Discovery of novel urea derivatives as ferroptosis and autophagy inducer for human colon cancer treatment.

A series of novel urea derivatives were designed, synthesized and evaluated for their inhibitory activities against HT-29 cells, and structure-activity relationships (SAR) were summarized. Compound 10p stood out from these derivatives, exhibiting the most potent antiproliferative activity. Further biological studies demonstrated that 10p arrested cell cycle at G2/M phase via regulating cell cycle-related proteins CDK1 and Cyclin B1. The underlying molecular mechanisms demonstrated that 10p induced cell death through ferroptosis and autophagy, but not apoptosis. Moreover, 10p-induced ferroptosis and autophagy were both related with accumulation of ROS, but they were independent of each other. Our findings substantiated that 10p combines ferroptosis induction and autophagy trigger in single molecule, making it a potential candidate for colon cancer treatment and is worth further development.