Synthesis and biological evaluation of nitroxide labeled pyrimidines as Aurora kinase inhibitors

Bioorg Med Chem Lett. 2019 Mar 1;29(5):694-699. doi: 10.1016/j.bmcl.2019.01.034.

You-Zhen Ma ¹, Zhen-Bo Tang ¹, Chun-Yan Sang ¹, Zhi-Yuan Qi ¹, Ling Hui ², Shi-Wu Chen ³

Affiliations

1 School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
2 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.
3 School of Pharmacy, Lanzhou University, Lanzhou 730000, China. Electronic address: chenshw@lzu.edu.cn.

PMID: 30728112 DOI: 10.1016/j.bmcl.2019.01.034

Abstract

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 IC₅₀ values in range of 0.89-11.41 μM, and kinases inhibition against Aurora A and B with the IC₅₀ 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.

Keywords

Anticancer; Aurora kinase; Nitroxides; Pyrimidine.

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