Design,synthesis and molecular modeling studies of new series of antitumor 1,2,4-triazines with potential c-Met kinase inhibitory activity |
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Affiliation: | 1. Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023, Zhejiang Province, China;2. College of Medicine, Jiaxing University, Jiaxing 314001, Zhejiang Province, China;1. Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China;2. College of Service, Naval Logistics College of PLA, Tianjin 300450, PR China;1. Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University In Egypt, Cairo, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, 11562 Cairo, Egypt;1. Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy;2. Department of Molecular Medicine, University of Padua, 35121 Padua, Italy;3. Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy;1. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt;2. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, October 6 University, Giza, Egypt;3. Pharmaceutical Chemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, Egypt;4. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr Elini St., Cairo 11562, Egypt |
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Abstract: | The receptor tyrosine kinase c-Met is an attractive target for therapeutic treatment of cancers nowadays. Herein we describe the design and synthesis of a novel series of 1,2,4-triazine derivatives based on our lead NCI 748494/1, possessing different N-linkers to aromatic and heterocyclic rings. In addition, a molecular hybrid series combining the 1,2,4-triazine scaffold to the well-known anticancer drug 6-mercaptopurine (6-MP) was synthesized in order to explore its “double-drug” antitumor effect. The synthesized compounds were evaluated for their in vitro antitumor activity against three c-Met addicted cancer cell lines (A549, HT-29 and MKN-45). Most compounds showed moderate to excellent antitumor activity. Compound 3d showed potent inhibitory activity more than reference Foretinib, BMS-777607 and NCI 748494/1 with IC50 values in the range 0.01–0.31 µM against the cancer cell lines. The calculated IC50 of 3d against c-Met kinase was found to be 2.71 µM, which is more potent than NCI 748494/1 (IC50 = 31.70 µM). Docking studies were performed to identify the binding mode of 3d with c-Met kinase domain in comparison to moderate and weak derivatives. The present study clearly demonstrates that 1,2,4-triazine ring exhibits promising antitumor activity and the double-drug optimization strategy led to identifying 3d as a potent c-Met kinase inhibitor suitable for further development. |
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Keywords: | 1,2,4-Triazines c-Met kinase inhibitors Antitumor evaluation Docking |
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