化学
细胞周期蛋白依赖激酶1
顺铂
细胞凋亡
肝细胞癌
细胞毒性
体内
G2水电站
下调和上调
细胞周期
PI3K/AKT/mTOR通路
细胞生长
癌症研究
细胞周期蛋白B1
肝癌
药理学
毒性
蛋白激酶B
体外
生物化学
化疗
生物
内科学
医学
生物技术
有机化学
基因
作者
Jichao Chen,Yiping Duan,Kan Yang,Jiahe Wang,Junjie Yan,Chenglei Gu,Shanglong Wang,Zheying Zhu,E‐Hu Liu,Jinyi Xu
标识
DOI:10.1016/j.bmc.2023.117156
摘要
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.
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