State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, China.
School of Pharmacy, Lanzhou University, Lanzhou, 730000, China.
Eur J Med Chem. 2022 Jan 15;228:113960. doi: 10.1016/j.ejmech.2021.113960. Epub 2021 Oct 29.
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.
胃癌是全球范围内一个重大的健康负担。以前，受中国传统医学吴茱萸治疗脾胃系统几千年的启发，我们发现 N14- 取代苯基吴茱萸碱衍生物是潜在的抗肿瘤药物，对拓扑异构酶 1（Top1）有良好的抑制作用。在此基础上，我们通过结构优化和构效关系研究（SARs）发现了一种针对胃癌的高度活性吴茱萸碱衍生物化合物 6t。进一步的抗肿瘤机制研究表明，化合物 6t 作为拓扑异构酶 1（Top1）的抑制剂，能够有效诱导细胞凋亡，明显将细胞周期阻滞在 G2/M 期，并显著抑制 SGC-7901 和 MGC-803 细胞系的迁移和侵袭，呈剂量依赖性。此外，化合物 6t 在体内的毒性较低，在 MGC-803 异种移植模型中表现出优异的抗肿瘤活性（TGI=70.12%）。综上所述，化合物 6t 作为一种治疗胃癌的潜在化疗药物具有广阔的应用前景。
