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Combining cross-metathesis and activity-based protein profiling: new ?-lactone motifs for targeting serine hydrolases.

ABSTRACT: ?-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 ?-methylene-?-lactones offers rapid access to structurally diverse, previously unexplored ?-lactones. Combining this approach with competitive activity-based protein profiling (ABPP) identified lead ?-lactone inhibitors/probes for several serine hydrolases, including disease-associated enzymes and enzymes of uncharacterized function. The structural diversity afforded by the ?-methylene-?-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.

SUBMITTER: Camara K

PROVIDER: S-EPMC4279111 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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

Camara Kaddy K Kamat Siddhesh S SS Lasota Celina C CC Cravatt Benjamin F BF Howell Amy R AR

Bioorganic & medicinal chemistry letters 20150101 2

β-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 α-methylene-β-lactones offers rapid access to structurally diverse, previously unexplored β-lactones. Combining this approach with competitive activity-based protein profiling (ABPP) identified lead β-lactone inhibitors/probes for several serine hydrolases, including disease-associat ...[more]

PMID: 25541002

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