4.4 Article

Synthesis, Anticancer Evaluation and Molecular Docking of Hexahydroquinoline Derivatives as Mcl-1 Inhibitors and Apoptosis Inducers

期刊

ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY
卷 22, 期 11, 页码 2142-2155

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BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1871520621666211021133558

关键词

Hexahydroquinoline derivatives; NCI-60 panel screening; MTT assay; apoptosis; cell cycle analysis; Mcl-1 inhibition; caspase assay

资金

  1. Kadi Sarva Vishvavidhyalay, India [9/4/2019]

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This study synthesized new compounds and screened them for cytotoxicity. The active compound induced apoptosis by regulating the cell cycle, inhibiting the anti-apoptotic protein Mcl-1, and activating the pro-apoptotic proteins caspase-3 and caspase-9.
Background: Hexahydroquinoline as a small molecule was reported for good cytotoxicity and affinity towards Mcl-1. Hence, new compounds were explored as Mcl-1 inhibitors to be potent anticancer agents. Objective: Compounds were synthesized and screened for cytotoxicity. The active compound was evaluated for cell cycle analysis, Mcl-1 inhibition, caspase-3, and caspase-9 activation. Further compounds were docked with Mcl-1 to confirm the mechanism of cytotoxicity. Methods: Compounds were confirmed by spectral techniques and screened for cytotoxicity at National Cancer Institute (USA). The active derivatives were screened by SRB and MTT. In addition, the potent compound was studied for apoptosis and cell cycle analysis by PI staining, Mcl-1 inhibition by TR-FRET assay, and activation assay of caspase-3 and caspase-9 with the Elisa technique. Results: Compounds 6a and 6b exhibited the highest growth inhibition of 86.28% and 93.20% against SR and HOP-62, respectively. Compound 6a showed higher cytotoxicity (IC50 = 0.4 mu M) against THP-1 and HL-60. It showed 15-fold higher apoptosis compared to control by arresting cells at the Sub-G(1) in the cell cycle. It also showed a potent inhibition with IC50 of 1.5 mu M against the anti-apoptotic protein Mcl-1, which may induce apoptosis. Furthermore, apoptosis was evidenced by an increase in cleaved caspase-3 and caspase-9 to 4.20 and 3 folds, respectively higher than control. The docking score of compound 6a was in good agreement with the Mcl-1 inhibition assay. Conclusion: Compound 6a inhibited anti-apoptotic protein Mcl-1 and induced activation of pro-apoptotic proteins caspase-3 and caspase-9. These dual results suggested the mechanism of apoptosis and cytotoxicity.

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