Synthesis and antitumor potential of new arylidene ursolic acid derivatives via caspase‐8 activation

Abstract Continuing our studies on NO‐donating ursolic acid–benzylidene derivatives as potential antitumor agents, we designed and synthesized a series of new arylidene derivatives containing NO‐donating ursolic acid and aromatic heterocyclic units. Compounds 5c and 6c showed a significant broad‐spectrum antitumor activity. Compound 5c exhibited nearly three‐ to nine‐fold higher cytotoxicity as compared with the parent drug in A549, MCF‐7, HepG‐2, HT‐29, and HeLa cells, and it was also found to be the most potent apoptosis inducer of MCF‐7 cells. More importantly, compound 5c arrested the MCF‐7 cell cycle in the G1 phase, which was associated with caspase activation and a decrease of the Bcl‐2/Bax ratio. Meanwhile, compound 5c caused changes in morphological features, dissipation of the mitochondrial membrane potential, and accumulation of reactive oxygen species. A docking study revealed that the nitroxyethyl moiety of compound 5c may form hydrogen bonds with caspase‐8 amino acid residues (SER256 and HIS255). Together, these data suggest that NO‐donating ursolic acid–arylidene derivatives are potent apoptosis inducers in tumor cells.