Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, PR China.
Eur J Med Chem. 2018 Feb 10;145:805-812. doi: 10.1016/j.ejmech.2017.12.082. Epub 2018 Jan 11.
The inhibition of the members of aurora kinase family using ATP-competitive small molecules is an effective method for anticancer therapeutics. Based on our previous work, we synthesized 12 new N-trisubstituted pyrimidine derivatives and evaluated their biological activities and stabilities. Among them, compound 11j showed the best inhibition against aurora A kinase (IC = 7.1 nM), human leukemia cell line U937 (IC = 12.2 nM) and the growth of U937 xenograft tumors in vivo. By the flow cytometry and immunofluorescence analysis of U937, we found that compound 11j can induced polyploidy formation including (4N, 8N and 16N) and induce defects in both chromosome alignment and spindle formation. Furthermore, compound 11j exhibited good chemical, physical, and thermal stabilities. All these results suggested that 11j is a promising lead compound for further development of anticancer drugs.
使用 ATP 竞争性小分子抑制 Aurora 激酶家族成员是一种有效的抗癌治疗方法。基于我们之前的工作，我们合成了 12 种新型 N-三取代嘧啶衍生物，并评估了它们的生物活性和稳定性。其中，化合物 11j 对 Aurora A 激酶（IC=7.1nM）、人白血病细胞系 U937（IC=12.2nM）和 U937 异种移植肿瘤的生长具有最佳的抑制作用。通过 U937 的流式细胞术和免疫荧光分析，我们发现化合物 11j 可以诱导多倍体形成，包括（4N、8N 和 16N），并导致染色体排列和纺锤体形成缺陷。此外，化合物 11j 表现出良好的化学、物理和热稳定性。所有这些结果表明，11j 是进一步开发抗癌药物的有前途的先导化合物。
