Synthesis and biological evaluation of novel N-(piperazin-1-yl)alkyl-1H-dibenzo[a,c]carbazole derivatives of dehydroabietic acid as potential MEK inhibitors.
Hao ChenChao QiaoTing-Ting MiaoA-Liang LiWen-Yan WangZi-Hui YangPublished in: Journal of enzyme inhibition and medicinal chemistry (2020)
In this paper, a series of novel 1H-dibenzo[a,c]carbazole derivatives of dehydroabietic acid bearing different N-(piperazin-1-yl)alkyl side chains were designed, synthesised and evaluated for their in vitro anticancer activities against three human hepatocarcinoma cell lines (SMMC-7721, HepG2 and Hep3B). Among them, compound 10g exhibited the most potent activity against three cancer cell lines with IC50 values of 1.39 ± 0.13, 0.51 ± 0.09 and 0.73 ± 0.08 µM, respectively. In the kinase inhibition assay, compound 10g could significantly inhibit MEK1 kinase activity with IC50 of 0.11 ± 0.02 µM, which was confirmed by western blot analysis and molecular docking study. In addition, compound 10g 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 10g could be a potent MEK inhibitor and a promising anticancer agent worthy of further investigations.
Keyphrases
- molecular docking
- oxidative stress
- pi k akt
- cell death
- ionic liquid
- endothelial cells
- molecular dynamics simulations
- reactive oxygen species
- protein kinase
- papillary thyroid
- tyrosine kinase
- cell cycle arrest
- high throughput
- endoplasmic reticulum stress
- structure activity relationship
- cell proliferation
- young adults
- squamous cell carcinoma