Development of novel 9-O-substituted-13-octylberberine derivatives as potential anti-hepatocellular carcinoma agents. (31st December 2022)

• Record Type: Journal Article
• Authors: Chen, Jichao; Duan, Yiping; Yu, Xiaoxuan; Zhong, Jiarou; Bai, Jing; Li, Nian-Guang; Zhu, Zheying; Xu, Jinyi
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 37:Number 1(2022)
• Page Start: 2423
• Page End: 2433
• Publication Date: 2022-12-31
• Subjects: Hepatocellular carcinoma -- natural product -- berberine -- lipid-water partition coefficient -- mitochondrial dysfunction; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2022.2118268
• Languages: English
• ISSNs: 1475-6366

Abstract

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 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.