Abstract
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.
Highlights
Cancer has become the leading cause of human death worldwide and imposed tremendous health problem to human beings
Compound 3 was reacted with different substituted phenylhydrazines to afford a series of carbazole derivatives with different substituents on indole moieties (4a-j), which were converted to the corresponding N-bromoethyl derivatives 9a-j and N-(piperazin-1yl)ethyl derivatives 10a-j through similar two-step procedures
Similar relationships could be observed for compounds 7a-h and 8a-h. These results indicated that the introduction of alkyl, acyl or aryl substituents, especially bulky aryl groups on the nitrogen atom of piperazine moiety will significantly reduce the anticancer activity
Summary
Cancer has become the leading cause of human death worldwide and imposed tremendous health problem to human beings. FDA recently approved the combination of dabrafenib and trametinib for the treatment of BRAF-mutant metastatic melanoma, NSCLC and anaplastic thyroid cancer[26] These examples have highlighted the potential of MEK inhibitors as potential targeted anticancer drugs. QC2 showed moderate inhibitory activity in a preliminary screening of in vitro MEK1 inhibitory activity Based on these findings, the two compounds were subject to further structure modifications at the following sites: (i) the N-substituents on the piperazine moiety of the side chain; (ii) the length of the alkyl linker and (iii) the substituents on the indole benzene ring (Figure 2). The anticancer mechanisms of the active compounds will be extensively explored
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