Abstact

Our preliminary studies indicate that cevipabulin concurrently binds to both the vinca site and the gatorbulin site, and promotes tubulin degradation. To improve its antiproliferative activity and investigate the structure-activity relationships (SARs), thirty-eight cevipabulin derivatives were designed and synthesized based on the cevipabulin-tubulin cocrystal structure. Among them, compound 8g exerted optimal antiproliferative activity, with IC(50) values ranging from 0.016 to 0.035 muM against three tested tumor cell lines. The cocrystal structure of the 8g-tubulin complex revealed that it simultaneously occupies both the vinca site and the gatorbulin site, while maintaining a binding mode similar to that of cevipabulin. Furthermore, 8g promoted alphabeta-tubulin degradation and displayed good oral bioavailability. In an HT29 xenograft model, oral administration of 8g at doses of 20 and 40 mg/kg every 3 days resulted in potent in vivo antitumor activity, with tumor growth inhibition (TGI) rates of 41.0 % and 49.5 %, respectively. Moreover, 8g exhibited significantly reduced toxicity and fewer adverse effects compared to cevipabulin, supporting its potential as a promising therapeutic agent for cancer treatment.