Discovery of novel 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 5-(aminomethylene)pyrimidine-2,4,6-trione moiety as c-Met kinase inhibitors |
| |
| Affiliation: | 1. Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China;2. State Key Laboratory Breeding Base-Hebei Province Key Laboratory of Molecular Chemistry for Drug, College of Chemical & Pharmaceutical Engineering, Hebei University of Science & Technology, Shijiazhuang 050018, PR China;3. School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang, Jiangxi 330013, PR China;1. Key Laboratory of Structure-based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China;2. Chong Qing Yaopharma CO., LTD, Chongqing 401121, PR China;1. Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, PR China;2. Shenyang J & Health Bio-technic Development, Shenyang 110016, PR China;1. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China;2. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China;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. Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China;2. Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, China;3. Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072 Australia |
| |
| Abstract: | A series of novel quinoline derivatives bearing 5-(aminomethylene)pyrimidine-2,4,6-trione moiety were designed, synthesized, and evaluated for their c-Met kinase inhibitory activities and antiproliferative activities against 5 cancer cell lines (HT-29, H460, MKN-45, A549, and U87MG) in vitro. Most compounds showed moderate to excellent potency, with the most promising analogue 45 (c-Met half-maximal inhibitory concentration [IC50] = 1.15 nM) showing high selectivity versus 5 other tyrosine kinases, VEGFR-2, Flt-3, PDGFR-β, c-Kit, and EGFR. Structure–activity relationship studies indicated that electron-donating groups on the phenyl ring at the 3-position of pyrimidine-2,4,6-trione were required to increase the electron density on the 5-(aminomethylene)pyrimidine-2,4,6-trione moiety. |
| |
| Keywords: | c-Met Receptor tyrosine kinase Anti-tumor Quinoline derivatives Pyrimidine-2,4,6-trione |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
