基于嘧啶环骨架的新型微管聚合抑制剂的设计、合成及生物活性评价。
Design, synthesis, and biological activity evaluation of novel tubulin polymerization inhibitors based on pyrimidine ring skeletons.
机构信息
School of Pharmaceutical Sciences, and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China.
出版信息
Bioorg Med Chem Lett. 2023 Mar 15;84:129195. doi: 10.1016/j.bmcl.2023.129195. Epub 2023 Feb 23.
A library of new pyrimidine analogs was designed and synthesized of these, compound K10 bearing a 1,4‑benzodioxane moiety and 3,4,5‑trimethoxyphenyl group, exhibiting the most potent activity, with IC values of 0.07-0.80 μM against four cancer cell lines. Cellular-based mechanism studies elucidated that K10 inhibited microtubule polymerization, blocked the cell cycle at the G2/M phase, and eventually induced apoptosis of HepG2 cells. Additionally, K10 inhibited the migration and invasion of HepG2 cells in a dose-dependent manner. Overall, our work indicates that the tubulin polymerization inhibitor incorporating pyrimidine and the 3,4,5‑trimethoxyphenyl ring may deserve consideration for cancer therapy.
设计并合成了一系列新的嘧啶类似物库，其中化合物 K10 含有 1,4-苯并二恶烷部分和 3,4,5-三甲氧基苯基，表现出最强的活性，对四种癌细胞系的 IC 值为 0.07-0.80 μM。基于细胞的机制研究表明，K10 抑制微管聚合，将细胞周期阻滞在 G2/M 期，最终诱导 HepG2 细胞凋亡。此外，K10 以剂量依赖的方式抑制 HepG2 细胞的迁移和侵袭。总的来说，我们的工作表明，结合嘧啶和 3,4,5-三甲氧基苯基环的微管聚合抑制剂可能值得考虑用于癌症治疗。
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