Engineering an Antibiotic to Fight Cancer: Optimization of the Novobiocin Scaffold to Produce Anti-Proliferative Agents

Zhao, Huiping; Donnelly, Alison C.; Kusuma, Bhaskar Reddy; Brandt, Gary E. L.; Brown, Douglas; Rajewski, Roger A.; Bielhauer, George; Holzbeierlein, Jeffery M.; Cohen, Mark S.; Blagg, Brian S. J.

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Issue Date

2011-06-09

Author

Zhao, Huiping

Donnelly, Alison C.

Kusuma, Bhaskar Reddy

Brandt, Gary E. L.

Brown, Douglas

Rajewski, Roger A.

Bielhauer, George

Holzbeierlein, Jeffery M.

Cohen, Mark S.

Blagg, Brian S. J.

Publisher

American Chemical Society

Type

Article

Article Version

Scholarly/refereed, author accepted manuscript

Rights

This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm200148p.

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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 mid-nanomolar activity against a panel of cancer cell lines and serve as lead compounds that manifest their activities through Hsp90 inhibition.

Citation

Zhao, H., Donnelly, A. C., Kusuma, B. R., Brandt, G. E. L., Brown, D., Rajewski, R. A., … Blagg, B. S. J. (2011). Engineering an Antibiotic to Fight Cancer: Optimization of the Novobiocin Scaffold to Produce Anti-Proliferative Agents. Journal of Medicinal Chemistry, 54(11), 3839–3853. http://doi.org/10.1021/jm200148p

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