Remarkable Stereospecific Conjugate Additions to the Hsp90 Inhibitor Celastrol

被引：46

作者：

Klaic, Lada ^{[1
]}

Trippier, Paul C. ^{[1
]}

Mishra, Rama K. ^{[2
]}

Morimoto, Richard I. ^{[3
]}

Silverman, Richard B. ^{[1
,2
,3
,4
]}

机构：

[1] Northwestern Univ, Dept Chem, Evanston, IL 60208 USA

[2] Northwestern Univ, Ctr Mol Innovat & Drug Discovery, Evanston, IL 60208 USA

[3] Northwestern Univ, Dept Mol Biosci, Evanston, IL 60208 USA

[4] Northwestern Univ, Chem Life Proc Inst, Evanston, IL 60208 USA

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2011年 / 133卷 / 49期

基金：

美国国家卫生研究院;

关键词：

HEAT-SHOCK; COMPLEX; CHAPERONE; ACID; AGGREGATION; ANTIOXIDANT; PRISTIMERIN;

D O I：

10.1021/ja208359a

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Celastrol, an important natural product and Hsp90 inhibitor with a wide range of biological and medical activities and broad use as a biological probe, acts by an as yet undetermined mode of action. It is known to undergo Michael additions with biological sulfur nucleophiles. Here it is demonstrated that nucleophiles add to the pharmacophore of celastrol in a remarkable stereospecific manner. Extensive characterization of the addition products has been obtained using NMR spectrometry, nuclear Overhauser effects, and density functional theory to determine facial selectivity and gain insight into the orbital interactions of the reactive centers. This stereospecificity of celastrol may be important to its protein target selectivity.

引用

页码：19634 / 19637

页数：4

共 39 条

[1] Preclinical studies of celastrol and acetyl lsogambogic acid in melanoma [J].