Development of novel 9-O-substituted-13-octylberberine derivatives as potential anti-hepatocellular carcinoma agents

Chen, Jichao; Duan, Yiping; Yu, Xiaoxuan; Zhong, Jiarou; Bai, Jing; Li, Nian Guang; Zhu, Zheying; Xu, Jinyi

Abstract

A series of novel 9-O-substituted-13-octylberberine derivatives were designed, synthesised and evaluated for their anti-hepatocellular carcinoma (HCC) activities. Compound 6k showed the strongest activity against three human hepatoma cells including HepG2, Sk-Hep-1 and Huh-7 cells with IC50 values from 0.62 to 1.69 μM, which were much superior to berberine (IC50 >50 μM). More importantly, 6k exhibited lower cytotoxicity against normal hepatocytes L-02 with good lipid-water partition properties. The mechanism studies revealed that 6k caused G2/M phase arrest of the cell cycle, stabilised G-quadruplex DNA, and induced apoptosis via a mitochondrial apoptotic pathway. Finally, the invivo anti-HCC activity of 6k was validated in the H22 liver cancer xenograft mouse model. Collectively, the current study would provide a new insight into the discovery of novel, safe and effective anti-HCC agents.

Citation

Chen, J., Duan, Y., Yu, X., Zhong, J., Bai, J., Li, N. G., …Xu, J. (2022). Development of novel 9-O-substituted-13-octylberberine derivatives as potential anti-hepatocellular carcinoma agents. Journal of Enzyme Inhibition and Medicinal Chemistry, 37(1), 2423-2433. https://doi.org/10.1080/14756366.2022.2118268

• Journal Article Type: Article
• Acceptance Date: Aug 21, 2022
• Online Publication Date: Sep 6, 2022
• Publication Date: Dec 1, 2022
• Deposit Date: Sep 10, 2022
• Publicly Available Date: Sep 13, 2022
• Journal: Journal of enzyme inhibition and medicinal chemistry
• Print ISSN: 1475-6366
• Electronic ISSN: 1475-6374
• Publisher: Informa Healthcare
• Peer Reviewed: Peer Reviewed
• Volume: 37
• Issue: 1
• Pages: 2423-2433
• DOI: https://doi.org/10.1080/14756366.2022.2118268
• Keywords: Drug Discovery; Pharmacology; General Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/10920295
• Publisher URL: https://www.tandfonline.com/doi/full/10.1080/14756366.2022.2118268