Design, synthesis and biological evaluation of novel nitric oxidedonating protoberberine derivatives as antitumor agentsTools Chen, Jichao, Wang, Tianyu, Xu, Shengtao, Lin, Aijun, Yao, Hequan, Xie, Weijia, Zhu, Zheying and Xu, Jinyi (2017) Design, synthesis and biological evaluation of novel nitric oxidedonating protoberberine derivatives as antitumor agents. European Journal of Medicinal Chemistry, 132 . pp. 173-183. ISSN 0223-5234 Full text not available from this repository.AbstractA 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.
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