Design, synthesis and biological evaluation of novel 9-N-substituted-13-alkylberberine derivatives from Chinese

Affiliations

• School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: chenjichao@njucm.edu.cn.
• State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
• Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding 071002, China.
• School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
• Division of Molecular Therapeutics & Formulation, School of Pharmacy, the University of Nottingham, University Park Campus, Nottingham NG7 2RD, UK.
• School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: liuehu2011@163.com.
• State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China. Electronic address: jinyixu@china.com.

PMID: 36640595 DOI: 10.1016/j.bmc.2023.117156

Abstract

A series of novel 9-N-substituted-13-alkylberberine derivatives from Chinese medicine were designed and synthesized with improved anti-hepatocellular carcinoma (HCC) activities. The optimal compound 4d showed strong activities against HepG2, Sk-Hep-1, Huh-7 and Hep3B cells with IC50values of 0.58-1.15 μM, which were superior to positive reference cisplatin. Interestingly, 4d exhibited over 40-fold more potent activity against cisplatin-resistant HepG2/DPP cells while showing lower cytotoxicity in normal LX-2 cells. The mechanism studies revealed 4d greatly stabilized G-quadruplex DNA leading to intracellular c-MYC expression downregulation, blocked G2/M-phase cell cycle by affecting related p-cdc25c, cdc2 and cyclin B1 expressions, and induced apoptosis by a ROS-promoted PI3K/Akt-mitochondrial pathway. Furthermore, 4d possessed good pharmacokinetic properties and significantly inhibited the tumor growth in the H22 liver cancer xenograft mouse model without obvious toxicity. Altogether, the remarkably biological profiles of 4d both in vitro and in vivo would make it a promising candidate for HCC therapy.

Keywords: Berberine; G-quadruplex DNA; Hepatocellular carcinoma; Mitochondrial dysfunction; PI3K/Akt pathway.