Design, synthesis and biological evaluation of novel nitric oxide-donating protoberberine derivatives as antitumor agents

• Published in: European journal of medicinal chemistry 2017-05, Vol.132, p.173-183
• Main Authors: Chen, Jichao, Wang, Tianyu, Xu, Shengtao, Lin, Aijun, Yao, Hequan, Xie, Weijia, Zhu, Zheying, Xu, Jinyi
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis - drug effects; Berberine; Berberine Alkaloids - chemistry; Berberine Alkaloids - pharmacology; Carcinoma, Hepatocellular - drug therapy; Cell Cycle Checkpoints - drug effects; Hep G2 Cells; Heterografts; Humans; Hybrid compound; Liver Neoplasms - drug therapy; Mice; Nitric oxide (NO) donor; Nitric Oxide - metabolism; Palmatine
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.03.027

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 IC50 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. [Display omitted] •Eighteen novel NO-donating protoberberine derivatives were synthesized.•Most compounds showed significantly enhanced in vitro anti-proliferative activity.•15a exhibited good selectivity between tumor cells and normal liver LO-2 cells.•The antitumor activity of 15a in HepG2 cells was diminished by an NO scavenger.•15a effectively inhibited liver tumor growth in an in vivo mouse model.