Design, synthesis and biological evaluation of novel 4-phenoxyquinoline derivatives containing 3-oxo-3,4-dihydroquinoxaline moiety as c-Met kinase inhibitors

Ju Liu; Di Yang; Xiuxiu Yang; Minhua Nie; Guodong Wu; Zhunchao Wang; Wei Li; Yajing Liu; Ping Gong

doi:10.1016/j.bmc.2017.06.037

Design, synthesis and biological evaluation of novel 4-phenoxyquinoline derivatives containing 3-oxo-3,4-dihydroquinoxaline moiety as c-Met kinase inhibitors

Bioorg Med Chem. 2017 Aug 15;25(16):4475-4486. doi: 10.1016/j.bmc.2017.06.037. Epub 2017 Jun 27.

Authors

Ju Liu¹, Di Yang², Xiuxiu Yang², Minhua Nie², Guodong Wu², Zhunchao Wang², Wei Li³, Yajing Liu⁴, Ping Gong⁵

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; College of Pharmacy of Liaoning University, Key Laboratory of New Drug Research and Development of Liaoning Province, 66 Chongshan Road, Huanggu District, Shenyang 10036, 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.
³ Department of Pharmaceutical Engineering, Shenyang University of Chemical Technology, 11 Street, Jingjijishukaifa District, Shenyang 110142, PR China.
⁴ 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: lyjpharm@126.com.
⁵ 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: 28716639
DOI: 10.1016/j.bmc.2017.06.037

Abstract

A series of novel 4-phenoxyquinoline derivatives containing 3-oxo-3,4-dihydroquinoxaline moiety were synthesized and evaluated for their c-Met kinase inhibitory activity and antiproliferative activity against five cancer cell lines (HT-29, H460, A549, MKN-45 and U87MG) in vitro. Most of the compounds exhibited moderate-to-significant cytotoxicity as compared with foretinib. The most promising compound 41 (with c-Met IC₅₀ value of 0.90nM) showed remarkable cytotoxicity against HT-29, H460, A549, MKN-45 and U87MG cell lines with IC₅₀ values of 0.06μM, 0.05μM, 0.18μM, 0.023μM and 0.66μM, respectively, and thus it was 1.22- to 3.50-fold more potent than foretinib. Their preliminary structure-activity relationships (SARs) studies indicate that electron-withdrawing groups on the terminal phenyl rings are beneficial for improving the antitumor activity.

Keywords: 4-Phenoxyquinoline derivatives; Antitumor activity; Synthesis; c-Met inhibitors.

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
Humans
Models, Molecular
Molecular Structure
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*
Quinoxalines / chemistry
Quinoxalines / pharmacology*
Structure-Activity Relationship

Substances

3-oxo-3,4-dihydroquinoxaline
Antineoplastic Agents
Protein Kinase Inhibitors
Quinolines
Quinoxalines
Proto-Oncogene Proteins c-met