Combining cross-metathesis and activity-based protein profiling: New β-lactone motifs for targeting serine hydrolases

被引：23

作者：

Camara, Kaddy ^{[1
]}

Kamat, Siddhesh S. ^{[2
]}

Lasota, Celina C. ^{[1
]}

Cravatt, Benjamin F. ^{[2
]}

Howell, Amy R. ^{[1
]}

机构：

[1] Univ Connecticut, Dept Chem, Storrs, CT 06269 USA

[2] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92307 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 02期

基金：

美国国家卫生研究院; 美国国家科学基金会;

关键词：

beta-Lactones; Serine hydrolases; Cross metathesis; alpha-Methylene-beta-lactones; ABPP; FATTY-ACID SYNTHASE; ASYMMETRIC-SYNTHESIS; ENANTIOSELECTIVE SYNTHESES; GAMMA-BUTYROLACTONES; THIOESTERASE DOMAIN; INHIBITOR ORLISTAT; NATURAL-PRODUCT; GROWTH; ALPHA; CARBONYLATION;

D O I：

10.1016/j.bmcl.2014.11.038

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

beta-Lactones are a privileged structural motif as enzyme inhibitors and chemical probes, particularly for the inhibition of enzymes from the serine hydrolase class. Herein, we demonstrate that cross-metathesis (CM) of alpha-methylene-beta-lactones offers rapid access to structurally diverse, previously unexplored beta-lactones. Combining this approach with competitive activity-based protein profiling (ABPP) identified lead beta-lactone inhibitors/probes for several serine hydrolases, including disease-associated enzymes and enzymes of uncharacterized function. The structural diversity afforded by the alpha-methylene-beta-lactone scaffold thus expands the landscape of serine hydrolases that can be targeted by small-molecule inhibitors and should further the functional characterization of enzymes from this class through the optimization of target-selective probes. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：317 / 321

页数：5