Design, Synthesis and Antitumor Evaluation of Novel Dehydroabietic Acid Derivatives Bearing an α,β-Unsaturated Ketone Moiety.

Abstract

A series of dehydroabietic acid (DHAA) derivatives containing α,β-unsaturated ketone moieties were designed, synthesized and evaluated as anticancer agents. The inhibitory activities of target compounds against SW480, HepG2, MDA-MB-231 human cancer cell lines and one normal hepatocyte cell L02 cells were estimated by methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay in vitro. The results indicated that the most promising compound 2g displayed the most significant effect against MDA-MB-231 cells with an IC₅₀ value of 8.62 µM, roughly 10-fold lower than that of parent compound DHAA and fourfold lower than that of 5-Fu. Mechanistic investigations showed that 2g efficiently arrested the cell cycle at the G1 phase and induced apoptosis, accompanied by the generation of intracellular reactive oxygen species (ROS), loss of mitochondrial membrane potential, and inhibition of the NF-κB signaling pathway. These results indicated that compound 2g might be a promising lead compound for further investigation.