2. Academic Validation
  3. N(14)-substituted evodiamine derivatives as dual topoisomerase 1/tubulin-Inhibiting anti-gastrointestinal tumor agents

N(14)-substituted evodiamine derivatives as dual topoisomerase 1/tubulin-Inhibiting anti-gastrointestinal tumor agents

  • Eur J Med Chem. 2023 Jul 5;255:115366. doi: 10.1016/j.ejmech.2023.115366.
Jiedan Deng 1,  Lin Long 2,  Xue Peng 2,  Weifan Jiang 2,  Ying Peng 3,  Xi Zhang 3,  Yuting Zhao 4,  Ying Tian 4,  Zhen Wang 5,  Linsheng Zhuo 6
Affiliations

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 Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
  • 4 The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
  • 5 School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; 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; Postdoctoral Station for Basic Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: [email protected].
PMID: 37099835 DOI: 10.1016/j.ejmech.2023.115366
Abstract

Gastrointestinal tumor is an important factor threatening human health. Natural product-based drug discovery is a popular paradigm for expanding the chemical space and identifying new molecular entities that ameliorate human disease. Evodiamine-inspired medicinal chemistry presents therapeutic potential for treating tumors in different tissues via multi-target inhibition. Here, by focusing on the discovery of anti-gastrointestinal tumor drugs, a series of N(14) alkyl-substituted evodiamine derivatives were designed and synthesized. The structure-activity relationship studies culminated in the identification of the N(14)-propyl-substituted evodiamine analog 6b, which showed low nanomolar inhibitory activity against MGC-803 (IC50 = 0.09 μM) and RKO (IC50 = 0.2 μM) cell lines. Moreover, compound 6b was effective in inducing Apoptosis, arresting the cell cycle in the G2/M phase, and inhibiting migration and invasion of MGC-803 and RKO cell lines in a dose-dependent manner in vitro. Further antitumor mechanism studies revealed that compound 6b significantly inhibited Topoisomerase 1 (inhibition rate of 58.3% at 50 μM) and tubulin polymerization (IC50 = 5.69 μM). Overall, compound 6b represents a promising dual Topoisomerase 1/tubulin-targeting lead structure for the treatment of gastrointestinal tumor.

Keywords

Anti-Tumor; Evodiamine derivatives; Top 1/ tubulin inhibitor.

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