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 <i>via</i> 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 <b>3a</b> exhibited the most potent cytotoxicity, with IC₅₀ values ranging from 0.03 to 0.63 µM. Research on the antitumor mechanism revealed that compound <b>3a</b> selectively inhibits the expression of glutathione peroxidase GPX4, inducing ferroptosis in A549 cells.