Design, synthesis, and biological evaluation of diaryl heterocyclic derivatives targeting tubulin polymerization with potent anticancer activities.

A series of diaryl heterocyclic analogues were designed and synthesized as tubulin polymerization inhibitors. Among them, compound 6y showed the highest antiproliferative activity against HCT-116 colon cancer cell line with an IC values of 2.65 μM. Compound 6y also effectively inhibited tubulin polymerization in vitro (IC of 10.9 μM), and induced HCT-116 cell cycle arrest in G2/M phase. In addition, compound 6y exhibited high metabolic stability on human liver microsomes (T = 106.2 min). Finally, 6y was also effective in suppressing tumor growth in a HCT-116 mouse colon model without apparent toxicity. Collectively, these results suggest that 6y represents a new class of tubulin inhibitors deserving further investigation.