Discovery of novel 2,4-disubstituted pyrimidines as Aurora kinase inhibitors |
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| Institution: | 1. The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700, PR China;2. State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China;3. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 South Xianlie Road, Guangzhou, 510060, PR China;4. Institute of Natural Medicine and Green Chemistry, School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, 510006, PR China;5. Department of Chemistry, McGill University, Montreal, Quebec, H3A 2K6, Canada;1. Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia;2. College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of Korea;3. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;4. Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea;5. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo P.O. Box 11562, Egypt;6. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, New Giza University, New giza, km 22, Cairo–Alexandria Desert Road, Cairo, Egypt;7. Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea;8. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt;9. Department of Pharmaceutical Organic Chemistry, Beni-Suef University, Beni-Suef 62514, Egypt;10. Department of Orthopedics and Traumatology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt;11. Clinical Pharmacy Department, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia;12. Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia;1. Department of Chemistry, University of Delhi, Delhi 110007, India;2. National Center for Natural Products Research, University of Mississippi, MS-38677, USA;3. Department of Biomolecular Sciences, University of Mississippi, MS-38677, USA;4. Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia |
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| Abstract: | In order to explore novel Aurora kinase inhibitors, a series of novel 2,4-disubstituted pyrimidines were designed, synthesized and evaluated their in vitro anti-proliferative activities against a panel of cancerous cell lines (A549, HCT-116 and MCF-7). Among them, compound 12a showed the moderate to high anti-proliferative activities against A549 (IC50 = 12.05 ± 0.45 μM), HCT-116 (IC50 = 1.31 ± 0.41 μM) and MCF-7 (IC50 = 20.53 ± 6.13 μM) cells, as well as the Aurora A and Aurora B inhibitory activities with the IC50 values of 309 nM and 293 nM, respectively. Furthermore, compound 12a induced apoptosis by upregulated the pro-apoptotic proteins Bax and decreased the anti-apoptotic protein Bcl-xl in HCT-116 cells. Moreover, the molecular docking study showed that compound 12a had good binding modes with Aurora A and Aurora B and the bioinformatics prediction discovered that compound 12a exhibited good drug likeness using SwissADME. Taken together, these results indicated that 12a may be a potential anticancer compound that was worthy of further development as Aurora kinase inhibitor. |
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| Keywords: | Aurora kinase Pyrimidine Apoptosis Anticancer |
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