Discovery and optimization of novel 4-phenoxy-6,7-disubstituted quinolines possessing semicarbazones as c-Met kinase inhibitors

Baohui Qi; Bin Mi; Xin Zhai; Ziyi Xu; Xiaolong Zhang; Zeru Tian; Ping Gong

doi:10.1016/j.bmc.2013.06.026

Discovery and optimization of novel 4-phenoxy-6,7-disubstituted quinolines possessing semicarbazones as c-Met kinase inhibitors

Bioorg Med Chem. 2013 Sep 1;21(17):5246-60. doi: 10.1016/j.bmc.2013.06.026. Epub 2013 Jun 19.

Authors

Baohui Qi¹, Bin Mi, Xin Zhai, Ziyi Xu, Xiaolong Zhang, Zeru Tian, Ping Gong

Affiliation

¹ Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning Province 110016, PR China.

PMID: 23838381
DOI: 10.1016/j.bmc.2013.06.026

Abstract

A novel series of N(1)-(3-fluoro-4-(6,7-disubstituted-quinolin-4-yloxy)phenyl)-N(4)-arylidenesemicarbazide derivatives were synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against A549, HT-29, MKN-45 and MDA-MB-231 cancer cell lines in vitro. Several potent compounds were further evaluated against three other cancer cell lines (U87MG, NCI-H460 and SMMC7721). Most of compounds tested exhibited moderate to excellent activity. The studies of SARs identified the most promising compound 28 (c-Met IC50=1.4nM) as a c-Met kinase inhibitor. In this study, a promising compound 28 was identified, which displayed 2.1-, 3.3-, 48.4- and 3.6-fold increase against A549, HT-29, U87MG and NCI-H460 cell lines, respectively, compared with that of Foretinib.

Keywords: Anti-tumor; Kinase inhibitor; Quinoline; Semicarbazone; c-Met.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / toxicity
Binding Sites
Cell Line, Tumor
Cell Survival / drug effects
Drug Evaluation, Preclinical
Drug Screening Assays, Antitumor
HT29 Cells
Humans
Molecular Docking Simulation
Phosphorylation / drug effects
Protein Binding
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / toxicity
Protein Structure, Tertiary
Proto-Oncogene Proteins c-met / antagonists & inhibitors*
Proto-Oncogene Proteins c-met / metabolism
Quinolines / chemical synthesis
Quinolines / chemistry*
Quinolines / toxicity
Semicarbazides / chemical synthesis*
Semicarbazides / chemistry
Semicarbazides / toxicity
Semicarbazones / chemical synthesis
Semicarbazones / chemistry*
Semicarbazones / toxicity
Structure-Activity Relationship

Substances

Antineoplastic Agents
N1-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yloxy)phenyl)-N4-(2,4-difluorobenzylidene)semicarbazide
Protein Kinase Inhibitors
Quinolines
Semicarbazides
Semicarbazones
Proto-Oncogene Proteins c-met