The design, synthesis, in vitro biological evaluation and molecular modeling of novel benzenesulfonate derivatives bearing chalcone moieties as potent anti-microtubulin polymerization agents

Abstract

A series of novel 3,4-dimethoxylbenzenesulfonate derivatives containing a chalcone structure were synthesized and evaluated for their anti-proliferative activities against HepG2, HCT-116, MCF-7 and HeLa cell lines, as well as the effects of compound 10b on mitotic arrest and cell cycle of MCF-7 carcinoma cell line. Most importantly, the results of DAPI staining under co-focal microscope justified that compound 10b functioned even at relatively low concentration. The analogues showed a potent bio-activity towards tumor cells with IC₅₀ values at nano-mole class, compared with those of positive control drug Colchicine, whose IC₅₀ were 150.4 nM for MCF-7, 123.9 nM for HepG2, 125.4 nM for HCT-116 and 131.4 nM for HeLa cells. Also, a molecular docking modeling was utilized to reveal the binding mode of derivatives and microtubule. Among all the synthesized compounds, compound 10b stands out as IC₅₀ values against all the selected cell lines were at average 80 nM (in which the values against MCF-7 and HepG2 were similar; about 79.2 nM). In this research, we gave strong evidence upon the optimized stratagem for ligands targeting the colchicine-binding site on microtubules, explaining the attribution that the analogues were designed upon the structure of chalcone and combretastatin A-4.