Design, synthesis and bioactivity evaluation of novel evodiamine derivatives with excellent potency against gastric cancer
- Eur J Med Chem. 2022 Jan 15:228:113960. doi: 10.1016/j.ejmech.2021.113960.
- 1. State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, China.
- 2. School of Pharmacy, Lanzhou University, Lanzhou, 730000, China.
- 3. School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: [email protected].
- 4. State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, China; School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; School of Pharmacy, Lanzhou University, Lanzhou, 730000, China. Electronic address: [email protected].
Gastric Cancer represents a significant health burden worldwide. Previously, inspired by the traditional Chinese medicine Wu-Chu-Yu to treat the spleen and stomach system for thousands of years, we identified N14-phenyl substituted evodiamine derivatives as potential antitumor agents with favorable inhibition on Top1. Herein, structural optimization and structure-activity relationship studies (SARs) led us to discovering a highly active evodiamine derivative compound 6t against gastric Cancer. Further anti-tumor mechanism studies revealed that compound 6t played as the inhibition of Topoisomerase 1 (Top1), effectively induced Apoptosis, obviously arrested the cell cycle at the G2/M phase, and significantly inhibited the migration and invasion of SGC-7901 and MGC-803 cell lines in a dose-dependent manner. Moreover, the compound 6t was low toxicity in vivo and exhibited excellent anti-tumor activity (TGI = 70.12%) in the MGC-803 xenograft models. In summary, compound 6t represents a promising candidate as a potential chemotherapeutic agent against gastric Cancer.