期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 1, 期 7, 页码 311-315出版社
AMER CHEMICAL SOC
DOI: 10.1021/ml100070r
关键词
Heat shock protein 90; Hsp90 inhibitors; novobiocin; stucture-activity relationships; breast cancer
资金
- NIH/NCI [CA120458]
- NATIONAL CANCER INSTITUTE [U01CA120458] Funding Source: NIH RePORTER
Structural modifications to the coumarin core and benzamide side chain of novobiocin have successfully transformed the natural product from a selective DNA gyrase inhibitor into a potent inhibitor of the Hsp90 C-terminus. However, no structure-activity relationship studies have been conducted on the noviose appendage, which represents the rate limiting synthon in the preparation of analogues. Therefore, a series of sugar mimics and nonsugar derivatives were synthesized and evaluated to identify simplified compounds that exhibit Hsp90 inhibition. Evaluation against two breast cancer cell lines demonstrated that replacement of the stereochemical complex noviose with simplified alkyl amines increased antiproliferative activity, resulting in novobiocin analogues that manifest IC50 values in the midnanomolar range.
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