1. Academic Validation
  2. Design, synthesis and anti-hepatocellular carcinoma activity of 3-arylisoquinoline alkaloids

Design, synthesis and anti-hepatocellular carcinoma activity of 3-arylisoquinoline alkaloids

  • Eur J Med Chem. 2022 Jan 15;228:113985. doi: 10.1016/j.ejmech.2021.113985.
Xuemei Deng 1 Tian Luo 1 Zhao Li 1 Huaixiu Wen 2 Honghua Zhang 1 Xiaoyan Yang 3 Fang Lei 1 Dan Liu 1 Tao Shi 1 Quanyi Zhao 1 Zhen Wang 4
Affiliations

Affiliations

  • 1 School of Pharmacy, Lanzhou University, Lanzhou, 730000, China.
  • 2 Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences and Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Xining, 810008, PR China.
  • 3 School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
  • 4 School of Pharmacy, Lanzhou University, Lanzhou, 730000, China; School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: zhenw@lzu.edu.cn.
Abstract

This article describes the syntheses and biological activity of five 3-arylisoquinoline Natural Products corydamine (1), N-formyl Corydamine (2), hypecumine (3), Decumbenine B (XW) and 2-(1,3-dioxolo [4,5-h]isoquinolin-7-yl)-4,5-dimethoxy-N-methyl-Benzeneethanamine (A), and twelve analogues. Among them, 1, 2, and A were synthesized for the first time. In vitro screening for anti-proliferative activity showed that derivative 1a could significantly inhibit the proliferation of HCC cells (IC50 = 9.82 μM on Huh7 cells and 6.83 μM on LM9 cells), and arrest cell cycle at G2/M phase. The mechanistic studies further suggested compound 1a was a dual inhibitor of Topo I and Topo II, and Topo II inhibitory activity was superior to etoposide. In addition, 1a could significantly inhibit the invasion and migration of Cancer cells by inhibiting the expression of MMP-9, and induce Apoptosis through inhibiting the activation of the PI3K/Akt/mTOR signaling pathway. Moreover, in vivo studies demonstrated 1a could obviously reduce the growth of xenograft tumor and possessed good pharmacokinetic parameters, which indicated the potential value of 1a in treating liver Cancer.

Keywords

3-Arylisoquinoline; Topoenzyme I and II dual Inhibitor.

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