Discovery of novel 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 5-(aminomethylene)pyrimidine-2,4,6-trione moiety as c-Met kinase inhibitors

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• 作者：Qidong Tang ; Guogang Zhang ; Xinming Du ; Wufu Zhu ; Ruijuan Li ; Huafang Lin ; Pengcheng Li ; Maosheng Cheng ; Ping Gong ; Yanfang Zhao
• 关键词：c-Met ; Receptor tyrosine kinase ; Anti-tumor ; Quinoline derivatives ; Pyrimidine-2 ; 4 ; 6-trione
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：15 February, 2014
• 年：2014
• 卷：22
• 期：4
• 页码：1236-1249
• 全文大小：2507 K

文摘

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-尾, 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.