Department of Medicinal Chemistry and Pharmaceutical Analysis, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi Province, China; Faculty of Pharmacy, School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an, Shaanxi Province, China.
Faculty of Pharmacy, School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an, Shaanxi Province, China.
Bioorg Chem. 2022 Jan;118:105486. doi: 10.1016/j.bioorg.2021.105486. Epub 2021 Nov 14.
The colchicine binding site of tubulin is a promising target for discovering novel antitumor agents which exert the antiangiogenic effect and are not susceptible to multidrug resistance. For identifying novel tubulin inhibitors, structure-based virtual screening was applied to identify hit 9 which displayed moderate tubulin polymerization inhibition and broad-spectrum in vitro antitumor activity. Structural optimization was performed, and biological assay revealed analog E27 displayed the best antitumor activity with IC values ranging from 7.81 μM to 10.36 μM, and improved tubulin polymerization inhibitory activity (IC = 16.1 μM). It significantly inhibited cancer cell migration and invasion, induced cell apoptosis and arrested the cell cycle at G2/M phase. Moreover, the apoptotic effect of E27 is related to the increased ROS level, the decrease of MMP, and the abnormal expression of apoptosis-related proteins. Taken together, these results suggested E27 was a promising lead compound for discovering novel tubulin-targeted antitumor agents.
秋水仙碱结合微管蛋白位点是发现新型抗肿瘤药物的一个有前途的靶点，这些药物具有抗血管生成作用，并且不易产生多药耐药性。为了鉴定新型微管蛋白抑制剂，我们应用基于结构的虚拟筛选来鉴定具有中等微管蛋白聚合抑制作用和广谱体外抗肿瘤活性的命中化合物 9。进行了结构优化，生物测定显示类似物 E27 显示出最好的抗肿瘤活性，IC 值范围为 7.81 μM 至 10.36 μM，并且提高了微管蛋白聚合抑制活性（IC = 16.1 μM）。它显著抑制癌细胞迁移和侵袭，诱导细胞凋亡，并将细胞周期阻滞在 G2/M 期。此外，E27 的凋亡作用与 ROS 水平的升高、MMP 的降低和凋亡相关蛋白的异常表达有关。总之，这些结果表明 E27 是一种有前途的新型微管蛋白靶向抗肿瘤药物的先导化合物。
