Synthesis of C-Neoglycosides of digoxigenin and their anticancer activities.

Cardiac glycosides exhibit significant anticancer effects and the glycosyl substitution at C position of digoxigenin is pivotal for their biological activity. In order to study the structure-activity relationship (SAR) of cardiac glycosides toward cancers and explore more potent anticancer agents, a series of C-O-neoglycosides and C-MeON-neoglycosides of digoxigenin were synthesized by the Koenigs-Knorr and neoglycosylation method, respectively. In addition, digoxigenin bisdigitoxoside and monodigitoxoside were prepared from digoxin by sodium periodate (NaIO) oxidation and 6-aminocaproic acid hydrolysis. The SAR analysis revealed that C-O-neoglycosides of digoxigenin exhibited stronger cytotoxicity and induction of Nur77 expression of tumor cells than C-MeON-neoglycosides. Also, 3β-O-glycosides exhibited stronger anticancer effects than 3α-O-glycosides. Among them, 3β-O-(β-l-fucopyranosyl)-digoxigenin (3i) showed the highest activity on induction of Nur77 expression and translocation from the nucleus to cytoplasm, leading to cancer cell apoptosis.