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Design, synthesis and biological evaluation of novel 9-N-substituted-13-alkylberberine derivatives from Chinese medicine as anti-hepatocellular carcinoma agents

Chen, Jichao; Duan, Yiping; Yang, Kan; Wang, Jiahe; Yan, Junjie; Gu, Chenglei; Wang, Shanglong; Zhu, Zheying; Liu, E-Hu; Xu, Jinyi

Design, synthesis and biological evaluation of novel 9-N-substituted-13-alkylberberine derivatives from Chinese medicine as anti-hepatocellular carcinoma agents Thumbnail


Authors

Jichao Chen

Yiping Duan

Kan Yang

Jiahe Wang

Junjie Yan

Chenglei Gu

Shanglong Wang

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

E-Hu Liu

Jinyi Xu



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 IC values 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. [Abstract copyright: Copyright © 2023 Elsevier Ltd. All rights reserved.]

Citation

Chen, J., Duan, Y., Yang, K., Wang, J., Yan, J., Gu, C., …Xu, J. (2023). Design, synthesis and biological evaluation of novel 9-N-substituted-13-alkylberberine derivatives from Chinese medicine as anti-hepatocellular carcinoma agents. Bioorganic and Medicinal Chemistry, 79, Article 117156. https://doi.org/10.1016/j.bmc.2023.117156

Journal Article Type Article
Acceptance Date Jan 6, 2023
Online Publication Date Jan 8, 2023
Publication Date Feb 1, 2023
Deposit Date Feb 10, 2023
Publicly Available Date Mar 29, 2024
Journal Bioorganic and Medicinal Chemistry
Print ISSN 0968-0896
Electronic ISSN 1464-3391
Peer Reviewed Peer Reviewed
Volume 79
Article Number 117156
DOI https://doi.org/10.1016/j.bmc.2023.117156
Keywords G-quadruplex DNA, PI3K/Akt pathway, Berberine, Mitochondrial dysfunction, Hepatocellular carcinoma
Public URL https://nottingham-repository.worktribe.com/output/16789796
Publisher URL https://www.sciencedirect.com/science/article/pii/S0968089623000044?via%3Dihub

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