Synthesis and anticancer properties of 3-methylene-4-(2-oxoalkyl)-3,4-dihydrocoumarins

Abstract

A simple and general strategy for the synthesis of 3-methylene-4-(2-oxoalkyl)-3,4-dihydrocoumarins has been developed. The elaborated synthetic protocol includes 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD)- or Cs₂CO₃-promoted conjugate addition of enolizable ketones to 3-(diethoxyphosphoryl)coumarins followed by Horner–Wadsworth–Emmons reaction of the resulting 3-diethoxyphosphoryl-4-(2-oxoalkyl)-3,4-dihydrocoumarins with formaldehyde. For prochiral ketones, the corresponding α-methylene-δ-lactones were obtained as single syn-diastereoisomers. All α-methylene-δ-lactones were evaluated in vitro for their cytotoxic activity against two human leukemia cell lines, HL-60 and NALM-6, as well as the MCF-7 breast cancer cell line. One selected compound, 13h, was further tested in order to elucidate the mechanism behind its cytotoxic effect. In MCF-7 cells, this compound was shown to induce subG0/G1 cell cycle arrest, increased Bax and decreased Bcl-2 mRNA levels, and cause the dissipation of the mitochondrial membrane potential which indicated that it induced the intrinsic pathway of apoptosis.