Construction of the Pharmacophore Model of Glycogen Synthase Kinase-3 Inhibitors

A three dimensional pharmacophore model has been generated for glycogen synthase kinase-3 （GSK-3） inhibitots. A dataset consisting of 89 compounds was selected on the basis of the information content of the structures and activity data as required by the CATALYST system. The optimum model with four features （one hydrogen-bond acceptor unit, one ring aromatic unit, and two hydrophobic aromatic units） was selected with a good correlation coefficient （0.95）. This model is able to predict the activity of other known GSK-3 inhibitors not included in the model generation, and can be further used to identify structurally diverse compounds with desired biological activity by virtual screening.     

Novel aromatic carboxamides from dehydroabietylamine as potential fungicides: Design,synthesis and antifungal evaluation

The present study was carried out to design and synthesize a number of novel aromatic carboxamide derivatives of dehydroabietylamine. The preliminary antifungal assay indicated that most of title compounds displayed moderate to good antifungal activity toward the six fungal strains in vitro. Compounds 3i, 3q, 4b and 4d showed significant antifungal activity against Sclerotinia sclerotiorum, with EC₅₀ values ranging from 0.067 ～ 0.393 mg/L. Compounds 3i, 4b and 4d also showed pronounced mycelial growth inhibition activities against B. cinerea and A. solani. Furthermore, in the in vivo assay, compound 4b exhibited brilliant protective activity against S. sclerotiorum-infected rape leaves. Meanwhile, the in vivo bioassay on tomato plants infected by B. cinerea showed that compound 3i and 4d displayed excellent protective activity at 200 mg/L, which were near to boscalid. Primary mechanistic study revealed that 4b could inhibit sclerotia formation as well as reduce the exopolysaccharide level. SEM and TEM analysis indicated that 4b possessed a strong ability to destroy the surface morphology of mycelia, cell structure and seriously interfere with the growth of the fungal pathogen. In addition, 4b exhibited good inhibitory activity (IC₅₀ = 23.3 ± 1.6 μM) toward succinate dehydrogenase (SDH). Molecular modeling study confirmed the binding modes between compound 4b and SDH. The above antifungal results and fungicidal mechanism study revealed that this class of dehydroabietylamine derivatives could be potential SDH inhibitors and lead compounds for novel fungicides development.     

Synthesis, Structure and H+/K+-ATPase Inhibitory Activity of Novel Triazolyl Substituted Tetrahydrobenzofuran Derivatives via One-pot Three-component Click Reaction

Eleven triazolyl substituted tetrahydrobenzofuran derivatives were synthesized in high yields as novel H⁺/K⁺‐ATPase inhibitor via one‐pot CuI‐catalyzed three‐component click reaction of azide, secondary amine and 3‐bromopropyne under mild conditions in water. Their structures were characterized by NMR, IR, ESI‐MS, elemental analysis and single‐crystal X‐ray diffraction analysis. Most of the target compounds exhibited better H⁺/K⁺‐ATPase inhibitory activity than commercial omeprazole with IC₅₀ values less than 15 µmol·L^?1. The initial structure‐activity analysis suggested that the triazole substituted by cycloalkyl, aromatic ring or O‐containing side‐chain seemed to be beneficial for enhancing the activity.     

Efficient Entropy-Driven Inhibition of Dipeptidyl Peptidase III by Hydroxyethylene Transition-State Peptidomimetics

Dipeptidyl peptidase III (DPP3) is a ubiquitously expressed Zn-dependent protease, which plays an important role in regulating endogenous peptide hormones, such as enkephalins or angiotensins. In previous biophysical studies, it could be shown that substrate binding is driven by a large entropic contribution due to the release of water molecules from the closing binding cleft. Here, the design, synthesis and biophysical characterization of peptidomimetic inhibitors is reported, using for the first time an hydroxyethylene transition-state mimetic for a metalloprotease. Efficient routes for the synthesis of both stereoisomers of the pseudopeptide core were developed, which allowed the synthesis of peptidomimetic inhibitors mimicking the VVYPW-motif of tynorphin. The best inhibitors inhibit DPP3 in the low μM range. Biophysical characterization by means of ITC measurement and X-ray crystallography confirm the unusual entropy-driven mode of binding. Stability assays demonstrated the desired stability of these inhibitors, which efficiently inhibited DPP3 in mouse brain homogenate.     

Determination of triapine,a ribonucleotide reductase inhibitor,in human plasma by liquid chromatography tandem mass spectrometry

Triapine is an inhibitor of ribonucleotide reductase (RNR). Studies have shown that triapine significantly decreases the activity of RNR and enhanced the radiation‐mediated cytotoxicity in cervical and colon cancer. In this work, we have developed and validated a selective and sensitive LC‐MS/MS method for the determination of triapine in human plasma. In this method, 2‐[(3‐fluoro‐2‐pyridinyl)methylene] hydrazinecarbothioamide (NSC 266749) was used as the internal standard (IS); plasma samples were prepared by deproteinization with acetonitrile; tripaine and the IS were separated on a Waters Xbridge Shield RP₁₈ column (3.5 µm; 2.1 × 50 mm) using a mobile phase containing 25.0% methanol and 75.0% ammonium bicarbonate buffer (10.0 mm , pH 8.50; v/v); column eluate was monitored by positive turbo‐ionspray tandem mass spectrometry; and quantitation of triapine was carried out in multiple‐reaction‐monitoring mode. The method developed had a linear calibration range of 0.250–50.0 ng/mL with correlation coefficient of 0.999 for triapine in human plasma. The IS‐normalized recovery and the IS‐normalized matrix factor of triapine were 101–104% and 0.89–1.05, respectively. The accuracy expressed as percentage error and precision expressed as coefficient of variation were ≤±6 and ≤8%, respectively. The validated LC‐MS/MS method was applied to the measurement of triapine in patient samples from a phase I clinical trial. Copyright © 2015 John Wiley & Sons, Ltd.     

Antivitamins B12—Some Inaugural Milestones

The recently delineated structure- and reactivity-based concept of antivitamins B₁₂ has begun to bear fruit by the generation, and study, of a range of such B₁₂-dummies, either vitamin B₁₂-derived, or transition metal analogues that also represent potential antivitamins B₁₂ or specific B₁₂-antimetabolites. As reviewed here, this has opened up new research avenues in organometallic B₁₂-chemistry and bioinorganic coordination chemistry. Exploratory studies with antivitamins B₁₂ have, furthermore, revealed some of their potential, as pharmacologically interesting compounds, for inducing B₁₂-deficiency in a range of organisms, from hospital resistant bacteria to laboratory mice. The derived capacity of antivitamins B₁₂ to induce functional B₁₂-deficiency in mammalian cells and organs also suggest their valuable potential as growth inhibitors of cancerous human and animal cells.     

Simultaneous quantification of ondansetron and tariquidar in rat and human plasma using a high performance liquid chromatography‐ultraviolet method

Ondansetron, a widely used antiemetic agent, is a P‐glycoprotein (P‐gp) substrate and therefore expression of P‐gp at the blood–brain barrier limits its distribution to the central nervous system (CNS), which was observed to be reversed by coadministration with P‐gp inhibitors. Tariquidar is a potent and selective third‐generation P‐gp inhibitor, and coadministration with ondansetron has shown improved ondansetron distribution to the CNS. There is currently no reported bioanalytical method for simultaneously quantifying ondansetron with a third‐generation P‐gp inhibitor. Therefore, we aimed to develop and validate a method for ondansetron and tariquidar in rat and human plasma samples. A full validation was performed for both ondansetron and tariquidar, and sample stability was tested under various storage conditions. To demonstrate its utility, the method was applied to a preclinical pharmacokinetic study following coadministration of ondansetron and tariquidar in rats. The presented method will be valuable in pharmacokinetic studies of ondansetron and tariquidar in which simultaneous determination may be required. In addition, this is the first report of a bioanalytical method validated for quantification of tariquidar in plasma samples.