Synthesis, biological evaluation and molecular modeling study of 2-amino-3,5-disubstituted-pyrazines as Aurora kinases inhibitors.

Autor: Bo YX; School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China., Xiang R; 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., Xu Y; School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China., Hao SY; School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China., Wang XR; School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China., Chen SW; School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China. Electronic address: chenshw@lzu.edu.cn.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2020 Mar 01; Vol. 28 (5), pp. 115351. Date of Electronic Publication: 2020 Jan 31.
DOI: 10.1016/j.bmc.2020.115351
Abstrakt: 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 50 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 50 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.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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