Medicinal Chemistry - Volume 12, Issue 4, 2016

Background: Fibroblast growth factor (FGF) receptors (FGFRs) play a key role in tumor growth and angiogenesis. The present report describes our search for an extracellularly binding FGFR inhibitor using a combined molecular modeling and de novo design strategy. Methods: Based upon crystal structures of the receptor with its native ligand and knowledge of inhibiting peptides, we have developed a computational protocol that predicts the putative binding of a molecule to the extracellular domains of the receptor. This protocol, or scoring function, was used in combination with the de novo synthesis program 'SYNOPSIS' to generate high scoring and synthetically accessible compounds. Results: Eight compounds belonging to 3 separate chemical classes were synthesized. One of these compounds, alofanib (RPT835), was found to be an effective inhibitor of the FGF/FGFR2 pathway. The preclinical in vitro data support an allosteric inhibition mechanism of RPT835. RPT835 potently inhibited growth of KATO III gastric cancer cells expressing FGFR2, with GI50 value of 10 nmol/L. Conclusion: These results provide strong rationale for the evaluation of compound in advanced cancers.

Autism spectrum disorders (ASD) may be attributed to altered composition of polyunsaturated fatty acids. We examined the relationships between the plasma ratios of docosahexaenoic acid (DHA)/arachidonic acid (AA) and eicosapentaenoic acid (EPA)/AA, and biomarkers of AA-related signaling mediators, i.e., ceruloplasmin, transferrin and superoxide dismutase, with the behavioral symptoms of 30 individuals with ASD (mean age, 13.0 years old) and 20 age- and gender-matched normal controls (mean age, 13.6 years old). Behavioral symptoms were assessed using the Aberrant Behavior Checklists (ABC). The ASD group had significantly higher plasma DHA/AA and EPA/AA ratios, as well as ABC scores, compared to the control group. The plasma ceruloplasmin levels in the ASD group were significantly reduced compared to those in the control group. Multiple linear regression demonstrated that plasma DHA/AA ratio was a fitting model for distinguishing the ASD group from the control group. These findings suggested that increased plasma DHA/AA ratio may be related to lower plasma levels of ceruloplasmin, which may contribute to the pathophysiology of behavioral symptoms in 30 individuals with ASD.

Kinase insert Domain-containing Receptor (KDR) is one of the currently validated targets for anticancer drug discovery and development. Herein, a series of o-amino-arylurea derivatives have been synthesized and evaluated for their kinase inhibitory activity. The optimization on the basis of biological screening and molecular modeling resulted in obvious increase in KDR kinase inhibitory activity compared with the hit compound. Eventually, we identified a potent inhibitor 5a of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-((quinolin-4-ylmethyl) amino)pyridin-3-yl)urea scaffold against KDR (IC50 = 0.0689 μM), which can serve as good starting point for further KDR inhibitor optimization and development.

Hypoxia inducible factor-1 (HIF-1) is a key mediator during cancer cells to adapt tumor hypoxic condition. In this study, a series of adamantane-based compounds were synthesized and evaluated as potential inhibitors of HIF-1α. Examination of their structure-activity relationship (SAR) identified the adamantane-containing indole derivative 20a as a potent inhibitor of HIF-1α in Hep3B cell lines under tumor hypoxia (IC50 = 0.02 μM). The study herein may provide valuable information for the development of novel therapeutics against cancer and tumor angiogenesis.

Background: Human SIRT1 is a class III histone deacetylase (HDAC) family protein. As the overexpression of hSIRT1 leads to cancer, inhibiting its HDAC function may be a better strategy for the treatment of cancer. Till now, only a few reported inhibitor compounds have reached the stage of animal studies; hence, identifying high efficacy inhibitors of hSIRT1 is essential. Objective: The main objective of the study is to obtain a new class of inhibitor compounds of hSIRT1 by the rational structure-based method. Methodology: We performed virtual screening using AutoDock Vina for the HDAC domain of hSIRT1 against the Drug- Bank library containing 1,716 compounds. The recently determined crystal structure of the HDAC domain of hSIRT1 (PDB Id: 4KXQ) was used for docking studies. Subsequently, we performed molecular dynamics simulations and an invitro deacetylase assay for selected compounds. Results: Virtual screening studies yielded seven compounds from two chemical classes, namely diphenyl and oxycoumarin derivatives. Molecular dynamic simulations confirmed that the predicted seven compounds bind well to their respective complex structures. Moreover, four commercially available drugs containing the predicted compounds showed significant inhibition of hSIRT1 deacetylase activity in comparison to the known hSIRT1 inhibitor (sirtinol). Conclusion: Our results indicate that the compounds of the diphenyl and oxycoumarin series may serve as useful scaffolds in the development of new chemical libraries of hSIRT1 inhibitory activity.

Nine novel mono-oxime reactivators bearing xylene linker were synthesized in an effort to improve previously prepared xylene bisoximes and monocarbamoyl-monooximes. The novel compounds were tested in vitro on the model of tabun-, paraoxon-, methylparaoxon- and DFP-inhibited human erythrocyte AChE. Their reactivation ability was compared to pralidoxime, asoxime, obidoxime and two previously prepared xylene linked bisoximes (K107, K108). All compounds showed minimal reactivation of tabun-inhibited AChE at selected concentration scale. This finding was explained by molecular modelling study. Bisoximes obidoxime and K108 resulted as the best reactivators for paraoxon-, methylparaoxon- and DFP-inhibited AChE. The loss of nonoxime moiety lead to the loss of reactivation ability within the novel compounds. Though the novel reactivators did not exceed previously known compounds, they confirmed former SAR findings for xylene-linked AChE reactivators.

Neuronal Nitric Oxide synthase (nNOS) is an attractive challenging target for the treatment of various neurodegenerative disorders. To date, several structure-based studies were conducted to search novel selective nNOS inhibitors. Objective: Discovery of novel nNOS lead scaffolds through the integration of ligand-based threedimensional (3D) pharmacophore (s) with quantitative structure-activity relationship model. Method: The pharmacophoric space of ten structurally diverse sets acquired from 145 previously reported nNOS inhibitors was scrutinize to fabricate representative pharmacophores. Afterwards, genetic algorithm together with multiple linear regression analysis was applied to find out an optimal pharmacophoric models and 2D physicochemical descriptors able to produce optimal predictive QSAR equation (r2 116 =0.76, F = 353, r2 LOO = 0.69, r2 PRESS against 29 external test ligands =0.51). A minimum of three binding modes between ligands and nNOS binding pocket rationalized by the emergence of three pharmacophoric models in the QSAR equation were illustrated. The QSAR-selected pharmacophores were validated by receiver operating characteristic curves analysis and afterward invested as a tool for screening national cancer institute (NCI) database. Results: Low micro molar novel nNOS inhibitors were revealed. Conclusion: Two structurally diverse compounds 148 and 153 demonstrated new scaffolds toward the discovery of potent nNOS inhibitors.

Background: Triaryl oxadiazoles have been proven to be useful agents against various types of cancer cell lines. Nevertheless, their mechanism of action is not fully understood. Objective: Synthesis and cytotoxic activity of a new group of triaryl oxadiazoles; 3,4-diaryl-5-(4- pyridinyl)-1,2,4-oxadiazole derivatives, will be discussed in this study. Their cytotoxic activity has been examined in 4 different cell lines by MTT method. Method: 3,4-Diaryl-5-(4-pyridinyl)-1,2,4-oxadiazole derivatives were prepared from condensation of different imines with 4-substituted benzohydroxyiminoyl chlorides. The antiproliferative activity of the final compounds was examined in MCF-7, AGS, HT-29 and NIH3T3 cell lines by MTT assay, using different concentrations of each compound to determine their IC50. The cytotoxic activity of paclitaxel, doxorubicin and combretastatin A-4 was evaluated as positive controls. Results: All compounds demonstrated cytotoxic activity in mentioned cell lines, in a dose dependent manner. Among all, 6d-2 showed the highest cytotoxicity in AGS and MCF-7 cell lines with IC50 19.84 and 9.91 respectively and 6c-2 was the most potent in HT-29 with IC50 27.60. In addition, 6c-1, one of the most potent compounds, showed an interestingly low cytotoxic effect on NIH3T3 cell line, which is a noncancerous cell line. In the molecular modeling study, all compounds had comparable binding energy in Colchicine binding site and 6c-2 had the best-predicted binding energy. Conclusion: Together, our data suggest that the synthesized compounds have a partially selective mechanism of action against cancer cells and possibly a lower toxic effect on normal cells, making them interesting candidates for the synthesis of new anticancer agents.