Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization.
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.
Langenhan
Joseph M
JM
Laboratory for Biosynthetic Chemistry, Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin, Madison, WI 53705, USA.
Peters
Noël R
NR
Guzei
Ilia A
IA
Hoffmann
F Michael
FM
Thorson
Jon S
JS
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002301:Cardiac Glycosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004074:Digitoxin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006031:Glycosylation; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D015394:Molecular Structure; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D002301:Cardiac Glycosides; D004791:Enzyme Inhibitors; D004074:Digitoxin; D000254:Sodium-Potassium-Exchanging ATPase