1. Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization.
- Author
-
Langenhan JM, Peters NR, Guzei IA, Hoffmann FM, and Thorson JS
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Cardiac Glycosides chemical synthesis, Cardiac Glycosides pharmacology, Cell Line, Tumor, Digitoxin analogs & derivatives, Digitoxin chemical synthesis, Digitoxin chemistry, Digitoxin pharmacology, Drug Design, Drug Screening Assays, Antitumor, Drug Stability, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Glycosylation, Humans, Hydrolysis, Mice, Molecular Structure, Sodium-Potassium-Exchanging ATPase antagonists & inhibitors, Antineoplastic Agents chemistry, Cardiac Glycosides chemistry
- Abstract
Glycosylated natural products are reliable platforms for the development of many front-line drugs, yet our understanding of the relationship between attached sugars and biological activity is limited by the availability of convenient glycosylation methods. When a universal chemical glycosylation method that employs reducing sugars and requires no protection or activation is used, the glycorandomization of digitoxin leads to analogs that display significantly enhanced potency and tumor specificity and suggests a divergent mechanistic relationship between cardiac glycoside-induced cytotoxicity and Na+/K+-ATPase inhibition. This report highlights the remarkable advantages of glycorandomization as a powerful tool in glycobiology and drug discovery.
- Published
- 2005
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