Synthesis and cytotoxicity evaluation of regioisomeric substituted N-phenyl-3′-(chrom-4-one-3-yl)-isoxazolidines: induction of apoptosis through a mitochondrial-dependent pathway

Abstract

Regio- and stereoselective 1,3-dipolar cycloadditions of C-(chrom-4-one-3-yl)-N-phenylnitrones (5) with different mono-substituted, disubstituted and cyclic dipolarophiles were carried out to obtain substituted N-phenyl-3′-(chrom-4-one-3-yl)-isoxazolidines (7a–p, 10a–c and 12a–c). Some of the obtained isoxazolidines display significant cytotoxicity against several human cancer cell lines. The preliminary bioassay results revealed that compound 10c showed higher cytotoxicity than paclitaxel against the A549 cell line with an IC₅₀ value of 0.7 μM. Compound 10c induces apoptosis through a mitochondrial-dependent pathway in human promyelocytic leukemia (HL-60) cells as revealed by induced apoptotic bodies' formation, DNA ladder, increased Sub-G₀ DNA fraction and loss of mitochondrial membrane potential (ΔΨ_m) in HL-60 cells.