Fluorinated 4-Methylideneisoxazolidin-5-ones: Synthesis and Apoptosis-Inducing Antiproliferative Activity

Abstract

Sesquiterpene lactones, featuring an α-methylene-γ-lactone moiety, serve as lead compounds for anticancer drug development. Their nitrogen-containing analogues, namely, 4-methylideneisoxazolidin-5-ones, have attracted special attention for their promising anticancer properties. Installing a fluorine atom at the exocyclic double bond of these analogues is highly desirable for improving metabolic stability, bioavailability, and lipophilicity, yet this has not been achieved to date due to the lack of an efficient synthetic method, representing a major obstacle in drug development. Herein, we report a Ni(II)-catalyzed [3 + 2] cycloaddition/rearrangement cascade reaction of gem-difluorocyclopropenyl imides and N-Bn nitrones, providing direct access to (Z)-4-(monofluoroalkylidene)isoxazolidin-5-ones in good to high yields. The compounds 3aw and 3as show promising in vitro antiproliferative activity against mouse mammary carcinoma 4T1 cells (IC50 = 6.85 ± 0.43 μM) and human lung carcinoma A549 cells (IC50 = 10.34 ± 0.07 μM), respectively. Mechanistic studies reveal that the activity occurs via a mitochondria-mediated intrinsic apoptotic pathway.