期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 25, 期 2, 页码 317-321出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2014.11.038
关键词
beta-Lactones; Serine hydrolases; Cross metathesis; alpha-Methylene-beta-lactones; ABPP
资金
- National Science Foundation [CHE-0111522, CHE-1048717]
- US National Institutes of Health [DA033760]
- 9th Irving S. Sigal Postdoctoral Fellowship, American Chemical Society
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.
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