Design, synthesis and biological evaluation of novel 9-N-substituted-13-alkylberberine derivatives from Chinese medicine as anti-hepatocellular carcinoma agents. (1st February 2023)

• Record Type: Journal Article
• Authors: Chen, Jichao; Duan, Yiping; Yang, Kan; Wang, Jiahe; Yan, Junjie; Gu, Chenglei; Wang, Shanglong; Zhu, Zheying; Liu, E-Hu; Xu, Jinyi
• Is Part Of: Bioorganic & medicinal chemistry. Volume 79(2023)
• Publication Date: 2023-02-01
• Subjects: Hepatocellular carcinoma -- Berberine -- G-quadruplex DNA -- Mitochondrial dysfunction -- PI3K/Akt pathway; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2023.117156
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Novel berberine derivatives were synthesized with improved anti-HCC activity. 4d showed selective cytotoxicity against hepatoma cell lines including resistant cells. 4d greatly stabilized G-quadruplex DNA with higher affinity over duplex DNA. 4d induced apoptosis through a ROS-promoted PI3K/Akt-mitochondrial pathway. 4d suppressed tumor growth in xenograft mouse model with good pharmacokinetic properties. 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 IC50 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.