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.
Department of Chemistry, Center for Chemical Methodology and Library Development (CMLD-BU), Boston University , 590 Commonwealth Avenue Boston, Massachusetts 02215, United States.
Neil J
NJ
Lajkiewicz
Armand B
AB
Cognetta
Micah J
MJ
Niphakis
Benjamin F
BF
Cravatt
John A
JA
Porco
D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry*; D001688:Biological Products / Q000737:chemistry*; D003500:Cyclization; D006867:Hydrolases / Q000737:chemistry*; D007783:Lactones / Q000737:chemistry*; D015394:Molecular Structure; D012694:Serine / Q000737:chemistry*; D013237:Stereoisomerism
D001572:Benzofurans; D001688:Biological Products; D007783:Lactones; C483989:methyl rocaglate; D012694:Serine; D006867:Hydrolases