Design Synthesis and Biological Evaluation of Novel Substituted 4H 1 2 4 Triazole Derivatives as Anti Cancer Agents

Abstract

Statistically, Colorectal carcinoma (CRC) has been found to be the third most deadly cancer newlinewith increasingly high rate of prevalence, incidences mortality, and morbidity as per the WHO newlinereports. The tumor cells involve the aberrant Wnt-signalling pathway in more than 90% of newlineCRC cases where tankyrase enzymes promote the proliferation of tumor through this Wnt newlinesignalling cascade. These undruggable targets were therefore selected for this work and newlineextensive computational studies were carried out to design better tankyrase inhibitors. The use newlineof 3D-QSAR studies, pharmacophore modeling and virtual screening, molecular docking and newlineMD simulation studies using TNKS enzymes was employed to analyze, understand, and apply newlinethe knowledge of spatial atomic arrangements, key ligand-receptor interactions, their affinity, newlineand their structural parameters to become druggable. Different softwares like Sybyl X1.2, newlineSchrodinger s glide module etc. were employed to carry out these extensive studies. The newlinedesigned molecules were synthesized in reasonable quantities and structurally confirmed by newlinetheir characterization using Mass spectroscopy, NMR spectroscopy (1H-NMR and 13C-NMR) newlineand FTIR spectroscopy. Purity of each synthesized compound was assessed using HPLC newlineanalysis. All synthesized molecules were utilized to assess their potential as anticancer agents newlinewith the application of in vitro biological evaluation. The cytotoxicity and antiproliferative newlineactions of each synthesized compounds at three different concentrations (i.e., 30 and#956;M, 3 and#956;M and newline0.3 and#956;M) were evaluated using Vero E6 cell lines, and other cancer cell lines including newlinecolorectal cancer cell lines (HT29 and SW480), lung cancer cell lines (A549) and breast cancer newlinecell lines (MDA-MB231). Doxorubicin and XAV939 were used as reference standards to newlineevaluate the comparative biological activity of these molecules. The best compounds found newlinefrom this screening were subjected for apoptosis analysis using flow cytometry-based annexin- newlineV-FITC/PI method at two different concentrations (i.e., 5 and#956;