Discovery of novel coumarin-indole derivatives as tubulin polymerization inhibitors with potent anti-gastric cancer activities

Novel coumarin-indole derivatives were designed, synthesized and evaluated as tubulin polymerization inhibitors targeting the colchicine binding site. Among these compounds, compound MY-413 displayed the most potent inhibitory activities against gastric cancer cell line MGC-803 with an IC50 value of 0.011 mu M. Furthermore, the IC50 values of compound MY-413 was less than 0.1 mu M for other 17 cancer cell lines and less than 0.05 mu M for other 8 cancer cell lines. Compound MY-413 effectively inhibited the tubulin polymerization (IC50 = 2.46 mu M) by binding to the colchicine site. Screening for the inhibitory effects of compound MY-413 on 61 kinases, it was found that compound MY-413 could inhibit MAPK pathways-related kinases. Because of the inhibitory effects of compound MY-413 on tubulin polymerization and MAPK signaling pathway, compound MY-413 induced cell apoptosis, arrested the cell cycle in the G2/M phase, induced the inhibition of cell proliferation and migration in gastric cancer cells MGC-803 and HGC-27. In addition, compound MY-413 could significantly inhibit tumor growth in MGC-803 xenograft tumor models with tumor growth inhibition (TGI) rates of 70% (15 mg/kg) and 80% (30 mg/kg) without obvious toxicity. Consistent with the in vitro results, compound MY-413 also inhibited MAPK signaling pathway, and induced apoptosis and proliferation inhibition in vivo. In conclusion, this work indicated that compound MY-413 was a promising lead compound for the further investigation as a potential anti-gastric cancer agent.

Automated summary

This study designed, synthesized, and evaluated novel coumarin-indole derivatives as tubulin polymerization inhibitors targeting the colchicine binding site. Compound MY-413 showed potent inhibitory activities against gastric cancer cells, inhibited tubulin polymerization, and MAPK signaling pathway, induced cell apoptosis and proliferation inhibition both in vitro and in vivo. In addition, MY-413 significantly inhibited tumor growth in xenograft tumor models without obvious toxicity. Overall, MY-413 is a promising lead compound for further investigation as a potential anti-gastric cancer agent.