Combining cross-metathesis and activity-based protein profiling: New β-lactone motifs for targeting serine hydrolases. Issue 2 (15th January 2015)

• Record Type: Journal Article
• Authors: Camara, Kaddy; Kamat, Siddhesh S.; Lasota, Celina C.; Cravatt, Benjamin F.; Howell, Amy R.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 2(2015)
• Page Start: 317
• Page End: 321
• Publication Date: 2015-01-15
• Subjects: β-Lactones -- Serine hydrolases -- Cross metathesis -- α-Methylene-β-lactones -- ABPP; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2014.11.038
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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-associated enzymes and enzymes of uncharacterized function. The structural diversity afforded by the α-methylene-β-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.