State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 17#3rd Section, Ren Min South Road, Chengdu 610041, China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 17#3rd Section, Ren Min South Road, Chengdu 610041, China.
Bioorg Chem. 2020 Apr;97:103695. doi: 10.1016/j.bioorg.2020.103695. Epub 2020 Feb 24.
A series of 3-(((9H-purin-6-yl) amino) methyl) pyridin-2(1H)-one derivatives were designed, synthesized and confirmed as tubulin polymerization inhibitors. All compounds were evaluated for their anti-proliferative activities on three colorectal carcinoma (CRC) cell lines. Among these compounds, SKLB0565 displayed noteworthy potency against eight CRC cell lines with IC values ranging from 0.012 μM and 0.081 μM. Besides, SKLB0565 inhibited tubulin polymerization, caused G2/M phase cell cycle arrest, depolarized mitochondria and induced cell apoptosis in CRC cells. Furthermore, SKLB0565 suppressed cell migration and disrupted the capillary tube formation of human umbilical vein endothelial cells (HUVECs). Our data clarified that SKLB0565 is a promising anti-tubulin agent for CRC therapy which is worthy of further evaluation.
设计、合成并确证了一系列 3-(((9H-嘌呤-6-基)氨基)甲基)吡啶-2(1H)-酮衍生物，它们被证实为微管蛋白聚合抑制剂。所有化合物均在三种结直肠癌细胞系（CRC）上评估了其抗增殖活性。在这些化合物中，化合物 SKLB0565 对八种 CRC 细胞系表现出显著的抑制活性，IC50 值范围为 0.012 μM 至 0.081 μM。此外，SKLB0565 抑制微管蛋白聚合，导致 CRC 细胞的 G2/M 期细胞周期阻滞、线粒体去极化和诱导细胞凋亡。此外，SKLB0565 抑制细胞迁移并破坏人脐静脉内皮细胞（HUVECs）的毛细血管管形成。我们的数据阐明了 SKLB0565 是一种很有前途的用于 CRC 治疗的抗微管蛋白药物，值得进一步评估。
