Optimization and biological evaluation of nicotinamide derivatives as Aurora kinase inhibitors |
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| Institution: | 1. Universidad de Navarra, Department of Pharmaceutical Technology and Chemistry, Instituto de Salud Tropical, Pamplona 31008, Spain;2. Department of Parasitology, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios De Granada/University of Granada, Granada 18071, Spain;3. Universidad de Navarra, Department of Pharmacology and Toxicology, Pamplona 31008, Spain;4. Department of Pharmaceutical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro 21949-900, Brazil;1. Department of Chemical Research, MRL 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA;2. Department of Oncology, MRL 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA;3. Department of DMPK, MRL 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA;4. Department of Structural Chemistry, MRL 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA;5. Department of Chemical Research, MRL 320 Bent Street, Cambridge, MA 02141, USA;6. AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212, USA;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 |
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| Abstract: | Aurora kinases are known to be overexpressed in various solid tumors and implicated in oncogenesis and tumor progression. A series of nicotinamide derivatives were synthesized and their biological activities were evaluated, including kinase inhibitory activity against Aur A and Aur B and in vitro antitumor activity against SW620, HT-29, NCI-H1975 and Hela cancer cell lines. In addition, the study of antiproliferation, cytotoxicity and apoptosis was performed meanwhile. As the most potent inhibitor of Aur A, 4-((3-bromo-4-fluorophenyl)amino)-6-chloro-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)nicotinamide (10l) showed excellent antitumor activity against SW620 and NCI-H1975 with IC50 values were 0.61 and 1.06 μM, while the IC50 values of reference compound were 3.37 and 6.67 μM, respectively. Furthermore, binding mode studies indicated that compound 10l forms better interaction with Aur A. |
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| Keywords: | Antitumor Aurora kinases Kinase inhibitors Nicotinamide SAR |
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