Synthesis of C3-Neoglycosides of digoxigenin and their anticancer activities.

Cardiac glycosides exhibit significant anticancer effects and the glycosyl substitution at C 3 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 3 - O -neoglycosides and C 3 -MeO N -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 4 ) oxidation and 6-aminocaproic acid hydrolysis. The SAR analysis revealed that C 3 - O -neoglycosides of digoxigenin exhibited stronger cytotoxicity and induction of Nur77 expression of tumor cells than C 3 -MeO N -neoglycosides. Also, 3 β - O -glycosides exhibited stronger anticancer effects than 3 α - O -glycosides. Among them, 3 β - 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.