Thioether and ether derivatives of diphyllin: synthesis and inducing tumor ferroptosis activity

A series of nine diphyllin thioether and four ether derivatives were designed and successfully synthesised via epoxide nucleophilic ring-opening reaction. These compounds demonstrated pronounced cytotoxic activity against the human cancer cell lines HepG2, HCT-15, and A549. Notably, thioether derivative 3a exhibited the most potent cytotoxicity, with IC50 values ranging from 0.03 to 0.63 µM. Research on the antitumor mechanism revealed that compound 3a selectively inhibits the expression of glutathione peroxidase GPX4, inducing ferroptosis in A549 cells.