Remodeling Natural Products: Chemistry and Serine Hydrolase Activity of a Rocaglate-Derived β‑Lactone

Flavaglines
are a class of natural products with potent insecticidal
and anticancer activities. β-Lactones are a privileged structural
motif found in both therapeutic agents and chemical probes. Herein,
we report the synthesis, unexpected light-driven di-epimerization,
and activity-based protein profiling of a novel rocaglate-derived
β-lactone. In addition to in vitro inhibition
of the serine hydrolases ABHD10 and ACOT1/2, the most potent β-lactone
enantiomer was also found to inhibit these enzymes, as well as the
serine peptidases CTSA and SCPEP1, in PC3 cells.