Synthesis and bioactive evaluation of N -((1-methyl-1 H -indol-3-yl)methyl)- N -(3,4,5-trimethoxyphenyl)acetamide derivatives as agents for inhibiting tubulin polymerization.

Based on the inhibitory effect of CA-4 analogues and indoles on tubulin polymerization, we designed and synthesized a series of N -((1-methyl-1 H -indol-3-yl)methyl)-2-(1 H -pyrazol-1-yl or triazolyl)- N -(3,4,5-trimethoxyphenyl)acetamides. All the synthesized compounds were evaluated for their in vitro antiproliferative activities against HeLa, MCF-7 and HT-29 cancer cell lines, and some of the target compounds demonstrated effective activities towards the three tumour cell lines. Among them, compound 7d exhibited the most potent activities against HeLa (IC 50 = 0.52 μM), MCF-7 (IC 50 = 0.34 μM) and HT-29 (IC 50 = 0.86 μM). Mechanistic studies revealed that compound 7d induced cell apoptosis in a dose-dependent manner, arrested the cells in the G2/M phase and inhibited polymerization of tubulin via a consistent way with colchicine. Therefore, 7d is a potential agent for the further development of tubulin polymerization inhibitors.