Design and Synthesis of New Tubulin Polymerization Inhibitors Inspired from Combretastatin A‐4: an Anticancer Agent

A series of 30 small hybrid molecules are synthesized inspired from Combretastatin A-4 (CA-4), where ethylene-bridge of CA-4 is replaced with two five-membered heterocyclic rings, viz. isoxazoline and 1, 2, 3-triazole. These are joined by a methylene linker, with substitutions at A and B - ring position of CA-4. The new molecular entities have shown significant cytotoxicity to cancer cell from the IC(50)0.49 mu M-3.17 mu M with 1-((4,5-Dihydro-3-(2,5-dimethoxyphenyl)isoxazol-5-yl)methyl)-4-(4-methoxyphenyl)-1H-1,2,3-triazole displayed IC(50)0.422 +/- 0.07 mu M for A-549 -lung cancer cell line and IC(50)0.498 +/- 0.03 mu M for MDA-MB-231-breast cancer cell line. The western blot analysis, confocal staining and also byin vitrotubulin polymerization assay established the target specificity of the molecules as a tubulin polymerization inhibitor. Molecular docking & Molecular dynamics studies confirmed the binding interaction patterns of these molecules at the Colchicine binding site of tubulin and have correlated the observed experimental result with variation in structure satisfactorily.