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
  • 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.