2. Academic Validation
  3. Design, synthesis and biological evaluation of novel nitric oxide-donating protoberberine derivatives as antitumor agents

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

  • Eur J Med Chem. 2017 May 26:132:173-183. doi: 10.1016/j.ejmech.2017.03.027.
Jichao Chen 1,  Tianyu Wang 1,  Shengtao Xu 1,  Aijun Lin 1,  Hequan Yao 2,  Weijia Xie 1,  Zheying Zhu 3,  Jinyi Xu 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
  • 2 State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China. Electronic address: hyao@cpu.edu.cn.
  • 3 Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham NG7 2RD, UK. Electronic address: Zheying.Zhu@nottingham.ac.uk.
  • 4 State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China. Electronic address: jinyixu@china.com.
PMID: 28359045 DOI: 10.1016/j.ejmech.2017.03.027
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.

Keywords

Antitumor activity; Berberine; Hybrid compound; Nitric oxide (NO) donor; Palmatine.

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