Design, synthesis and bio-evaluation of novel 2-aryl-4-(3,4,5-trimethoxy-benzoyl)-5-substituted-1,2,3-triazoles as the tubulin polymerization inhibitors

Abstract

A series of 2-aryl-4-(3,4,5-trimethoxybenzoyl)-5-substituted-1,2,3-triazoles were designed, synthesized and evaluated for the anticancer activities. Based on the model of DMAM-colchicine-tubulin complex interactions, various saturated nitrogen-containing heterocycles were introduced to the C5-position of 1,2,3-triazol to interact with a tolerant region at the entrance of the binding-pocket and increase the aqueous solubility of the compounds. All designed compounds were concisely synthesized by one-pot oxidative cyclization. Most compounds exhibited moderate antiproliferative activity with IC₅₀ values in the micromolar to sub-micromolar range. Among them, 5g posed N-acyl-piperazine moiety at the C5-position of B-ring showed most potent against cancer cells, with IC₅₀ values of 0.084-0.221 μM 5g potently disrupted microtubule/tubulin dynamics, induced cell cycle arrest at G2/M phase in SGC-7901 cells. In addition, molecular modeling studies suggested that 5g probably binds to the colchicine site of tubulin.

Keywords: Antiproliferative activities; Aqueous solubility; G2/M phase; Microtubule; Molecular modeling.