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

被引：31

作者：

Tang, Qidong ^{[1
]}

Zhang, Guogang ^{[2
]}

Du, Xinming ^{[1
]}

Zhu, Wufu ^{[3
]}

Li, Ruijuan ^{[1
]}

Lin, Huafang ^{[1
]}

Li, Pengcheng ^{[1
]}

Cheng, Maosheng ^{[1
]}

Gong, Ping ^{[1
]}

Zhao, Yanfang ^{[1
]}

机构：

[1] Shenyang Pharmaceut Univ, Sch Pharmaceut Engn, Minist Educ, Key Lab Struct Based Drug Design & Discovery, Shenyang 110016, Peoples R China

[2] Hebei Univ Sci & Technol, Coll Chem & Pharmaceut Engn, Key Lab Mol Chem Drug, State Key Lab Breeding Base Hebei Prov, Shijiazhuang 050018, Peoples R China

[3] Jiangxi Sci & Technol Normal Univ, Sch Pharm, Nanchang 330013, Jiangxi, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2014年 / 22卷 / 04期

基金：

中国国家自然科学基金;

关键词：

c-Met; Receptor tyrosine kinase; Anti-tumor; Quinoline derivatives; Pyrimidine-2,4,6-trione; HEPATOCYTE GROWTH-FACTOR; CELL LUNG-CANCER; PROSTATE-CANCER; SIGNALING PATHWAY; TYROSINE KINASE; TUMOR-GROWTH; DESIGN; IDENTIFICATION; METASTASIS; RECEPTOR;

D O I：

10.1016/j.bmc.2014.01.014

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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-beta, 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. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：1236 / 1249

页数：14

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