IR/75/ER

Directory of Open Access Journals (Sweden)

Azar Tahghighi

2017-04-01

Full Text Available Background: Cutaneous Leishmaniasis (CL is endemic in many tropical and subtropical regions of the world. Due to the prolonged duration of therapy, adverse effect and resistance to current drugs in the treatment of CL, the dis­covery of novel, efficient, and safe leishmanicidal drugs is required. The aims of the present study was to synthesis of new compounds based on the active compounds of 5-(5-nitrofuran-2-yl- and 5-(5-nitrothiophen-2-yl-1,3,4-thia­diazole bearing the linear amino alcohol of 3-aminopropan-1-ol in the C-2 position of thiadiazole ring and evaluation of their activity against the promastigote and amastigote forms of Leishmania major.Methods: Reaction between the solution of 5-(5-nitro heteroaryl-2-chloro-1, 3, 4-thiadiazole and piperidin-4-ol in absolute ethanol was performed and the resulting products were evaluated against promastigotes form of L. major with MTT assay and amastigote form of L. major in murine peritoneal macrophages. In addition, the toxicity of these compounds was assessed against mouse peritoneal macrophages with MTT assay.Results: New synthetic compounds 5a-b showed moderate in vitro antileishmanial activity against L. major pro­mastigotes with IC50 values of 68.9 and 27 µM, respectively. These compounds have also demonstrated a good antiamastigote activity in terms of amastigote number per macrophage, the percentage of macrophage infectivity and infectivity index.Conclusion: Novel cyclic compounds 5a-b were synthesized and exhibited less antipromastigote and antiamastigote activity compared to linear analogues.

Interstellar Lithium and Rubidium in the Diffuse Gas Near IC 443

Science.gov (United States)

Ritchey, Adam M.; Taylor, C. J.; Federman, S. R.; Lambert, D. L.

2011-01-01

We present an analysis of interstellar lithium and rubidium from observations made with the Hobby-Eberly Telescope at McDonald Observatory of the Li I λ6707 and Rb I λ7800 absorption lines along four lines of sight through the supernova remnant IC 443. The observations probe interstellar material polluted by the ejecta of a core-collapse (Type II) supernova and can thus be used to constrain the contribution from massive stars to the synthesis of lithium and rubidium. Production of 7Li is expected to occur through neutrino spallation in the helium and carbon shells of the progenitor star during the terminal supernova explosion, while both 6Li and 7Li are synthesized via spallation and fusion reactions involving cosmic rays accelerated by the remnant. Gamma-ray emission from IC 443 provides strong evidence for the interaction of accelerated cosmic rays with the ambient atomic and molecular gas. Rubidium is also produced by massive stars through the weak s-process in the He- and C-burning shells and the r-process during core collapse. We examine interstellar 7Li/6Li isotope ratios as well as Li/K and Rb/K ratios along each line of sight, and discuss the implications of our results in the context of nucleosynthesis associated with Type II supernovae.

Mecano-synthesis of the alloy 25%Fe-50%Cu-25%Nb

International Nuclear Information System (INIS)

Sousa, Keytiane; Oliveira, Michel Picanco de; Guimaraes, Renan da Silva; Moreira Junior, Valdenir; Filgueira, Marcello

2016-01-01

In general, this study aims at the application of mechanical grinding to the system 25% Fe-50% Cu-25% Nb and studies the production process of these powders during milling. The evolution of the structure during the synthesis and the effect of variation of the grinding time were studied by diffraction of X-rays (XRD) and Scanning Electron Microscopy coupled EDS (SEM + EDS) in order to obtain the sizes of crystallites, the phase formation and its evolution with grinding time, and also the homogeneity of the mixture. The particle size distribution was analyzed by laser sedigraph technique. The powders synthesis were performed for milling time of 2.5, 5 and 10 hours. The mechanical grinding showed to be effective with the solid solution formation in the early grinding times. The XRD showed the solid solution formation with subsequent reduction and disappearance of Cu peaks. Through the technique of laser sedigraph it was observed the increase of the particle size followed by the its reduction in the milling time of 10h, a fact that characterizes the mechanical grinding process for ductile powder particles. Thus, the study demonstrated the effectiveness of the mechanical grinding to obtain powder of Fe-Cu-Nb and further processing and application of diamond cutting tools. (author)

Cytotoxicity, Antioxidant and Apoptosis Studies of Quercetin-3-O Glucoside and 4-(β-D-Glucopyranosyl-1→4-α-L-Rhamnopyranosyloxy)-Benzyl Isothiocyanate from Moringa oleifera.

Science.gov (United States)

Maiyo, Fiona C; Moodley, Roshila; Singh, Moganavelli

2016-01-01

Moringa oleifera, from the family Moringaceae, is used as a source of vegetable and herbal medicine and in the treatment of various cancers in many African countries, including Kenya. The present study involved the phytochemical analyses of the crude extracts of M.oleifera and biological activities (antioxidant, cytotoxicity and induction of apoptosis in-vitro) of selected isolated compounds. The compounds isolated from the leaves and seeds of the plant were quercetin-3-O-glucoside (1), 4-(β-D-glucopyranosyl-1→4-α-L-rhamnopyranosyloxy)-benzyl isothiocyanate (2), lutein (3), and sitosterol (4). Antioxidant activity of compound 1 was significant when compared to that of the control, while compound 2 showed moderate activity. The cytotoxicity of compounds 1 and 2 were tested in three cell lines, viz. liver hepatocellular carcinoma (HepG2), colon carcinoma (Caco-2) and a non-cancer cell line Human Embryonic Kidney (HEK293), using the MTT cell viability assay and compared against a standard anticancer drug, 5-fluorouracil. Apoptosis studies were carried out using the acridine orange/ethidium bromide dual staining method. The isolated compounds showed selective in vitro cytotoxic and apoptotic activity against human cancer and non-cancer cell lines, respectively. Compound 1 showed significant cytotoxicity against the Caco-2 cell line with an IC50 of 79 μg mL(-1) and moderate cytotoxicity against the HepG2 cell line with an IC50 of 150 μg mL(-1), while compound 2 showed significant cytotoxicity against the Caco- 2 and HepG2 cell lines with an IC50 of 45 μg mL(-1) and 60 μg mL(-1), respectively. Comparatively both compounds showed much lower cytotoxicity against the HEK293 cell line with IC50 values of 186 μg mL(-1) and 224 μg mL(-1), respectively.

Design, Synthesis and in vitro Biochemical Activity of Novel Amino Acid Sulfonohydrazide Inhibitors of MurC.

Science.gov (United States)

Frlan, Rok; Kovač, Andreja; Blanot, Didier; Gobec, Stanislav; Pečar, Slavko; Obreza, Aleš

2011-06-01

Mur ligases are essential enzymes involved in the cytoplasmic steps of peptidoglycan synthesis which remain attractive, yet unexploited targets. In order to develop new antibacterial agents, we have designed a series of new MurC and MurD inhibitors bearing amino acid sulfonohydrazide moiety. The L-Leu series of this class displayed the highest enzyme inhibition with IC50 in the concentration range between 100 and 500 µM, with L-Thr, L-Pro and L-Ala derivatives being inactive. The most promising compound of the series also expressed weak antibacterial activity against S. aureus with MIC = 128 µg/mL.

Selectivity of recombinant human leukotriene D(4), leukotriene B(4), and lipoxin A(4) receptors with aspirin-triggered 15-epi-LXA(4) and regulation of vascular and inflammatory responses.

Science.gov (United States)

Gronert, K; Martinsson-Niskanen, T; Ravasi, S; Chiang, N; Serhan, C N

2001-01-01

Aspirin-triggered lipoxin A(4) (ATL, 15-epi-LXA(4)) and leukotriene D(4) (LTD(4)) possess opposing vascular actions mediated via receptors distinct from the LXA(4) receptor (ALX) that is involved in leukocyte trafficking. Here, we identified these receptors by nucleotide sequencing and demonstrate that LTD(4) receptor (CysLT(1)) is induced in human vascular endothelia by interleukin-1beta. Recombinant CysLT(1) receptor gave stereospecific binding with both [(3)H]-LTD(4) and a novel labeled mimetic of ATL ([(3)H]-ATLa) that was displaced with LTD(4) and ATLa ( approximately IC(50) 0.2 to 0.9 nmol/L), but not with a bioinactive ATL isomer. The clinically used CysLT(1) receptor antagonist, Singulair, showed a lower rank order for competition with [(3)H]-ATLa (IC(50) approximately 8.3 nmol/L). In contrast, LTD(4) was an ineffective competitive ligand for recombinant ALX receptor with [(3)H]-ATLa, and ATLa did not compete for [(3)H]-LTB(4) binding with recombinant LTB(4) receptor. Endogenous murine CysLT(1) receptors also gave specific [(3)H]-ATLa binding that was displaced with essentially equal affinity by LTD(4) or ATLa. Systemic ATLa proved to be a potent inhibitor (>50%) of CysLT(1)-mediated vascular leakage in murine skin (200 microg/kg) in addition to its ability to block polymorphonuclear leukocyte recruitment to dorsal air pouch (4 microg/kg). These results indicate that ATL and LTD(4) bind and compete with equal affinity at CysLT(1), providing a molecular basis for aspirin-triggered LXs serving as a local damper of both vascular CysLT(1) signals as well as ALX receptor-regulated polymorphonuclear leukocyte traffic.

The Gcn4 transcription factor reduces protein synthesis capacity and extends yeast lifespan.

Science.gov (United States)

Mittal, Nitish; Guimaraes, Joao C; Gross, Thomas; Schmidt, Alexander; Vina-Vilaseca, Arnau; Nedialkova, Danny D; Aeschimann, Florian; Leidel, Sebastian A; Spang, Anne; Zavolan, Mihaela

2017-09-06

In Saccharomyces cerevisiae, deletion of large ribosomal subunit protein-encoding genes increases the replicative lifespan in a Gcn4-dependent manner. However, how Gcn4, a key transcriptional activator of amino acid biosynthesis genes, increases lifespan, is unknown. Here we show that Gcn4 acts as a repressor of protein synthesis. By analyzing the messenger RNA and protein abundance, ribosome occupancy and protein synthesis rate in various yeast strains, we demonstrate that Gcn4 is sufficient to reduce protein synthesis and increase yeast lifespan. Chromatin immunoprecipitation reveals Gcn4 binding not only at genes that are activated, but also at genes, some encoding ribosomal proteins, that are repressed upon Gcn4 overexpression. The promoters of repressed genes contain Rap1 binding motifs. Our data suggest that Gcn4 is a central regulator of protein synthesis under multiple perturbations, including ribosomal protein gene deletions, calorie restriction, and rapamycin treatment, and provide an explanation for its role in longevity and stress response.The transcription factor Gcn4 is known to regulate yeast amino acid synthesis. Here, the authors show that Gcn4 also acts as a repressor of protein biosynthesis in a range of conditions that enhance yeast lifespan, such as ribosomal protein knockout, calorie restriction or mTOR inhibition.

Extracción de cobre desde soluciones clorhídricas con LIX 860N-IC y LIX 84-IC

Directory of Open Access Journals (Sweden)

Navarro, Carlos María

2001-08-01

Full Text Available In this work, the extraction of copper from chloride solutions with two hydroxyoximes: 5- nonylsalicylaldoxime (LIX 860N-IC and 2-hydroxy-5-nonylacetophenona oxime (LIX 84-IC is discussed. The results showed that an increase in the acidity and an increase in the total concentration of chloride ions in the aqueous phase decreased significantly the extraction of copper as well as the extraction of iron for both extractants. This effect of the chloride ions can be explained by the formation of a series of chloro complexes of Cu(II and Fe(III in the aqueous phase. The effect of initial pH and total chloride concentration on the extraction of chloride by the organic phase suggests that LIX 860N-IC, and to a lesser extent LIX 84-IC, extract small amounts of the cationic complex, CuCl⁺. An increase in the concentration of chloride ions also produced a small decrease in the rate of copper extraction with both hydroxyoximes.

En este trabajo se discute el estudio de la extracción de cobre desde soluciones clorhídricas con dos hidroxioximas: 5-nonilsalicilaldoxima (LIX 860N-IC, y 2-hidroxi-5 nonilacetofenona oxima (LIX 84-IC. Los resultados indicaron que al aumentar la acidez o aumentar la concentración de cloruro en la fase acuosa se produce una significativa disminución en la extracción de cobre y hierro con ambas hidroxioximas. Este efecto del ion cloruro se explica por la formación de varios clorocomplejos de Cu(II y Fe(III en la solución acuosa. El efecto del pH y la concentración total de cloruro en la extracción de cloruro sugiere que el LIX 860N-IC, y en menor grado el LIX 84-IC extraen pequeñas cantidades del catión monovalente, CuCl⁺. Se determinó también que un aumento en la concentración de cloruro en la solución acuosa produce una leve disminución en la velocidad de extracción del cobre con ambas hidroxioximas.

Measuring IC following a semi-qualitative approach: An integrated framework

Directory of Open Access Journals (Sweden)

Chiara Verbano

2013-09-01

Full Text Available Purpose: Considering the different IC measures adopted in literature, the advantages of adopting semi-qualitative measures, and the lack of an agreed system for IC evaluation, the purpose of the paper is to analyse literature on IC measurement following a semi-qualitative approach, with the final intent to build an IC measurement framework. Design/methodology/approach: A literature review on IC measurement system, following a semi-qualitative approach, has been conducted and analysed, in order to re-organize and synthesize all items used in previous researches. Findings: An integrated framework emerged from this research and it constitutes an IC  measurement system, created gathering and integrating different items previously adopted in literature. Each of these variables has been organized in categories belonging to one of the three main components of IC: human capital, internal structural capital and relational capital. Originality/value: This research provides an integrated tool for IC evaluation, fostering toward a well agreed measurement system that is still lacking in literature. This framework could be interesting  not only for the academic world, which in the last two decades reveals increasing attention to IC, but also for the management of the companies, that with IC measurement can increase awareness of the firm’s value and develop internal auditing system to support the management of these assets. Moreover, it could be a useful instrument for the communication of IC value to the external stakeholders, as customers, suppliers and especially shareholders, and to investors and financial analysts.

Synthesis and evaluation of cardiac glycoside mimics as potential anticancer drugs

DEFF Research Database (Denmark)

Jensen, Marie; Schmidt, Steffen; Fedosova, Natalya

2011-01-01

recent years cardiac glycosides have furthermore been suggested to possess valuable anticancer activity. To mimic the labile trisaccharide of digitoxin with a stabile carbohydrate surrogate, we have used sulfur linked ethylene glycol moieties of varying length (mono-, di-, tri- or tetra-ethylene glycol...... the shortest mimics were found to have highest efficacy, with the best ligand having a monoethylene glycol unit (IC(50) 0.24 μM), which was slightly better than digitoxigenin (IC(50) 0.64 μM), while none of the novel cardiac glycoside mimics display an in vitro effect as high as digitoxin (IC(50) 0.02 μM)....

Inhibition of DNA synthesis by chemical carcinogens in cultures of initiated and normal proliferating rat hepatocytes

International Nuclear Information System (INIS)

Novicki, D.L.; Rosenberg, M.R.; Michalopoulos, G.

1985-01-01

Rat hepatocytes in primary culture can be stimulated to replicate under the influence of rat serum and sparse plating conditions. Higher replication rates are induced by serum from two-thirds partially hepatectomized rats. The effects of carcinogens and noncarcinogens on the ability of hepatocytes to synthesize DNA were examined by measuring the incorporation of [3H]thymidine by liquid scintillation counting and autoradiography. Hepatocyte DNA synthesis was not decreased by ethanol or dimethyl sulfoxide at concentrations less than 0.5%. No effect was observed when 0.1 mM ketamine, Nembutal, hypoxanthine, sucrose, ascorbic acid, or benzo(e)pyrene was added to cultures of replicating hepatocytes. Estrogen, testosterone, tryptophan, and vitamin E inhibited DNA synthesis by approximately 50% at 0.1 mM, a concentration at which toxicity was noticeable. Several carcinogens requiring metabolic activation as well as the direct-acting carcinogen N-methyl-N'-nitro-N-nitrosoguanidine interfered with DNA synthesis. Aflatoxin B1 inhibited DNA synthesis by 50% (ID50) at concentrations between 1 X 10(-8) and 1 X 10(-7) M. The ID50 for 2-acetylaminofluorene was between 1 X 10(-7) and 1 X 10(-6) M. Benzo(a)pyrene and 3'-methyl-4-dimethylaminoazobenzene inhibited DNA synthesis 50% between 1 X 10(-5) and 1 X 10(-4) M. Diethylnitrosamine and dimethylnitrosamine (ID50 between 1 X 10(-4) and 5 X 10(-4) M) and 1- and 2-naphthylamine (ID50 between 1 X 10(-5) and 5 X 10(-4) M) caused inhibition of DNA synthesis at concentrations which overlapped with concentrations that caused measurable toxicity

Substituted Pyrazinecarboxamides: Synthesis and Biological Evaluation

Directory of Open Access Journals (Sweden)

Katarina Kralova

2006-03-01

Full Text Available Condensation of the corresponding chlorides of some substituted pyrazine-2-carboxylic acids (pyrazine-2-carboxylic acid, 6-chloropyrazine-2-carboxylic acid, 5-tert-butylpyrazine-2-carboxylic acid or 5-tert-butyl-6-chloropyrazine-2-carboxylic acid withvarious ring-substituted aminothiazoles or anilines yielded a series of amides. Thesyntheses, analytical and spectroscopic data of thirty newly prepared compounds arepresented. Structure-activity relationships between the chemical structures and the anti-mycobacterial, antifungal and photosynthesis-inhibiting activity of the evaluatedcompounds are discussed. 3,5-Bromo-4-hydroxyphenyl derivatives of substitutedpyrazinecarboxylic acid, 16-18, have shown the highest activity against Mycobacteriumtuberculosis H37Rv (54-72% inhibition. The highest antifungal effect againstTrichophyton mentagrophytes, the most susceptible fungal strain tested, was found for5-tert-butyl-6-chloro-N-(4-methyl-1,3-thiazol-2-ylpyrazine-2-carboxamide (8, MIC =31.25 μmol·mL-1. The most active inhibitors of oxygen evolution rate in spinachMolecules 2006, 11 243 chloroplasts were the compounds 5-tert-butyl-6-chloro-N-(5-bromo-2-hydroxyphenyl- pyrazine-2-carboxamide (27, IC50 = 41.9 μmol·L-1 and 5-tert-butyl-6-chloro-N-(1,3- thiazol-2-yl-pyrazine-2-carboxamide (4, IC50 = 49.5 μmol·L-1.

24 CFR 50.20 - Categorical exclusions subject to the Federal laws and authorities cited in § 50.4.

Science.gov (United States)

2010-04-01

... the Federal laws and authorities cited in § 50.4. 50.20 Section 50.20 Housing and Urban Development... the Federal laws and authorities cited in § 50.4. (a) The following actions, activities and programs... individual compliance requirements of other environmental statutes, Executive orders and HUD standards cited...

A remotely-controlled locomotive IC driven by electrolytic bubbles and wireless powering.

Science.gov (United States)

Hsieh, Jian-Yu; Kuo, Po-Hung; Huang, Yi-Chun; Huang, Yu-Jie; Tsai, Rong-Da; Wang, Tao; Chiu, Hung-Wei; Wang, Yao-Hung; Lu, Shey-Shi

2014-12-01

A batteryless remotely-controlled locomotive IC utilizing electrolytic bubbles as propelling force is realized in 0.35 μm CMOS technology. Without any external components, such as magnets and on-board coils, the bare IC is wirelessly powered and controlled by a 10 MHz ASK modulated signal with RS232 control commands to execute movement in four moving directions and with two speeds. The receiving coil and electrolysis electrodes are all integrated on the locomotive chip. The experiment successfully demonstrated that the bare IC moved on the surface of an electrolyte with a speed up to 0.3 mm/s and change moving directions according to the commands. The total power consumptions of the chip are 207.4 μW and 180 μ W while the output electrolysis voltages are 2 V and 1.3 V, respectively.

Synthesis and evaluation of 2-benzylidene-1-tetralone derivatives for monoamine oxidase inhibitory activity.

Science.gov (United States)

Amakali, Klaudia T; Legoabe, Lesetja Jan; Petzer, Anel; Petzer, Jacobus P

2018-05-01

Chalcone has been identified as a promising lead for the design of monoamine oxidase (MAO) inhibitors. This study attempted to discover potent and selective chalcone-derived MAO inhibitors by synthesising a series consisting of various cyclic chalcone derivatives. The cyclic chalcones were selected based on the possibility that their restricted structures would confer a higher degree of MAO isoform selectivity, and included the following chemical classes: 1-indanone, 1-tetralone, 1-benzosuberone, chromone, thiochromone, 4-chromanone and 4-thiochromanone. The results showed that the cyclic chalcones are in general good potency, and in most instances specific inhibitors of the human MAO-B isoform. Among these compounds, the 4-chromanone derivative was the most potent MAO-B inhibitor with an IC50 value of 0.156 µM. To further investigate the MAO inhibition of cyclic chalcones, a series of twenty-three 2-benzylidene-1-tetralone derivatives were synthesised and evaluated as MAO inhibitors. Most 2-benzylidene-1-tetralones possess good inhibitory activity and specificity for MAO-B with the most potent inhibitor displaying an IC50 value of 0.0064 µM, while the most potent MAO-A inhibitor possessed an IC50 value of 0.754 µM. This study thus shows that certain cyclic chalcones are human MAO-B inhibitors, compounds that could be suitable for the treatment of neurodegenerative disorders such as Parkinson's disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

50 CFR 17.4 - Pre-Act wildlife.

Science.gov (United States)

2010-10-01

... 50 Wildlife and Fisheries 2 2010-10-01 2010-10-01 false Pre-Act wildlife. 17.4 Section 17.4 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF THE INTERIOR (CONTINUED) TAKING, POSSESSION, TRANSPORTATION, SALE, PURCHASE, BARTER, EXPORTATION, AND IMPORTATION OF WILDLIFE AND...

Targetting the hemozoin synthesis pathway for antimalarial drug and detected by TEM (Transmission electron microscope)

Science.gov (United States)

Abbas, Jamilah; Artanti, Nina; Sundowo, Andini; Dewijanti, Indah Dwiatmi; Hanafi, Muhammad; Lisa, Syafrudin, Din

2017-11-01

Malaria is a major public health problem mainly due to the development of resistance by the most lethal causative parasite species, the alarming spread of drug resistance and limited number of effective drug available now. Therefore it is important to discover new antimalarial drug. Malaria is caused by a singlecelled parasite from the genus Plasmodium. Plasmodium falciparum parasite infect red blood cells, ingesting and degradation hemoglobin in the acidic food vacuola trough a sequential metabolic process involving multiple proteases. During these process, hemoglobin is utilized as the predominant source of nutrition. Proteolysis of hemoglobin yields amino acid for protein synthesis as well as toxic heme. Massive degradation of hemoglobin generates large amount of toxic heme. Malaria parasite has evolved a distinct mechanism for detoxification of heme through conversion into insoluble crystalline pigment, known as hemozoin (β hematoin). Hemozoin synthesis is an indispensable process for the parasite and is the target for action of several known antimalarial drug. TEM (Transmission Electron Microscope) technology for hemozoin formation in vitro assay was done in this research. Calophyllum aerophyllum Lauterb as medicinal plants was used as a source of antimalarial drug. Acetone extracts of C. lowii showed growth inhibition against parasite P. falciparum with IC50 = 5.2 µg/mL. Whereas from hexane, acetone and methanol fraction of C. aerophyllum showed growth inhibition with IC50 = 0.054, 0.055 and 0.0054 µg/mL respectively. New drug from Calophyllum might have potential compounds that have unique structures and mechanism of action which required to develop new drug for treatment of sensitive and drug resistant strain of malaria.

Design, Synthesis, and Biological Evaluation of Peptidomimetic N-Substituted Cbz-4-Hyp-Hpa-Amides as Novel Inhibitors of Plasmodium falciparum.

Science.gov (United States)

Bacherikov, Valeriy A; Chittiboyina, Amar G; Avery, Mitchell A

2017-08-01

A new series of peptidomimetic N-substituted Cbz-4-Hyp-Hpa-amides were designed, synthesized, and evaluated for inhibition of the Plasmodium falciparum. Substituents on the N-atom of the amide group were selected alkyl-, allyl-, aryl-, 2-hydroxyethyl-, 2-cyanoethyl-, cyanomethyl-, 2-hydroxyethyl-, 2,2-diethoxyethyl-, or 2-ethoxy-2-oxoethylamino groups, and about of 40 new compounds were synthesized and evaluated for antiplasmodial activity in vitro. Antimalarial activity has been investigated as for the final peptide mimetics, and their immediate predecessors, carrying TBDMS or TBDPS protecting groups on 4-hydroxyproline residue and 18 derivatives exhibited toxicity against P. falciparum. Of these agents, compound 23e was shown to have potent antimalarial activity with IC 50 528 ng/ml. © 2017 Wiley-VHCA AG, Zurich, Switzerland.

18 CFR 50.4 - Stakeholder participation.

Science.gov (United States)

2010-04-01

... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Stakeholder... ELECTRIC TRANSMISSION FACILITIES § 50.4 Stakeholder participation. A Project Participation Plan is required to ensure stakeholders have access to accurate and timely information on the proposed project and...

Green synthesis in acid water of 5,7,3’,4’-O-tetramethylquercetin

Directory of Open Access Journals (Sweden)

Zhong-lei WANG

2014-04-01

Full Text Available Objective: To synthesize 5,7,3′,4′-O-tetramethylrutin. Methods: With absolute N,N-dimethylformamide as the solvent, rutin and methyl iodide were stirring reaction at room temperature for 48h in the presence of potassium carbonate to obtain 5,7,3′,4′-O-tetramethylrutin, after filtering, rinsing with acetone and concentration under reduced pressure. The concentrate was heated and refluxed for about 1h in 0.50% hydrochloric acid, and then cooled and filtered. The precipitation was washed to neutral with distilled water. Results: The synthesis of 5,7,3′,4′-O-tetramethylquercetin was achieved through the steps above, and it has the same anti-influenza virus effect with oseltamivir, the yield was 92.2%. Conclusion: This method owns the characteristics of high yield, simple process, stable and feasible.

A combined thermodynamic cycle based on methanol dissociation for IC (internal combustion) engine exhaust heat recovery

International Nuclear Information System (INIS)

Fu, Jianqin; Liu, Jingping; Xu, Zhengxin; Ren, Chengqin; Deng, Banglin

2013-01-01

In this paper, a novel approach for exhaust heat recovery was proposed to improve IC (internal combustion) engine fuel efficiency and also to achieve the goal for direct usage of methanol as IC engine fuel. An open organic Rankine cycle system using methanol as working medium is coupled to IC engine exhaust pipe for exhaust heat recovery. In the bottom cycle, the working medium first undergoes dissociation and expansion processes, and is then directed back to IC engine as fuel. As the external bottom cycle and the IC engine main cycle are combined together, this scheme forms a combined thermodynamic cycle. Then, this concept was applied to a turbocharged engine, and the corresponding simulation models were built for both of the external bottom cycle and the IC engine main cycle. On this basis, the energy saving potential of this combined cycle was estimated by parametric analyses. Compared to the methanol vapor engine, IC engine in-cylinder efficiency has an increase of 1.4–2.1 percentage points under full load conditions, while the external bottom cycle can increase the fuel efficiency by 3.9–5.2 percentage points at the working pressure of 30 bar. The maximum improvement to the IC engine global fuel efficiency reaches 6.8 percentage points. - Highlights: • A combined thermodynamic cycle using methanol as working medium for IC engine exhaust heat recovery is proposed. • The external bottom cycle of exhaust heat recovery and IC engine working cycle are combined together. • IC engine fuel efficiency could be improved from both in-cylinder working cycle and external bottom cycle. • The maximum improvement to the IC engine global fuel efficiency reaches 6.8 percentage points at full load

Type synthesis for 4-DOF parallel press mechanism using GF set theory

Science.gov (United States)

He, Jun; Gao, Feng; Meng, Xiangdun; Guo, Weizhong

2015-07-01

Parallel mechanisms is used in the large capacity servo press to avoid the over-constraint of the traditional redundant actuation. Currently, the researches mainly focus on the performance analysis for some specific parallel press mechanisms. However, the type synthesis and evaluation of parallel press mechanisms is seldom studied, especially for the four degrees of freedom(DOF) press mechanisms. The type synthesis of 4-DOF parallel press mechanisms is carried out based on the generalized function(GF) set theory. Five design criteria of 4-DOF parallel press mechanisms are firstly proposed. The general procedure of type synthesis of parallel press mechanisms is obtained, which includes number synthesis, symmetrical synthesis of constraint GF sets, decomposition of motion GF sets and design of limbs. Nine combinations of constraint GF sets of 4-DOF parallel press mechanisms, ten combinations of GF sets of active limbs, and eleven combinations of GF sets of passive limbs are synthesized. Thirty-eight kinds of press mechanisms are presented and then different structures of kinematic limbs are designed. Finally, the geometrical constraint complexity( GCC), kinematic pair complexity( KPC), and type complexity( TC) are proposed to evaluate the press types and the optimal press type is achieved. The general methodologies of type synthesis and evaluation for parallel press mechanism are suggested.

The defective nature of ice Ic and its implications for atmospheric science

Science.gov (United States)

Kuhs, W. F.; Hansen, T. C.

2009-04-01

The possible atmospheric implication of ice Ic (cubic ice) has already been suggested some time ago in the context of snow crystal formation [1]. New findings from air-borne measurements in cirrus clouds and contrails have put ice Ic into the focus of interest to understand the so-called "supersaturation puzzle" [2,3,4,5]. Our recent microstructural work on ice Ic [6,7] appears to be highly relevant in this context. We have found that ice Ic is characterized by a complex stacking fault pattern, which changes as a function of temperature as well as time. Indeed, from our own [8] and other group's work [9] one knows that (in contrast to earlier believe) ice Ic can form up to temperatures at least as high as 240K - thus in the relevant range for cirrus clouds. We have good preliminary evidence that the "cubicity" (which can be related to stacking fault probabilities) as well as the particle size of ice Ic are the relevant parameters for this correlation. The "cubicity" of stacking faulty ice Ic (established by diffraction) correlates nicely with the increased supersaturation at decreasing temperatures observed in cirrus clouds and contrails, a fact, which may be considered as further evidence for the presence of ice Ic. Moreover, the stacking faults lead to kinks in the outer shapes of the minute ice Ic crystals as seen by cryo scanning electron microscopy (cryo-SEM); these defective sites are likely to play some role in heterogeneous reactions in the atmosphere. The cryo-SEM work suggests that stacking-faulty ice Ic has many more active centres for such reactions than the usually considered thermodynamically stable form, ice Ih. [1] T Kobayashi & T Kuroda (1987) Snow Crystals. In: Morphology of Crystals (ed. I Sunagawa), Terra Scientific Publishing, Tokyo, pp.649-743. [2] DM Murphy (2003) Dehydration in cold clouds is enhanced by a transition from from cubic to hexagonal ice. Geophys.Res.Lett.,30, 2230, doi:10.1029/2003GL018566. [3] RS Gao & 19 other authors (2004

Synthesis of Poly(3,4-Ethylenedioxy thiophene)-Poly(Styrene-4-Sulfonate) Composites for Support Fuel Cell Catalyst Layer

International Nuclear Information System (INIS)

Eko Sulistiyono; Murni Handayani

2009-01-01

Synthesis of poly(3,4-ethylenedioxy thiophene)-poly(styrene-4-sulfonate) composites for support fuel cell catalyst layer are synthesis composites which become fuel cell catalyst support so that catalyst has optimal performance. Main function of composites is support platinum particle for application in fuel cell. This article explains the result of composites production process from ( 3,4 Ethylenedioxy thiophene) and Sodium poly( styrene - 4-sulfonate) using two methods Jingning Shan method (method 1) and Zhigang Qi and Peter G.Pickup method (method 2). Analysis of the synthesis results used Scanning Electron Microscopic –Electron Dispersive X – Ray Spectrophotometer (SEM-EDS ). The analysis result show that both methods produce polymer agglomerate into a sponge-like morphology. Composite from method 1 has morphology, pores and proton transport better than composite produced by method 2. (author)

Design, synthesis, in vitro Evaluation and docking studies on dihydropyrimidine-based urease inhibitors.

Science.gov (United States)

Iftikhar, Fatima; Ali, Yousaf; Ahmad Kiani, Farooq; Fahad Hassan, Syed; Fatima, Tabeer; Khan, Ajmal; Niaz, Basit; Hassan, Abbas; Latif Ansari, Farzana; Rashid, Umer

2017-10-01

In our previous report, we have identified 3,4-dihydropyrimidine scaffold as promising class of urease inhibitor in a structure based virtual screen (SBVS) experiment. In present study, we attempted to optimize the scaffold by varying C-5 substituent. The elongation of the C-5 chain was achieved by the reaction of C-5 ester with hydrazine leading to C-5 carbohydrazides which were further used as building blocks for the synthesis of fifteen new compounds having diverse moieties. A significantly higher in vitro urease inhibitory activity with IC 50 values in submicromolar range was observed for semithiocarbazide derivatives (4a-c, 0.58-0.79µM) and isatin Schiff base derivative 5a (0.23µM). Docking analysis suggests that the synthesized compounds were anchored well in the catalytic site and extending to the entrance of binding pocket and thus restrict the mobility of the flap by interacting with its key amino acid residues. The overall results of urease inhibition have shown that these compounds can be further optimized and developed as lead urease inhibitors. Copyright © 2017 Elsevier Inc. All rights reserved.

Synthesis, characterisation and biomedical applications of curcumin conjugated chitosan microspheres.

Science.gov (United States)

Saranya, T S; Rajan, V K; Biswas, Raja; Jayakumar, R; Sathianarayanan, S

2018-04-15

Curcumin is a diaryl heptanoid of curcuminoids class obtained from Curcuma longa. It possesses various biological activities like anti-inflammatory, hypoglycemic, antioxidant, wound-healing, and antimicrobial activities. Chitosan is a biocompatible, biodegradable and non-toxic natural polymer which enhances the adhesive property of the skin. Chemical conjugation will leads to sustained release action and to enhance the bioavailability. This study aims to synthesis and characterize biocompatible curcumin conjugated chitosan microspheres for bio-medical applications. The Schiff base reaction was carried out for the preparation of curcumin conjugated chitosan by microwave method and it was characterised using FTIR and NMR. Curcumin conjugated chitosan microspheres (CCCMs) were prepared by wet milling solvent evaporation method. SEM analysis showed these CCCMs were 2-5μm spherical particles. The antibacterial activities of the prepared CCCMs were studied against Staphylococcus aureus and Escherichia coli, the zone of inhibition was 28mm and 23mm respectively. Antioxidant activity of the prepared CCCMs was also studied by DPPH and H 2 O 2 method it showed IC 50 esteem value of 216μg/ml and 228μg/ml, and anti-inflammatory activity results showed that CCCMs having IC 50 value of 45μg/ml. The results conclude that the CCCMs having a good antibacterial, antioxidant and anti-inflammatory activities. This, the prepared CCCMs have potential application in preventing skin infections. Copyright © 2017. Published by Elsevier B.V.

N-Substituted 5-Amino-6-methylpyrazine-2,3-dicarbonitriles: Microwave-Assisted Synthesis and Biological Properties

Directory of Open Access Journals (Sweden)

Ondrej Jandourek

2014-01-01

Full Text Available In this work a series of 15 N-benzylamine substituted 5-amino-6-methyl-pyrazine-2,3-dicarbonitriles was prepared by the aminodehalogenation reactions using microwave assisted synthesis with experimentally set and proven conditions. This approach for the aminodehalogenation reaction was chosen due to its higher yields and shorter reaction times. The products of this reaction were characterized by IR, NMR and other analytical data. The compounds were evaluated for their antibacterial, antifungal and herbicidal activity. Compounds 3 (R = 3,4-Cl, 9 (R = 2-Cl and 11 (R = 4-CF3 showed good antimycobacterial activity against Mycobacterium tuberculosis (MIC = 6.25 µg/mL. It was found that the lipophilicity is important for antimycobacterial activity and the best substitution on the benzyl moiety of the compounds is a halogen or trifluoromethyl group according to Craig’s plot. The activities against bacteria or fungi were insignificant. The presented compounds also inhibited photosynthetic electron transport in spinach chloroplasts and the IC50 values of the active compounds varied in the range from 16.4 to 487.0 µmol/L. The most active substances were 2 (R = 3-CF3, 3 (R = 3,4-Cl and 11 (R = 4-CF3. A linear dependence between lipophilicity and herbicidal activity was observed.

One-pot synthesis of 4,8-dibromobenzo[1,2-c;4,5-c']bis[1,2,5]thiadiazole.

Science.gov (United States)

Tam, Teck Lip; Li, Hairong; Wei, Fengxia; Tan, Ke Jie; Kloc, Christian; Lam, Yeng Ming; Mhaisalkar, Subodh G; Grimsdale, Andrew C

2010-08-06

A one-step synthesis of 4,8-dibromobenzo[1,2-c;4,5-c']bis[1,2,5]thiadiazole with use of 1,2,4,5-tetraaminobenzene tetrahydrobromide and thionyl bromide in good yield is reported. This unit can then be used in the synthesis of low bandgap materials via palladium-catalyzed coupling reactions. The approach offers a quick and easy way to prepare low bandgap materials as compared to the current literature methods.

Design, synthesis, and biological evaluation of achiral analogs of duocarmycin SA.

Science.gov (United States)

Daniell, Kristen; Stewart, Michelle; Madsen, Erik; Le, Minh; Handl, Heather; Brooks, Natalie; Kiakos, Konstantinos; Hartley, John A; Lee, Moses

2005-01-03

The design, synthesis, as well as biochemical and biological evaluation of two novel achiral analogs of duocarmycin SA (DUMSA), 1 and 2, are described. Like CC-1065 and adozelesin, compounds 1 and 2 covalently reacted with adenine-N3 in AT-rich sequences and led to the formation of DNA strand breaks upon heating. The cytotoxicity of compounds 1 and 2 against human cancer cells (K562, LS174T) was determined using a MTT assay giving IC(50) values in the low nanomolar. Further cytotoxicity screening of compound 2 conducted by the NCI against a panel of 60 different human cancer cell lines indicated that it was particularly active against several solid tumor cells lines derived from the lung, colon, CNS, skin, and breast.

Bio-medical CMOS ICs

CERN Document Server

Yoo, Hoi-Jun

2011-01-01

This book is based on a graduate course entitled, Ubiquitous Healthcare Circuits and Systems, that was given by one of the editors. It includes an introduction and overview to biomedical ICs and provides information on the current trends in research.

2.5 Gb/s laser-driver GaAS IC

DEFF Research Database (Denmark)

Riishøj, Jesper

1993-01-01

A laser-diode driver GaAs IC incorporating an optional NRZ/RZ (non-return-to-zero/return-to-zero) conversion facility, having ECL (emitter-coupled logic) and SCFL (source-coupled FET logic)-compatible inputs and providing a 0-60-mA adjustable output current into a 50-Ω/5-V termination at bit rates...... obtained. To verify laser driving performance a back-to-back optical-fiber transmission experiment was performed, giving good optical eye diagrams at 2.5 Gb/s. The electrooptical interplay between laser-diode driver and laser-diode has been demonstrated using SPICE simulations...... up to 2 Gb/s NRZ and maintaining a clear eye opening of 50 mA at 2.5 Gb/s NRZ bit rate has been designed, using a commercial 1-μm gate-length (Fτ=12 GHz) GaAs MESFET foundry service. The high maximum output current is obtained by implementing the output driver as a cascode differential amplifier...

New coumarin derivatives: design, synthesis and use as inhibitors of hMAO.

Science.gov (United States)

He, Xu; Chen, Yan-Yan; Shi, Jing-Bo; Tang, Wen-Jiang; Pan, Zhi-Xiang; Dong, Zhi-Qiang; Song, Bao-An; Li, Jun; Liu, Xin-Hua

2014-07-15

A series new 2H-chromene-3-carboxamides (4a-4i) and S-2H-chromene-3-carbothioates (5j-5t) were synthesized and evaluated as monoamine oxidase A and B inhibitors. Among them, compound 5k (IC50=0.21μM, IC50 iproniazid=7.65μM) showed the most activity and higher MAO-B selectivity (189.2-fold vs 1-fold) with respect to the MAO-A isoform. The need to clarify at a 3D level some important molecular aspects of discussed SAR, we undertaked a number of docking simulations to better assess. The steric effect was analyzed interms of both posing and scoring by investigating the nature of the binding interactions. The docking results of active compound 5k with hMAO-B complex indicated that conserved residue ILE 199 was important for ligand binding via Sigma-Pi interaction. Copyright © 2014 Elsevier Ltd. All rights reserved.

Recent Progress in Planetary Laboratory Astrophysics achieved with NASA Ames' COSmIC Facility

Science.gov (United States)

Salama, Farid; Sciamma-O'Brien, Ella; Bejaoui, Salma

2016-10-01

We describe the characteristics and the capabilities of the laboratory facility, COSmIC, that was developed at NASA Ames to generate, process and analyze interstellar, circumstellar and planetary analogs in the laboratory [1]. COSmIC stands for "Cosmic Simulation Chamber" and is dedicated to the study of neutral and ionized molecules and nanoparticles under the low temperature and high vacuum conditions that are required to simulate various space environments such as planetary atmospheres. COSmIC integrates a variety of state-of-the-art instruments that allow forming, processing and monitoring simulated space conditions for planetary, circumstellar and interstellar materials in the laboratory. The COSmIC experimental setup is composed of a Pulsed Discharge Nozzle (PDN) expansion, that generates a plasma in the stream of a free supersonic jet expansion, coupled to two high-sensitivity, complementary in situ diagnostics: a Cavity Ring Down Spectroscopy (CRDS) and laser induced fluorescence (LIF) systems for photonic detection [2, 3], and a Reflectron Time-Of-Flight Mass Spectrometer (ReTOF-MS) for mass detection [4].Recent results obtained using COSmIC will be highlighted. In particular, the progress that has been achieved in an on-going study investigating the formation and the characterization of laboratory analogs of Titan's aerosols generated from gas-phase molecular precursors [5] will be presented. Plans for future laboratory experiments on planetary molecules and aerosols in the growing field of planetary laboratory astrophysics will also be addressed, as well as the implications of studies underway for astronomical observations.References: [1] Salama F., in Organic Matter in Space, IAU S251, Kwok & Sandford eds, CUP, S251, 4, 357 (2008).[2] Biennier L., Salama, F., Allamandola L., & Scherer J., J. Chem. Phys., 118, 7863 (2003)[3] Tan X, & Salama F., J. Chem. Phys. 122, 84318 (2005)[4] Ricketts C., Contreras C., Walker, R., Salama F., Int. J. Mass Spec, 300

Suppression of glycosaminoglycan synthesis by articular cartilage, but not of hyaluronic acid synthesis by synovium, after exposure to radiation

International Nuclear Information System (INIS)

Hugenberg, S.T.; Myers, S.L.; Brandt, K.D.

1989-01-01

We recently found that injection of 2 mCi of yttrium 90 (90Y; approximately 23,000 rads) into normal canine knees stimulated glycosaminoglycan (GAG) synthesis by femoral condylar cartilage. The present investigation was conducted to determine whether radiation affects cartilage metabolism directly. Rates of GAG synthesis and degradation in normal canine articular cartilage were studied following irradiation. Cultured synovium from the same knees was treated similarly, to determine the effects of irradiation on hyaluronic acid synthesis. Twenty-four hours after exposure to 1,000 rads, 10,000 rads, or 50,000 rads, 35S-GAG synthesis by the cartilage was 93%, 69%, and 37%, respectively, of that in control, nonirradiated cartilage. The effect was not rapidly reversible: 120 hours after exposure to 50,000 rads, GAG synthesis remained at only 28% of the control level. Autoradiography showed marked suppression of 35S uptake by chondrocytes after irradiation. Cartilage GAG degradation was also increased following irradiation: 4 hours and 8 hours after exposure to 50,000 rads, the cartilage GAG concentration was only 66% and 54%, respectively, of that at time 0, while corresponding values for control, nonirradiated cartilage were 90% and 87%. In contrast to its effects on cartilage GAG metabolism, radiation at these levels had no effect on synovial hyaluronic acid synthesis

Suppression of glycosaminoglycan synthesis by articular cartilage, but not of hyaluronic acid synthesis by synovium, after exposure to radiation

Energy Technology Data Exchange (ETDEWEB)

Hugenberg, S.T.; Myers, S.L.; Brandt, K.D.

1989-04-01

We recently found that injection of 2 mCi of yttrium 90 (90Y; approximately 23,000 rads) into normal canine knees stimulated glycosaminoglycan (GAG) synthesis by femoral condylar cartilage. The present investigation was conducted to determine whether radiation affects cartilage metabolism directly. Rates of GAG synthesis and degradation in normal canine articular cartilage were studied following irradiation. Cultured synovium from the same knees was treated similarly, to determine the effects of irradiation on hyaluronic acid synthesis. Twenty-four hours after exposure to 1,000 rads, 10,000 rads, or 50,000 rads, 35S-GAG synthesis by the cartilage was 93%, 69%, and 37%, respectively, of that in control, nonirradiated cartilage. The effect was not rapidly reversible: 120 hours after exposure to 50,000 rads, GAG synthesis remained at only 28% of the control level. Autoradiography showed marked suppression of 35S uptake by chondrocytes after irradiation. Cartilage GAG degradation was also increased following irradiation: 4 hours and 8 hours after exposure to 50,000 rads, the cartilage GAG concentration was only 66% and 54%, respectively, of that at time 0, while corresponding values for control, nonirradiated cartilage were 90% and 87%. In contrast to its effects on cartilage GAG metabolism, radiation at these levels had no effect on synovial hyaluronic acid synthesis.

Synthesis, structures and urease inhibitory activity of cobalt(III) complexes with Schiff bases.

Science.gov (United States)

Jing, Changling; Wang, Cunfang; Yan, Kai; Zhao, Kedong; Sheng, Guihua; Qu, Dan; Niu, Fang; Zhu, Hailiang; You, Zhonglu

2016-01-15

A series of new cobalt(III) complexes were prepared. They are [CoL(1)(py)3]·NO3 (1), [CoL(2)(bipy)(N3)]·CH3OH (2), [CoL(3)(HL(3))(N3)]·NO3 (3), and [CoL(4)(MeOH)(N3)] (4), where L(1), L(2), L(3) and L(4) are the deprotonated form of N'-(2-hydroxy-5-methoxybenzylidene)-3-methylbenzohydrazide, N'-(2-hydroxybenzylidene)-3-hydroxylbenzohydrazide, 2-[(2-dimethylaminoethylimino)methyl]-4-methylphenol, and N,N'-bis(5-methylsalicylidene)-o-phenylenediamine, respectively, py is pyridine, and bipy is 2,2'-bipyridine. The complexes were characterized by infrared and UV-Vis spectra, and single crystal X-ray diffraction. The Co atoms in the complexes are in octahedral coordination. Complexes 1 and 4 show effective urease inhibitory activities, with IC50 values of 4.27 and 0.35 μmol L(-1), respectively. Complex 2 has medium activity against urease, with IC50 value of 68.7 μmol L(-1). While complex 3 has no activity against urease. Molecular docking study of the complexes with Helicobacter pylori urease was performed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Design, synthesis and activity of BBI608 derivatives targeting on stem cells.

Science.gov (United States)

Zhou, Qifan; Peng, Chen; Du, Fangyu; Zhou, Linbo; Shi, Yajie; Du, Yang; Liu, Dongdong; Sun, Wenjiao; Zhang, Meixia; Chen, Guoliang

2018-05-10

STAT3 plays a vital role in maintaining the self-renewal of tumor stem cells. BBI608, a small molecule identified by its ability to inhibit gene transcription driven by STAT3 and cancer stemness properties, can inhibit stemness gene expression and kill stemness-high cancer cells isolated from a variety of cancer types. In order to improve the pharmacokinetic properties of BBI608 and the antitumor activity, a series of BBI608 derivatives were designed and synthesized here. Most of these compounds were more potent than BBI608 on HepG2 cells, compound LD-8 had the most potent inhibitory activity among them and was 5.4-fold more potent than BBI608 (IC 50  = 11.2 μM), but had considerable activity on normal liver cells L-02. Compounds LD-17 (IC 50  = 3.5 μM) and LD-19 (IC 50  = 2.9 μM) were found to possess significant inhibitory activities and good selectivity. The results showed that compound LD-19 was worthy to investigate further as a lead compound according to its potent inhibitory activity, ideal ClogP value and better water solubility. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

S-Alkylated/aralkylated 2-(1H-indol-3-yl-methyl)-1,3,4- oxadiazole-5 ...

African Journals Online (AJOL)

Tropical Journal of Pharmaceutical Research July 2016; 15 (7): 1525-1533 ... 9.00 ± 4.12 µM against S. aureus, E.coli, and B. subtilis. One of ... agar culture medium for antibacterial evaluation. ... IC50 values (concentration that results in 50 %.

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

Directory of Open Access Journals (Sweden)

Negrutska V. V.

2009-12-01

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

One-pot synthesis and cytotoxicity studies of new Mannich base derivatives of polyether antibiotic--lasalocid acid.

Science.gov (United States)

Huczyński, Adam; Rutkowski, Jacek; Borowicz, Izabela; Wietrzyk, Joanna; Maj, Ewa; Brzezinski, Bogumil

2013-09-15

Seven Mannich base derivatives of polyether antibiotic Lasalocid acid (2a-2g) were synthesized and screened for their antiproliferative activity against various human cancer cell lines. A novel chemoselective one-pot synthesis of these Mannich bases was developed. Compounds 2a-2c and 2g with sterically smaller dialkylamine substituent, displayed potent antiproliferative activity (IC50: 3.2-7.3 μM), and demonstrated higher than twofold selectivity for specific type of cancer. The nature of Mannich base substituent on C-2 atom at the aromatic ring may be critical in the search for selectivity towards a particular cancer cell. Copyright © 2013 Elsevier Ltd. All rights reserved.

Synthesis of 4'-Selenoribonucleosides, the Building Blocks of 4'-SelenoRNA, Using a Hypervalent Iodine.

Science.gov (United States)

Saito-Tarashima, Noriko; Ota, Masashi; Minakawa, Noriaki

2017-09-18

Herein is described a detailed protocol for the synthesis of 4'-selenoribonucleoside derivatives that involves the use of a hypervalent iodine species. These derivatives are versatile units for the preparation of 4'-selenoRNA. Large-scale synthesis of a 4-selenosugar starting from D-ribose is achieved in eight steps, including a final chromatographic purification. The resulting 4-selenosugar is then subjected to the one-pot Pummerer-like reaction using hypervalent iodine in the presence of silylated nucleobases. The reaction with silylated uracil affords the desired 4'-selenouridine derivatives with excellent β-selectivity and in good yield. Conversely, when purine nucleobases are used in the Pummerer-like reaction, N7 4'-selenoribonucleoside isomers are obtained alongside the desired N9 isomers. However, the undesired N7 isomers can be converted to the desired N9 ones under acidic conditions. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.

Impact of FDA-Approved Drugs on the Prostaglandin Transporter OATP2A1/SLCO2A1.

Science.gov (United States)

Kamo, Shunsuke; Nakanishi, Takeo; Aotani, Rika; Nakamura, Yoshinobu; Gose, Tomoka; Tamai, Ikumi

2017-09-01

To understand interaction of drugs with the prostaglandin transporter OATP2A1/SLCO2A1 that regulates disposition of prostaglandins, we explored the impact of 636 drugs in an FDA-approved drug library on 6-carboxyfluorescein (6-CF) uptake by OATP2A1-expressing HEK293 cells (HEK/2A1). Fifty-one and 10 drugs were found to inhibit and enhance 6-CF uptake by more than 50%, respectively. Effect of the 51 drugs on 6-CF uptake was positively correlated with that on PGE 2 uptake (r = 0.64, p < 0.001). Among those, 5 drugs not structurally related to prostaglandins, suramin, pranlukast, zafirlukast, olmesartan medoxomil, and losartan potassium, exhibited more than 90% PGE 2 uptake inhibition. Inhibitory affinity of suramin to OATP2A1 was the highest (IC 50,2A1 of 0.17 μM), and its IC 50 values to MRP4-mediated PGE 2 transport (IC 50,MRP4 ) and PGE 2 synthesis in human U-937 cells treated with phorbol 12-myristate 13-acetate (IC 50,Syn ) were 73.6 and 336.7 times higher than IC 50,2A1 , respectively. Moreover, structure-activity relationship study in 29 nonsteroidal anti-inflammatory drugs contained in the library displayed inhibitory activities of anthranilic acid derivatives, but enhancing effects of propionic acid derivatives. These results demonstrate that suramin is a potent selective inhibitor of OATP2A1, providing a comprehensive information about drugs in clinical use that interact with OATP2A1. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Synthesis, fluorescence properties and the promising cytotoxicity of pyrene-derived aminophosphonates.

Science.gov (United States)

Lewkowski, Jarosław; Rodriguez Moya, Maria; Wrona-Piotrowicz, Anna; Zakrzewski, Janusz; Kontek, Renata; Gajek, Gabriela

2016-01-01

A large series of variously substituted amino(pyren-1-yl)methylphosphonic acid derivatives was synthesized using a modified aza-Pudovik reaction in 20-97% yields. The fluorescence properties of the obtained compounds were investigated revealing that N-alkylamino(pyren-1-yl)methylphosphonic derivatives are stronger emissive compounds than the corresponding N-aryl derivatives. N-Benzylamino(pyren-1-yl)methylphosphonic acid displayed strong fluorescence (ΦF = 0.68) in phosphate-buffered saline (PBS). The influence of a series of derivatives on two colon cancer cell lines HT29 and HCT116 was also investigated. The most promising results were obtained for N-(4-methoxyphenyl)amino(pyren-1-yl)methylphosphonate, which was found to be cytotoxic for the HCT116 cancer cell line (IC50 = 20.8 μM), simultaneously showing weak toxicity towards normal lymphocytes (IC50 = 230.8 µM).

Synthesis, fluorescence properties and the promising cytotoxicity of pyrene–derived aminophosphonates

Directory of Open Access Journals (Sweden)

Jarosław Lewkowski

2016-06-01

Full Text Available A large series of variously substituted amino(pyren-1-ylmethylphosphonic acid derivatives was synthesized using a modified aza-Pudovik reaction in 20–97% yields. The fluorescence properties of the obtained compounds were investigated revealing that N-alkylamino(pyren-1-ylmethylphosphonic derivatives are stronger emissive compounds than the corresponding N-aryl derivatives. N-Benzylamino(pyren-1-ylmethylphosphonic acid displayed strong fluorescence (ΦF = 0.68 in phosphate-buffered saline (PBS. The influence of a series of derivatives on two colon cancer cell lines HT29 and HCT116 was also investigated. The most promising results were obtained for N-(4-methoxyphenylamino(pyren-1-ylmethylphosphonate, which was found to be cytotoxic for the HCT116 cancer cell line (IC50 = 20.8 μM, simultaneously showing weak toxicity towards normal lymphocytes (IC50 = 230.8 µM.

Prostaglandin (PG) E3 synthesis elicted by adrenergic stimuli in guinea-pig trachea (GPT) is mediated primarily by B2 adrenergic receptors

International Nuclear Information System (INIS)

Nadel, G.L.; Malik, K.U.; Lew, D.B.

1990-01-01

The purpose of this study was to examine arachidonic acid (AA) metabolism and to characterize the type of adrenergic receptor (AR) involved in the production of the major metabolite of this fatty acid. [ 14 C]AA was incubated with GPT-rings and the radiolabelled products were extracted and separated by TLC method. The medium was also assayed for radiolabelled immunoreactive PG's (iPG's) and leukotrienes (LT) B4 and C4 by RIA or Enzyme immunoassay (EIA) after exposure to various AR agonists. [ 14 C]AA was incorporated into GPT-rings and metabolized mainly into iPGE2 and smaller amounts into PGF2α. Trace amounts of PGD2 and 6-keto-PGF1α but not LTB4 or LTC4 were detected by RIA and/or EIA. Incubation of GPT rings for 15 minutes with isoproterenol and salbutamol resulted in a significant increase of PGE2 synthesis (optimum conc: 10 -7 , 10 -7 M respectively). In contrast, dobutamine, norepinephrine, phenylnephrine and xylazine (up to 10 -6 M) did not significantly increase PGE2 production. Isoproterenol-induced iPGE2 production was inhibited by a selective β2 antagonist, butoxamine (70%: 10 -7 M, 91%: 10 -6 M) and somewhat reduced by β1 antagonists practolol and metoprolol (30-64%:10 -6 M). These data suggest that isoproterenol induced iPGE2 synthesis is primarily mediated via activation of β2 adrenergic receptor

Current status of ITER I&C system as integration begins

Energy Technology Data Exchange (ETDEWEB)

Davis, William, E-mail: william.davis@iter.org [ITER Organisation, Route de Vinon-sur Verdon, CS 90 046, 13067 St. Paul Lez Durance Cedex (France); Wallander, Anders [ITER Organisation, Route de Vinon-sur Verdon, CS 90 046, 13067 St. Paul Lez Durance Cedex (France); Yonekawa, Izuru [Nippon Advanced Technology Ltd., 3129-45 Hibara Muramatsu, Tokai, Naka-gun, Ibaraki 319-1112 (Japan)

2016-11-15

Highlights: • The ITER I&C system is organisationally complicated and technically challenging. • Standard technologies for the ITER I&C systems have been selected. • Supply of non-standard technologies will cause serious issues. • Differing levels of design maturity of plant I&C systems is a serious challenge. • Systems are in the final stages of design and are being delivered to site. - Abstract: The ITER I&C system is organisationally complicated and technically challenging, and integrating its many sub-systems into a single coherent system is critical for the ITER project to meet its objectives. This paper explains the integration risks being faced now and anticipated in the near future. Standardisation initiatives by the ITER central team to mitigate these risks are described. The paper also presents the architecture of the ITER I&C system, the current status of design and manufacture key developments made in recent years, and the current and future activities of the central I&C teams. Finally, a short description is given of the plant I&C systems that will be delivered to ITER in the near future.

El contenido de los mensajes icónicos: El discurso icónico como totalidad (2)

OpenAIRE

Dr. Raymond Colle

1999-01-01

En el capítulo anterior, hemos hablado de los códigos icónicos de modo general, por cuanto tienen algunas características comunes, en particular el uso de figuras como factores de los significantes. Sin embargo, como lo hemos señalado al final, no todos se construyen ni articulan de la misma manera. Tal como las lenguas son muchas y los códigos lingüísticos se rigen por diferentes reglas -aunque sobre la base de fonemas unidos secuencialmente-, los códigos icónicos son también variados y regi...

OSL signal of IC chips from mobile phones for dose assessment in accidental dosimetry

International Nuclear Information System (INIS)

Mrozik, A.; Marczewska, B.; Bilski, P.; Książek, M.

2017-01-01

The rapid assessment of the radiation dose is very important for the prediction of biological effects after unintended exposition. The materials for use as dosimeters in accidental dosimetry should be everyday objects which are usually placed near the human body, for example mobile phones. IC (Integrated Circuit) chip is one of several electronic components of mobile phones which give a luminescent signal. The measurements of samples from different mobile phones and smartphones were conducted by optically stimulated luminescence (OSL) and thermoluminescence (TL) methods. The OSL measurement was performed in two ways: with readouts at room temperature and at 100 °C. This work is focused on determination of OSL dose response of IC chips, minimum detectable dose (MDD), OSL signal stability in the time after the exposition, its repeatability and sensitivity to light. Several tests of the assessment of unknown doses were also conducted. The readouts at 100 °C indicate the reducing of the fading of OSL signal in the first hours after irradiation in comparison with room temperature readouts. The obtained results showed relatively good dosimetric properties of IC chips: their high sensitivity to the ionizing radiation, linear dose response up to 10 Gy and a good reproducibility of OSL signal which can allow the dose recovery of doses less than 2 Gy in 14 days after an incident with the accuracy better than 25%. The fading is a drawback of IC chips and the fading factor should be considered when calculating the dose. - Highlights: • IC chips from smartphones demonstrated high potential for accidental dosimetry. • Minimum detectable dose was estimated as a value of 50 mGy. • Samples showed linear dose response for the dose range from 0.05 Gy up to 10 Gy.

Synthesis of new 4-methyl-2-(4-pyridyl)-1,2,3,4-tetrahydroquinolines as potent antifungal compounds

Energy Technology Data Exchange (ETDEWEB)

Mendez, Leonor Y. Vargas [Universidad Santo Tomas, Bucaramanga (Colombia). Grupo de Investigaciones Ambientales; Zacchino, Susana A. [Universidad Nacional del Rosario, (Argentina). Lab. de Farmacognosia; Kouznetsov, Vladimir V. [Universidad Industrial de Santander, Bucaramanga (Colombia). Lab. de Quimica Organica y Biomolecular

2010-07-01

Synthesis, spectral characterization and biological results of new series of 2-(4-pyridyl)- 1,2,3,4-tetrahydroquinolines and their closer precursors, -N-aryl-N-[1-(4-pyridyl)but-3-enyl] amines are reported. It was found that both g-pyridyl substituted precursors and final products, tetrahydroquinolines, showed very good antifungal activities against Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Microsporum gypseun, Trichophyton rubrum and Trichophyton mentagrophytes. (author)

A facile synthesis of new 5-aryl-thiophenes bearing sulfonamide moiety via Pd(0-catalyzed Suzuki–Miyaura cross coupling reactions and 5-bromothiophene-2-acetamide: As potent urease inhibitor, antibacterial agent and hemolytically active compounds

Directory of Open Access Journals (Sweden)

Mnaza Noreen

2017-01-01

Full Text Available The present study reports a convenient approach for the synthesis of thiophene sulfonamide derivatives (3a–3k via Suzuki cross coupling reaction. This method of synthesis involved the reactions of various aryl boronic acids and esters with 5-bromthiophene-2-sulfonamide (2 under mild and suitable temperature conditions. The compounds synthesized in the present study were subjected to urease inhibition and hemolytic activities. The substitution pattern and the electronic effects of different functional groups (i.e., Cl, CH3, OCH3, F etc. available on the aromatic ring are found to have significant effect on the overall results. The compound 5-Phenylthiophene-2-sulfonamide 3a showed the highest urease inhibition activity with IC50 value ∼ 30.8 μg/mL compared with the thiourea (used as standard having IC50 value ∼ 43 μg/mL. Moreover, almost all of the compounds were examined for the hemolytic activity against triton X-100 with positive results obtained in most of the cases. In addition, the antibacterial activities of the derivatives of 5-arylthiophene-2-sulfonamide and 5-bromothiophene-2-acetamide were also investigated during the course of the study.

The pharmacological profile of CGP 28238, a novel highly potent anti-inflammatory compound.

Science.gov (United States)

Wiesenberg-Boettcher, I; Schweizer, A; Green, J R; Mueller, K; Maerki, F; Pfeilschifter, J

1989-01-01

CGP 28238 (6-(2,4-difluorophenoxy)-5-methylsulfonylamino-1-indanone ) exhibits very potent anti-inflammatory activity in rat adjuvant arthritis (ED40 = 0.05 mg/kg, p.o.) and pronounced analgesic and antipyretic activity in acute models in mice and rats (ED50 2-5 mg/kg, p.o.), but has clear advantages over reference NSAIDs with respect to gastro-intestinal tolerability. Threshold doses for gastro-intestinal ulcerogenicity in rats after single and repeated (10x) doses were found to be 30 mg/kg, p.o., and prostaglandin (PGE2) production in rat gastric and ileal mucosa was only marginally inhibited (ED50 greater than 30 mg/kg, p.o.). On the other hand, PGE2 production in rat inflammatory exudate and thromboxane synthesis in rat blood were inhibited with ED50 values of less than or equal to 2 mg/kg, p.o. Although CGP28238 does not inhibit cyclooxygenase in bovine seminal vesicle microsomal preparations (IC50 greater than 10(-3) mol/l), potent inhibition of prostaglandin synthesis was shown in various in vitro systems using human and animal cells with IC50 values of less than 10(-6) mol/l. IL-1-stimulated bone resorption and PGE2 production in murine calvarial cultures were inhibited with IC50 values of 3 x 10(-7) and 2 x 10(-8) mol/l, respectively. 5-Lipoxygenase (murine macrophages), phospholipase A2 (human PMN) and phospholipase C (human platelets) were not inhibited. CGP 28238 may represent a novel highly potent anti-inflammatory compound with improved gastro-intestinal safety.