Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
Bioorg Chem. 2021 Jan;106:104199. doi: 10.1016/j.bioorg.2020.104199. Epub 2020 Aug 26.
Hereby, we report our efforts on discovery and optimization of a new series of 5-aryl-4-(4-arylpiperazine-1-carbonyl)-1,2,3-thiadiazoles as new microtubule-destabilizing agents along our previous study. Guided by docking model analysis, we introduced the 1,2,3-thiadiazole moiety containing the hydrogen-bond acceptors as B-ring of XRP44X analogues. Extensive structure modifications were performed to investigate the detailed structure and activity relationships (SARs). Some compounds exhibited potent antiproliferative activities against three human cancer cell lines (SGC-7901, A549 and HeLa). The compound 5m exhibited the highest potency against the three cancer cell lines. The tubulin polymerization experiments indicated that compound 5m effectively inhibited the tubulin polymerization, and immunostaining assay revealed that it significantly disrupted microtubule dynamics. Moreover, cell cycle studies revealed that compound 5m dramatically arrested cell cycle progression at G2/M phase.
在此，我们报告了我们在发现和优化一系列新的 5-芳基-4-(4-芳基哌嗪-1-羰基)-1,2,3-噻二唑作为新的微管去稳定剂方面的努力，这是我们之前研究的延续。在对接模型分析的指导下，我们将含有氢键受体的 1,2,3-噻二唑部分作为 XR P44X 类似物的 B 环引入。进行了广泛的结构修饰，以研究详细的结构和活性关系 (SAR)。一些化合物对三种人癌细胞系 (SGC-7901、A549 和 HeLa) 表现出很强的抗增殖活性。化合物 5m 对三种癌细胞系的活性最高。微管聚合实验表明，化合物 5m 能有效抑制微管聚合，免疫染色实验表明它能显著破坏微管动力学。此外，细胞周期研究表明，化合物 5m 能显著将细胞周期阻滞在 G2/M 期。
