Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization

doi:10.1073/pnas.0503270102

Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization

^*Laboratory for Biosynthetic Chemistry, Pharmaceutical Sciences Division, and ^§University of Wisconsin National Cooperative Drug Discovery Group Program, School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705; ^†Keck University of Wisconsin Comprehensive Cancer Center Small Molecule Screening Facility, K6/569, 600 Highland Avenue, Madison, WI 53705; and ^‡X-Ray Crystallography Laboratory, Department of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, WI 53706

Edited by Kyriacos C. Nicolaou, The Scripps Research Institute, La Jolla, CA, and approved June 24, 2005 (received for review April 20, 2005)

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.

Footnotes

↵ ¶ To whom correspondence should be addressed. E-mail: jsthorson{at}pharmacy.wisc.edu.
Author contributions: J.M.L. and J.S.T. designed research; J.M.L., N.R.P., and I.A.G. performed research; J.M.L., N.R.P., I.A.G., F.M.H., and J.S.T. analyzed data; J.M.L. and J.S.T. wrote the paper; I.A.G. performed crystallography and analysis only; and F.M.H. performed cytotoxicity analysis and participated in discussion.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviation: DMF, dimethylformamide.
Data deposition: The atomic coordinates reported in this paper have been deposited in the Cambridge Crystallographic Data Centre, Cambridge CB2 1EZ, United Kingdom (CCDC reference nos. 269298 and 269299).