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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:25

Article

Camara, Kaddy¹  Kamat, Siddhesh S.²  Lasota, Celina C.¹  Cravatt, Benjamin F.²  Howell, Amy R.¹ 

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

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

关键词: beta-Lactones;    Serine hydrolases;    Cross metathesis;    alpha-Methylene-beta-lactones;    ABPP;   

DOI  :  10.1016/j.bmcl.2014.11.038

来源: Elsevier

【 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.

【 授权许可】

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