Design, synthesis and bioactivity evaluation of novel N-phenyl-substituted evodiamine derivatives as potent anti-tumor agents

  • Bioorg Med Chem. 2021 Dec 30;55:116595. doi: 10.1016/j.bmc.2021.116595.
Xiangyong Hao  1 ,  Jiedan Deng  2 ,  Honghua Zhang  3 ,  Ziyi Liang  4 ,  Fang Lei  2 ,  Yuqing Wang  2 ,  Xiaoyan Yang  5 ,  Zhen Wang  6
Affiliations
  • 1. Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730000, China.
  • 2. School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
  • 3. School of Pharmacy, Lanzhou University, Lanzhou 730000, China. Electronic address: [email protected].
  • 4. State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China.
  • 5. School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. Electronic address: [email protected].
  • 6. School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China; School of Pharmacy, Lanzhou University, Lanzhou 730000, China; State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China. Electronic address: [email protected].
PMID: 34990980 DOI: 10.1016/j.bmc.2021.116595
Abstract

Natural products are important sources for the development of therapeutic medicine, among which evodia fruit has a wide range of medicinal properties in traditional Chinese medicine. Evodiamine, the main active component of evodia fruit, has various anti-cancer effects and has been proved to be a Topo inhibitor. From our previous attempts of modifying evodiamine, we found that the N14 phenyl substituted derivatives had showed great anti-tumor activity, which prompted us to further explore the novel structures and activities of these compounds. Compound 6f, as a N14 3-fluorinated phenyl substituted evodiamine derivative, showed a certain inhibitory activity against Topo I at 200 μM. By studying its anti-tumor effects in vitro, compound 6f could inhibit proliferation and induce Apoptosis, as well as arrest the cell cycle of HGC-27 and HT-29 cell lines at G2/M phase in a concentration-dependent manner. Moreover, compound 6f could inhibit the migration and invasion of HGC-27 cell lines. Meanwhile, compound 6f could induce Apoptosis of HGC-27 cells by inhibiting PI3K/Akt pathway. Overall, this work demonstrated that the N14 phenyl-substituted evodiamine derivatives had a good inhibitory effect on tumor cells in vitro, providing a promising strategy for developing potential Anticancer agents for the treatment of gastrointestinal tumors.

Keywords
Anti-tumor; Evodiamine derivatives; PI3K/AKT.
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