Chen Jichao, Wang Tianyu, Xu Shengtao, Lin Aijun, Yao Hequan, Xie Weijia, Zhu Zheying, Xu Jinyi
State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
Eur J Med Chem. 2017 May 26;132:173-183. doi: 10.1016/j.ejmech.2017.03.027. Epub 2017 Mar 18.
A novel class of NO-donating protoberberine derivatives were synthesized and initially evaluated for their anti-hepatocellular carcinoma activities. Most of the compounds exhibited more potent activity against HepG2 cells than parent compounds berberine and palmatine. In particular, compound 15a exerted the strongest activity with an IC value of 1.36 μM. Moreover, most compounds released moderate levels of NO in vitro, and the antitumor activity of 15a in HepG2 cells was remarkably diminished by an NO scavenger. Interestingly, compound 15a displayed a broad-spectrum antitumor efficacy and possessed good selectivity between tumor cells (HepG2, SMMC-7721, HCT-116, HL-60) and normal liver LO-2 cells. The mechanism studies revealed that 15a blocked the G2 phase of the cell cycle and induced apoptosis of HepG2 cells by mitochondrial depolarization. Furthermore, 15a inhibited tumor growth in H22 liver cancer xenograft mouse model by 62.5% (w/w), which was significantly superior to parent compound palmatine (41.6%, w/w). Overall, the current study may provide a new approach for the discovery of novel antitumor agents.
合成了一类新型的一氧化氮供体型原小檗碱衍生物，并初步评估了它们的抗肝细胞癌活性。大多数化合物对HepG2细胞的活性比母体化合物黄连素和巴马汀更强。特别是，化合物15a表现出最强的活性，IC值为1.36 μM。此外，大多数化合物在体外释放中等水平的一氧化氮，并且一氧化氮清除剂显著降低了15a在HepG2细胞中的抗肿瘤活性。有趣的是，化合物15a显示出广谱抗肿瘤功效，并且在肿瘤细胞（HepG2、SMMC-7721、HCT-116、HL-60）和正常肝LO-2细胞之间具有良好的选择性。机制研究表明，15a阻断细胞周期的G2期，并通过线粒体去极化诱导HepG2细胞凋亡。此外，15a在H22肝癌异种移植小鼠模型中抑制肿瘤生长62.5%（w/w），显著优于母体化合物巴马汀（41.6%，w/w）。总体而言，当前研究可能为发现新型抗肿瘤药物提供一种新方法。
