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A Direct Comparison of the Anticancer Activities of Digitoxin MeON-Neoglycosides and O -Glycosides

2010; American Chemical Society; Volume: 1; Issue: 7 Linguagem: Inglês

10.1021/ml1000933

1948-5875

Anand Krishnan V. Iyer, Maoquan Zhou, Neelam Azad, Hosam A. Elbaz, Leo Wang, Derek K. Rogalsky, Yon Rojanasakul, George A. O’Doherty, Joseph M. Langenhan,

ATP Synthase and ATPases Research

Digitoxin is a cardiac glycoside currently being investigated for potential use in oncology. While a number of structure-activity relationship studies have been conducted, an investigation of anticancer activity as a function of oligosaccharide chain length has not yet been performed. We generated mono-, di-, and tri-O-digitoxoside derivatives of digitoxin and compared their activity to the corresponding MeON-neoglycosides. Both classes of cardenolide derivatives display comparable oligosaccharide chain length-dependent cytotoxicity toward human cancer cell lines. Further investigation revealed that both classes of compounds induce caspase-9-mediated apoptosis in non-small cell lung cancer cells (NCI-H460). Since O-glycosides and MeON-neoglycosides share a similar mode of action, the convenience of MeON-neoglycosylation could be exploited in future SAR work to rapidly survey large numbers of carbohydrates to prioritize selected O-glycoside candidates for traditional synthesis.