School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China.
Department of Medicinal, The Second Clinical Medical College of Northwest Minzu University & The Second Provincial People's Hospital of Gansu Province, Lanzhou 730000, PR China.
Bioorg Med Chem. 2020 Mar 1;28(5):115351. doi: 10.1016/j.bmc.2020.115351. Epub 2020 Jan 31.
Serine/threonine protein kinases Aurora A, B, and C play essential roles in cell mitosis and cytokinesis, and a number of Aurora kinase inhibitors have been evaluated in the clinic. Herein we report the synthesis and their antiproliferation of 3,5-disubstituted-2-aminopyrazines as kinases inhibitors. Amongst, 4-((3-amino-6- (3,5-dimethylisoxazol-4-yl)pyrazin-2-yl)oxy)-N-(3-chlorophenyl) benzamide (12Aj) exhibited the strongest antiproliferative activities against U38, HeLa, HepG2 and LoVo cells with IC values were 11.5 ± 3.2, 1.34 ± 0.23, 7.30 ± 1.56 and 1.64 ± 0.48 μM, as well as inhibited Aurora A and B with the IC values were 90 and 152 nM, respectively. Molecular docking studies indicated that 12Aj appeared to form stable hydrogen bonds with either Aurora A or Aurora B. Furthermore, 12Aj arrested HeLa cell cycle in G2/M phase by regulating protein levels of cyclinB1 and cdc2. In addition, the bioinformatics prediction further revealed that 12Aj possessed good drug likeness using SwissADME. These results suggested that 12Aj was worthy of future development of potent anticancer agents as pan-Aurora kinases.
丝氨酸/苏氨酸蛋白激酶 Aurora A、B 和 C 在细胞有丝分裂和胞质分裂中发挥着重要作用，许多 Aurora 激酶抑制剂已在临床上进行了评估。在此，我们报告了 3,5-二取代-2-氨基吡嗪作为激酶抑制剂的合成及其抗增殖活性。其中，4-((3-氨基-6-(3,5-二甲基异恶唑-4-基)吡嗪-2-基)氧基)-N-(3-氯苯基)苯甲酰胺（12Aj）对 U38、Hela、HepG2 和 LoVo 细胞表现出最强的抗增殖活性，IC 值分别为 11.5±3.2、1.34±0.23、7.30±1.56 和 1.64±0.48μM，同时对 Aurora A 和 Aurora B 的抑制作用分别为 90 和 152 nM。分子对接研究表明，12Aj 似乎与 Aurora A 或 Aurora B 形成稳定的氢键。此外，12Aj 通过调节细胞周期蛋白 B1 和 cdc2 的蛋白水平使 HeLa 细胞周期停滞在 G2/M 期。此外，生物信息学预测进一步表明，12Aj 具有良好的药物样性质，符合 SwissADME 标准。这些结果表明，12Aj 有望作为泛 Aurora 激酶的有效抗癌药物进一步开发。
