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

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 IC 50 values...

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Bibliographic Details
Published in:Journal of enzyme inhibition and medicinal chemistry 2022-12, Vol.37 (1), p.2423-2433
Main Authors: Chen, Jichao, Duan, Yiping, Yu, Xiaoxuan, Zhong, Jiarou, Bai, Jing, Li, Nian-Guang, Zhu, Zheying, Xu, Jinyi
Format: Article
Language:English
Subjects:
Apoptosis
Berberine
Cancer therapies
Cell cycle
Cytotoxicity
Hepatocellular carcinoma
Hepatocytes
Hepatoma
Laboratories
lipid-water partition coefficient
Lipids
Liver cancer
Medicine
Mitochondria
mitochondrial dysfunction
natural product
Natural products
Pharmaceutical sciences
Pharmacy
Research Paper
Xenografts
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Summary: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 IC 50 values from 0.62 to 1.69 μM, which were much superior to berberine (IC 50 >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 in vivo 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.
ISSN:1475-6366
1475-6374
DOI:10.1080/14756366.2022.2118268