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

Qidong Tang; Guogang Zhang; Xinming Du; Wufu Zhu; Ruijuan Li; Huafang Lin; Pengcheng Li; Maosheng Cheng; Ping Gong; Yanfang Zhao

doi:10.1016/j.bmc.2014.01.014

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

Bioorg Med Chem. 2014 Feb 15;22(4):1236-49. doi: 10.1016/j.bmc.2014.01.014. Epub 2014 Jan 22.

Authors

Affiliations

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.
⁴ 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. Electronic address: yanfangzhao@126.com.

PMID: 24485123
DOI: 10.1016/j.bmc.2014.01.014

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: Anti-tumor; Pyrimidine-2,4,6-trione; Quinoline derivatives; Receptor tyrosine kinase; c-Met.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology
Binding Sites
Cell Line, Tumor
Cell Survival / drug effects
Drug Evaluation, Preclinical
Enzyme Activation / drug effects
HT29 Cells
Humans
Molecular Docking Simulation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology
Protein Structure, Tertiary
Proto-Oncogene Proteins c-met / antagonists & inhibitors*
Proto-Oncogene Proteins c-met / metabolism
Pyrimidines / chemistry
Quinolines / chemical synthesis
Quinolines / chemistry*
Quinolines / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrimidines
Quinolines
quinoline
MET protein, human
Proto-Oncogene Proteins c-met
pyrimidine