Synthesis,biological evaluation and molecular modeling study of 2-amino-3,5-disubstituted-pyrazines as Aurora kinases inhibitors |
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| Institution: | 1. School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China;2. 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;1. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, 152 – 160 Pearse Street Trinity College Dublin, Dublin 2, Ireland;2. School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, 152 – 160 Pearse Street Trinity College Dublin, Dublin 2, Ireland;3. School of Biological and Health Sciences, Technology University Dublin, Dublin City Campus, Kevin St., Dublin 8 D08 NF82, Ireland;4. School of Chemistry, Trinity College Dublin, Dublin 2, Ireland;1. School of Pharmacy, Jinan University, Guangzhou 510632, China;2. YZ Health-tech Inc., Hengqin District, Zhuhai 519000, China;3. School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China;4. Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China;5. Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia;1. State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Haidian District, Beijing 100850, China;2. Department of Pharmacy, College of Animal Science and Technique, Heilongjiang Bayi Agricultural University, Xinyang Road 2, Daqing 163319, China;3. College of Chemistry & Pharmacy, Shaanxi Key Laboratory of Natural Products& Chemical Biology, Northwest A&F University, Yangling, Shaanxi 712100, China;1. Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries Research, National Research Centre, El‐Buhouth St., Dokki, P.O. Box 12622, Cairo, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt;3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, New Giza University, New Giza, Km 22 Cairo–Alexandria Desert Road, Cairo, Egypt;4. Università degli Studi di Firenze, Department NEUROFARBA – Pharmaceutical and Nutraceutical Section, University of Firenze, Via Ugo Schiff 6, I-50019, Sesto Fiorentino, Firenze, Italy;5. Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) – Helmholtz Centre for Infection Research (HZI), Department of Drug Design and Optimization, Campus Building E8.1, 66123 Saarbrücken, Germany;1. Department of Chemistry, Centre for Advanced Studies, Guru Nanak Dev University, Amritsar 143005, India;2. Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar 143005, India |
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| Abstract: | 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 IC50 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 IC50 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. |
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| Keywords: | Anti-tumor Aurora kinase Pyrazines Cell cycle |
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