Design, synthesis and biological evaluation of indole-based [1,2,4]triazolo[4,3-a] pyridine derivatives as novel microtubule polymerization inhibitors

Abstract

A series of indole-based [1,2,4]triazolo [4,3-a]pyridine derivatives was designed and synthesized as novel microtubulin polymerization inhibitors by using a conformational restriction strategy. These compounds exhibited moderate to potent anti-proliferative activities against a panel of cancer cell lines (HeLa, A549, MCF-7 and HCT116). Among them, compound 12d featuring a N-methyl-5-indolyl substituent at the C-6 position of the [1,2,4]triazolo [4,3-a]pyridine core exhibited the highest antiproliferative activity with the IC₅₀ values ranging from 15 to 69 nM, and remarkable inhibitory effect on tubulin polymerization with an IC₅₀ value of 1.64 μM. Mechanistic studies revealed that compound 12d induced cellular apoptosis and cell cycle arrest at the G₂/M phase in a dose-dependent fashion. Moreover, compound 12d significantly suppressed wound closure and disturbed microtubule networks.

Keywords: Anti-cancer activity; Inhibitors; Triazolo[4,3-a]pyridine; Tubulin polymerization.