Synthesis and biological evaluation of RON-neoglycosides as tumor cytotoxins |
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Authors: | Langenhan Joseph M Endo Matthew M Engle Jeffrey M Fukumoto Liane L Rogalsky Derek R Slevin Lauren K Fay Lindsay R Lucker Ryan W Rohlfing James R Smith Kyle R Tjaden Anja E Werner Halina M |
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Affiliation: | Department of Chemistry, Seattle University, Seattle, WA 98122, USA |
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Abstract: | Cardenolides such as digitoxin have been shown to inhibit cancer cell growth, to reduce cancer metastasis, and to induce apoptosis in tumor cells. Among the most potent digitoxin-based cytotoxins identified to date are MeON-neoglycosides generated via oxyamine neoglycosylation. Here, we report our studies of oxyamine neoglycosylation aimed at facilitating the elucidation of linkage-diversified digitoxin neoglycoside structure–activity relationships. We identified conditions suitable for the convenient synthesis of digitoxin neoglycosides and found that sugar structure, rather than RON-glycosidic linkage, exerts the strongest influence on neoglycoside yield and stereochemistry. We synthesized a library of digitoxin neoglycosides and assessed their cytotoxicity against eight human cancer cell lines. Consistent with previous findings, our data show that the structure of RON-neoglycosidic linkages influences both the potency and selectivity of digitoxin neoglycosides. |
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Keywords: | Glycoconjugate Glycosylalkoxylamines Hydrolysis rates Cardenolides Digitoxin |
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