Design, Synthesis, and Biological Evaluation of Novel Evodiamine Derivatives as Potential Antihepatocellular Carcinoma Agents

  • J Med Chem. 2022 Jun 9;65(11):7975-7992. doi: 10.1021/acs.jmedchem.2c00520.
Fang Lei  1 ,  Yongxia Xiong  2 ,  Yuqing Wang  1 ,  Honghua Zhang  1 ,  Ziyi Liang  3 ,  Junfang Li  1 ,  Yiyue Feng  1 ,  Xiangyong Hao  4 ,  Zhen Wang  1  2  3
Affiliations
  • 1. School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
  • 2. School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
  • 3. State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China.
  • 4. Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730000, China.
PMID: 35639640 DOI: 10.1021/acs.jmedchem.2c00520
Abstract

Evodiamine has many biological activities. Herein, we synthesize 23 disubstituted derivatives of N14-phenyl or the E-ring of evodiamine and conduct systematic structure-activity relationship studies. In vitro antiproliferative activity indicated that compounds F-3 and F-4 dramatically inhibited the proliferation of Huh7 (IC50 = 0.05 or 0.04 μM, respectively) and SK-Hep-1 (IC50 = 0.07 or 0.06 μM, respectively) cells. Furthermore, compounds F-3 and F-4 could double inhibit topoisomerases I and II, inhibit invasion and migration, block the cell cycle to the G2/M stage, and induce Apoptosis as well. Additionally, compounds F-3 and F-4 could also inhibit the activation of HSC-T6 and reduce the secretion of Collagen type I to slow down the progression of liver fibrosis. Most importantly, compound F-4 (TGI = 60.36%) inhibited tumor growth more significantly than the positive drug sorafenib. To sum up, compound F-4 has excellent potential as a strong candidate for the therapy of hepatocellular carcinoma.