Chen Jichao, Duan Yiping, Yang Kan, Wang Jiahe, Yan Junjie, Gu Chenglei, Wang Shanglong, Zhu Zheying, Liu E-Hu, Xu Jinyi
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
Bioorg Med Chem. 2023 Feb 1;79:117156. doi: 10.1016/j.bmc.2023.117156. Epub 2023 Jan 8.
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.
设计并合成了一系列源自中药的新型9-N-取代-13-烷基小檗碱衍生物，其抗肝细胞癌（HCC）活性有所提高。最优化合物4d对HepG2、Sk-Hep-1、Huh-7和Hep3B细胞表现出较强活性，IC值为0.58 - 1.15 μM，优于阳性对照顺铂。有趣的是，4d对顺铂耐药的HepG2/DPP细胞的活性比顺铂高40多倍，而在正常LX-2细胞中细胞毒性较低。机制研究表明，4d能极大地稳定G-四链体DNA，导致细胞内c-MYC表达下调，通过影响相关的p-cdc25c、cdc2和细胞周期蛋白B1的表达阻断G2/M期细胞周期，并通过ROS促进的PI3K/Akt-线粒体途径诱导细胞凋亡。此外，4d具有良好的药代动力学性质，在H22肝癌异种移植小鼠模型中显著抑制肿瘤生长，且无明显毒性。总之，4d在体外和体内均具有显著的生物学特性，使其成为治疗HCC的有前途的候选药物。
