Development of novel 9- O -substituted-13-octylberberine derivatives as potential anti-hepatocellular carcinoma agents.
Jichao ChenYiping DuanXiaoxuan YuJiarou ZhongJing BaiNian-Guang LiZheying ZhuJinyi XuPublished in: Journal of enzyme inhibition and medicinal chemistry (2022)
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.
Keyphrases
- induced apoptosis
- cell cycle
- endoplasmic reticulum stress
- oxidative stress
- signaling pathway
- mouse model
- cell cycle arrest
- cell proliferation
- cell death
- endothelial cells
- molecular docking
- small molecule
- fatty acid
- high throughput
- single cell
- circulating tumor
- anti inflammatory
- molecular dynamics simulations
- human health
- liver injury