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

被引：158

作者：

Zhao, Huiping ^{[1
]}

Donnelly, Alison C. ^{[1
]}

Kusuma, Bhaskar R. ^{[1
]}

Brandt, Gary E. L. ^{[1
]}

Brown, Douglas ^{[2
]}

Rajewski, Roger A. ^{[3
]}

Vielhauer, George ^{[4
]}

Holzbeierlein, Jeffrey ^{[4
]}

Cohen, Mark S. ^{[4
]}

Blagg, Brian S. J. ^{[1
]}

机构：

[1] Univ Kansas, Dept Med Chem, Lawrence, KS 66045 USA

[2] Univ Kansas, Biotechnol Innovat & Optimizat Ctr, Lawrence, KS 66047 USA

[3] Univ Kansas, Dept Pharmaceut Chem, Lawrence, KS 66047 USA

[4] Univ Kansas, Med Ctr, Dept Urol, Kansas City, KS 66160 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 11期

关键词：

DNA GYRASE; HSP90; INHIBITORS; COUMARIN INHIBITORS; CHAPERONE; ANALOGS; BINDING; HEAT-SHOCK-PROTEIN-90; MODULATION; TARGET;

D O I：

10.1021/jm200148p

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 similar to 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.

引用

页码：3839 / 3853

页数：15

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