School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
Experimental Center of Medicine, General Hospital of Lanzhou Military Command, Lanzhou 730050, China; Key Laboratory of Stem Cells and Gene Drug of Gansu Province, General Hospital of Lanzhou Military Command, Lanzhou 730050, China.
Bioorg Med Chem Lett. 2019 Mar 1;29(5):694-699. doi: 10.1016/j.bmcl.2019.01.034. Epub 2019 Jan 30.
To find novel effective Aurora kinases inhibitors, a series of structurally interesting nitroxide labeled pyrimidines were synthesized and evaluated their anti-proliferative and Aurora kinases inhibitory activities. Among them, butyl 2-(3-((5-fluoro-2-((4-((1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)carbamoyl) phenyl) amino)pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)acetate (22) possessed the most potent anti-proliferative effects against four carcinoma cell lines with IC values in range of 0.89-11.41 μM, and kinases inhibition against Aurora A and B with the IC values were 9.3 and 2.8 nM, respectively. Furthermore, compound 22 blocked the phosphorylation of Aurora A (T288), Aurora B (Thr232) and HisH3, decreased the expression of proteins TPX2, Eg5 and Bora, as well as disrupted the mitotic spindle formation in HeLa cells. Molecular docking studies indicated that compound 22 well interact with both Aurora A and B. The results showed that compound 22 is a potential anticancer agent as promising pan-Aurora kinase inhibitor.
为了寻找新型有效的 Aurora 激酶抑制剂，我们合成了一系列结构有趣的含硝酮标记的嘧啶，并评估了它们的抗增殖活性和 Aurora 激酶抑制活性。其中，丁基 2-(3-((5-氟-2-((4-((1-氧代-2,2,6,6-四甲基哌啶-4-基)氨基)苯甲酰基)氨基)嘧啶-4-基)氨基)-1H-吡唑-5-基)乙酸酯（22）对四种癌细胞系具有最强的抗增殖作用，IC 值范围为 0.89-11.41μM，对 Aurora A 和 B 的激酶抑制作用的 IC 值分别为 9.3 和 2.8nM。此外，化合物 22 能阻断 Aurora A（T288）、Aurora B（Thr232）和 HisH3 的磷酸化，降低 TPX2、Eg5 和 Bora 蛋白的表达，并破坏 HeLa 细胞中的有丝分裂纺锤体形成。分子对接研究表明，化合物 22 能与 Aurora A 和 B 均很好地相互作用。结果表明，化合物 22 是一种有潜力的抗癌药物，有望成为一种泛 Aurora 激酶抑制剂。
