Engineering an antibiotic to fight cancer: optimization of the novobiocin scaffold to produce anti-proliferative agents

J Med Chem. 2011 Jun 9;54(11):3839-53. doi: 10.1021/jm200148p.

Huiping Zhao ¹, Alison C Donnelly, Bhaskar R Kusuma, Gary E L Brandt, Douglas Brown, Roger A Rajewski, George Vielhauer, Jeffrey Holzbeierlein, Mark S Cohen, Brian S J Blagg

Affiliations

Affiliation

1 Department of Medicinal Chemistry, The University of Kansas, Lawrence, KS 66045-7563, USA.

PMID: 21553822 DOI: 10.1021/jm200148p

Abstract

Development of the DNA gyrase inhibitor, novobiocin, into a selective HSP90 Inhibitor was accomplished through structural modifications to the amide side chain, coumarin ring, and sugar moiety. These species exhibit ∼700-fold improved anti-proliferative activity versus the natural product as evaluated by cellular efficacies against breast, colon, prostate, lung, and other Cancer cell lines. Utilization of structure-activity relationships established for three novobiocin synthons produced optimized scaffolds, which manifest midnanomolar activity against a panel of Cancer cell lines and serve as lead compounds that manifest their activities through HSP90 inhibition.

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