K. Saravanan

Design and development of oxobenzimidazoles as novel androgen receptor antagonists

Antiandrogens are a novel class of anticancer agents that inhibit cancer cell proliferation and induce apoptosis in various cell lines. To find the lead compound from the oxobenzimidazole derivatives, receptor-ligand docking studies were initially performed using Schrödinger software. The best fit molecules were synthesized and characterized through IR, 1H-NMR, 13C-NMR and HRMS analyses. The structure of compound (9b) was further confirmed by single-crystal XRD analysis. The cell viability of the compounds was determined by MTT assay to find IC50 values against prostate cancer and breast cancer cell lines (PC-3, LNCaP, MCF-7 and MDA-MB-231). The ADME/T property studies were performed to rationalize the inhibitory properties of these compounds. It can be concluded from the study that 9b is the most active compound from the series against PC-3 and LNCaP cell lines.

Synthesis, structure prediction, pharmacokinetic properties, molecular docking and antitumor activities of some novel thiazinone derivatives

A novel series of thiazinone derivatives were obtained from unexpected cyclization of dimethyl acetylenedicarboxylate (DMAD) and diethyl acetylenedicarboxylate (DEAD) with corresponding 3-alkyl-2,6-diarylpiperidin-4-one thiosemicarbazones in dry methanol without catalyst under mild conditions. The structures of newly synthesized compounds were established on the basis of FT-IR, HR-Mass, 1H-NMR, 13C-NMR, 1H-1H COSY, 1H-13C COSY, DEPT-135, and HMBC spectral techniques. From 1H NMR, all newly synthesized compounds 17–24 were found to adopt chair conformation. The theoretical studies were carried out using Schrodinger software suite for the structure prediction, biochemical properties investigation and docking studies of all novel compounds. To study the antitumor activity, all the novel compounds were screened in vitro for their cytotoxicity and apoptosis activity against Hep G2 human liver cancer cell line. The biological analysis revealed that the newly synthesized compounds have good/moderate inhibitory activity against the tested cell line.

Design, synthesis and biological evaluation of 2-(4-phenylthiazol-2-yl) isoindoline-1,3-dione derivatives as anti-prostate cancer agents

The structural modification and molecular docking-based screening approaches on thiazole-based isoindolinediones were imposed to find the novel 2-(4-phenylthiazol-2-yl) isoindoline-1,3-dione derivatives. The best fit compounds (6a-n) were synthesized and evaluated their antiproliferative activities on the prostate cancer cell lines (PC-3 & LNCaP). Among them, the compound, 6m exhibited good activity, particularly on LNCaP (IC50=5.96±1.6μM), moderately active against PC-3 cell lines as compared to bicalutamide. The compound, 6m decreased the androgen-mediated transcription of ARE-mRNA in PSA, TMPRSS2, c-myc and cyclin D1 than R-bicalutamide. The compounds, 6e and 6f were reconfirmed through single crystal XRD analysis. The ADME profiling of the test compounds was evaluated to find the drug-likeness and pharmacokinetic parameters. These findings may provide vital information for the development of anti-prostate cancer agents.

Synthesis of novel 1,3-thiazin-4-ones by acetylene diester cyclization and their anticancer activities

GRAPHICAL ABSTRACT ABSTRACT A novel series of 1,3-thiazin-4-one derivatives containing a piperidyl ring (7–16) were designed and synthesized efficiently by thioamide and acetylene diester cyclization reaction via aminolysis of the ester group and the elimination of an alcohol molecule. The structures of all the novel compounds were established by their FTIR, Mass, 1H NMR, and 13C NMR spectral techniques. The newly synthesized compounds (7–16) were studied for their in vitro anticancer activity against human liver cancer cell lines Hep G2 using MTT assay. The IC50 values of the tested compounds were ranging in between 7.48 ± 0.71 and 56.57 ± 1.37 µM. Further, the apoptosis evaluation by the mitochondrial membrane potential using JC-1 dye was carried out and the results are in good agreement with the cytotoxicity studies.

Iminoenamine based novel androgen receptor antagonist exhibited anti-prostate cancer activity in androgen independent prostate cancer cells through inhibition of AKT pathway

Treatment by androgen receptor (AR) antagonists is one of the regimens for prostate cancer. The prolonged treatment with AR antagonist leads to the expression of point mutation in the ligand binding domain of the AR. This point mutation causes resistance to AR antagonist by converting them into an agonist. The T887A mutated AR was frequently expressed in androgen independent prostate cancer (AIPC) patients. Through literature survey and molecular modelling, we have identified a novel AR antagonist having a bulky β-iminoenamine BF2 complex scaffold. The tested and standard ligands were screened in AR positive (LNCaP, MCF-7 and MDA-MB-453), AR negative (PC3), and non-cancerous (3T3) cell lines through anti-proliferation assay. The ligand, ARA3 was the most potent molecule among all the tested ligands and was 7.6 folds selective for AR positive cell lines. The mechanism of anti-prostate cancer activity of ARA3 was confirmed by western blot, qPCR, and apoptotic assays in LNCaP (T887A positive AR) cells. Structural activity relationship was derived by correlating the in-vitro and in-silico data. Consequently, we have identified the essential functional groups that could prevent the resistance concerning mutant AR. The ARA3 induces the apoptosis in AIPC cells by preventing the AR mediated activation of AKT pathway. The bicalutamide did not induce the apoptosis because it failed to prevent the AR mediated activation of AKT.

Design, synthesis and biological evaluation of novel 1, 3-thiazolidine-2, 4-diones as anti-prostate cancer agents

BACKGROUND Androgen receptor is an attractive target for the treatment of prostate cancer. The 1,3- thiazolidine-2,4-diones possess a wide diversity of important biochemical effects and interesting pharmacological properties. OBJECTIVE The aim of the study is to find the experimental and computational methods to investigate the interference of 1,3-thiazolidine-2,4-diones with androgen receptor against prostate cancer. METHOD Structural modification and molecular docking-based virtual screening approaches were imposed to identify the novel 1,3-thiazolidine-2,4-diones by using Schrödinger (Maestro 9.5). The best fit molecules (3-12 & 23-31) were synthesized and characterized using spectroscopic techniques, then in vitro antioxidant and antiprostate cancer activities were evaluated. Further, the structure of the intermediate (18) was confirmed by single crystal XRD analysis. The mechanism studies were performed through the gene expression for the compounds, 29, 30, and 31, the standards, dihydrotestosterone and R-bicalutamide. RESULTS The compounds, 29, 30 and 31 showed comparatively significant antioxidant activity and better antiproliferative activity against PC-3 and LNCaP cell lines. Also, very low cytotoxicity was observed in the noncancerous cell (3T3). The compounds, 29, 30 and 31 significantly decreased the mRNA expression of ARstimulated genes, PSA and TMPRSS2, which demonstrated their anti-prostate cancer activities. ADME/T properties prediction of the compounds (3-12 and23-31) showed the promising drug-likeness and pharmacokinetic parameters without toxicity. Moreover, DFT calculations apparently confirmed the stable conformer of the compound, 31. CONCLUSION These findings may provide the essential information for the development of anti-prostate cancer agents.