Design, synthesis and biological evaluation of novel 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 4-oxo-3,4-dihydrophthalazine-1-carboxamide moieties as c-Met kinase inhibitors

Zijian Liu; Rui Wang; Ruiming Guo; Jinxing Hu; Ruijuan Li; Yanfang Zhao; Ping Gong

doi:10.1016/j.bmc.2014.05.013

Design, synthesis and biological evaluation of novel 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 4-oxo-3,4-dihydrophthalazine-1-carboxamide moieties as c-Met kinase inhibitors

Bioorg Med Chem. 2014 Jul 15;22(14):3642-53. doi: 10.1016/j.bmc.2014.05.013. Epub 2014 May 17.

Authors

Zijian Liu¹, Rui Wang¹, Ruiming Guo¹, Jinxing Hu¹, Ruijuan Li¹, Yanfang Zhao¹, Ping Gong²

Affiliations

¹ Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
² Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China. Electronic address: gongpinggp@126.com.

PMID: 24882675
DOI: 10.1016/j.bmc.2014.05.013

Abstract

A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 4-oxo-3,4-dihydrophthalazine-1-carboxamide moieties were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against H460, MKN-45, HT-29 and MDA-MB-231 cancer cell lines in vitro. Most compounds displayed good to excellent potency against four tested cancer cell lines as compared with foretinib. The SAR analyses indicated that compounds with halogen groups, especially fluoro groups at 4-position on the phenyl ring (moiety B) were more effective than those with nitro groups or methoxy groups. In this study, a promising compound 33 (c-Met IC50=1.63nM) was identified, which showed the most potent antitumor activities with IC50 values of 0.055μM, 0.071μM, 0.13μM, and 0.43μM against H460, MKN-45, HT-29 and MDA-MB-231 cell lines, respectively.

Keywords: 2-Phenylphthalazin-1(2H)-one; 4-Phenoxyquinoline derivatives; Antitumor activity; c-Met.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
HT29 Cells
Humans
Models, Molecular
Molecular Structure
Phthalazines / chemical synthesis
Phthalazines / chemistry
Phthalazines / pharmacology*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-met / antagonists & inhibitors*
Proto-Oncogene Proteins c-met / metabolism
Quinolines / chemical synthesis
Quinolines / chemistry
Quinolines / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
N-(3-fluoro-4-((6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-4-oxo-3,4-dihydrophthalazine-1-carboxamide
Phthalazines
Protein Kinase Inhibitors
Quinolines
MET protein, human
Proto-Oncogene Proteins c-met