Ao Jingsheng, Lai Chengyao, Wu Xiaofei, Chen Zhiyong, Yang Weijie, Qiu Liqin, Li Xiangpan, Cao Rihui
Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, 430072, PR China.
School of Chemistry, Sun Yat-sen University, Guangzhou, 510275, PR China.
Eur J Med Chem. 2025 Feb 5;283:117145. doi: 10.1016/j.ejmech.2024.117145. Epub 2024 Dec 5.
A series of novel β-carbolines with a flexible amino side chain at positions 1 and 3, respectively, were designed, synthesized and evaluated as potential antitumor agents. The results revealed that most of the compounds exhibited a broad spectrum of antiproliferative activity with IC value lower than 20 μM against human tumor cell lines. Among them, compound 2f was the most potent antiproliferative agent with IC value below 5.0 μM against human tumor cell lines. Subsequent studies on the in vivo antitumor efficacy of the representative compound 2f demonstrated its ability to hinder tumor progression and significantly diminish tumor mass in a mouse model of colorectal cancer. Further investigation on mechanisms of action showed that compound 2f induced autophagy via the ATG5/ATG7 pathway in HCT116 cells. These compounds may contribute to the development of therapeutic agents for colorectal cancer.
分别在1位和3位设计、合成并评估了一系列具有柔性氨基侧链的新型β-咔啉作为潜在的抗肿瘤药物。结果表明，大多数化合物表现出广谱的抗增殖活性，对人肿瘤细胞系的IC值低于20μM。其中，化合物2f是最有效的抗增殖剂，对人肿瘤细胞系的IC值低于5.0μM。随后对代表性化合物2f的体内抗肿瘤疗效研究表明，它能够在结直肠癌小鼠模型中阻碍肿瘤进展并显著减小肿瘤体积。对作用机制的进一步研究表明，化合物2f在HCT116细胞中通过ATG5/ATG7途径诱导自噬。这些化合物可能有助于开发结直肠癌治疗药物。
