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Design, synthesis and biological evaluation of novel nitric oxidedonating protoberberine derivatives as antitumor agents

Chen, Jichao; Wang, Tianyu; Xu, Shengtao; Lin, Aijun; Yao, Hequan; Xie, Weijia; Zhu, Zheying; Xu, Jinyi

Authors

Jichao Chen

Tianyu Wang

Shengtao Xu

Aijun Lin

Hequan Yao

Weijia Xie

ZHEYING ZHU Zheying.Zhu@nottingham.ac.uk
Associate Professor in International Pharmacy and Traditional Medicines

Jinyi Xu



Abstract

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.

Journal Article Type Article
Publication Date May 26, 2017
Journal European Journal of Medicinal Chemistry
Print ISSN 0223-5234
Electronic ISSN 0223-5234
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 132
APA6 Citation Chen, J., Wang, T., Xu, S., Lin, A., Yao, H., Xie, W., …Xu, J. (2017). Design, synthesis and biological evaluation of novel nitric oxidedonating protoberberine derivatives as antitumor agents. European Journal of Medicinal Chemistry, 132, doi:10.1016/j.ejmech.2017.03.027
DOI https://doi.org/10.1016/j.ejmech.2017.03.027
Keywords Berberine; Palmatine; Nitric oxide (NO) donor; Hybrid compound; Antitumor activity
Publisher URL http://www.sciencedirect.com/science/article/pii/S0223523417301848
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf
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