Synthesis and biological evaluation of novel -(piperazin-1-yl)alkyl-1-dibenzo[,]carbazole derivatives of dehydroabietic acid as potential MEK inhibitors.

In this paper, a series of novel 1-dibenzo[,]carbazole derivatives of dehydroabietic acid bearing different -(piperazin-1-yl)alkyl side chains were designed, synthesised and evaluated for their anticancer activities against three human hepatocarcinoma cell lines (SMMC-7721, HepG2 and Hep3B). Among them, compound exhibited the most potent activity against three cancer cell lines with IC values of 1.39 ± 0.13, 0.51 ± 0.09 and 0.73 ± 0.08 µM, respectively. In the kinase inhibition assay, compound could significantly inhibit MEK1 kinase activity with IC of 0.11 ± 0.02 µM, which was confirmed by western blot analysis and molecular docking study. In addition, compound could elevate the intracellular ROS levels, decrease mitochondrial membrane potential, destroy the cell membrane integrity, and finally lead to the oncosis and apoptosis of HepG2 cells. Therefore, compound could be a potent MEK inhibitor and a promising anticancer agent worthy of further investigations.