Design, synthesis and bioevaluation of 6-aryl-1-(3,4,5-trimethoxyphenyl)-1H-benzo[d]imidazoles as tubulin polymerization inhibitors

Abstract

A series of new 6-aryl-1-(3,4,5-trimethoxyphenyl)-1H-benzo[d]imidazoles as tubulin polymerization inhibitors targeting the colchicine-binding site were designed to restrict bioactive configuration of (Z,E)-vinylogous CA-4. All of the target compounds were synthesized and then evaluated for their in vitro antiproliferative activities. Among them, 2a exhibited the most potent activities against three cancer cell lines with IC₅₀ values in the range of 0.037-0.20 μM. Further mechanism studies revealed that 2a inhibited tubulin polymerization, disrupted cell microtubule networks, arrested the cell cycle at G2/M phase, induced apoptosis and hindered cancer cell migration. Moreover, 2a displayed significant in vivo antitumor efficacy in 4T1-xenograft mice model with tumor growth inhibition rate of 52% at the dose of 2.5 mg/kg. Colchicine competition assay and the docking model of 2a in complex with tubulin showed that 2a acted at the colchicine-binding site.

Keywords: 1H-benzo[d]imidazole; Colchicine-binding site; Molecular docking; Restriction configuration; Tubulin.