Discovery of N1-(4-((7-(3-(4-ethylpiperazin-1-yl)propoxy)-6-methoxyquinolin-4-yl)oxy)-3,5-difluorophenyl)-N3-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)urea as a multi-tyrosine kinase inhibitor for drug-sensitive and drug-resistant cancers treatment

Baohui Qi; Ying Yang; Guowei Gong; Huan He; Xupeng Yue; Xin Xu; Yun Hu; Junming Li; Tao Chen; Xiaobing Wan; Anmian Zhang; Guobiao Zhou

doi:10.1016/j.ejmech.2018.11.057

Discovery of N¹-(4-((7-(3-(4-ethylpiperazin-1-yl)propoxy)-6-methoxyquinolin-4-yl)oxy)-3,5-difluorophenyl)-N³-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)urea as a multi-tyrosine kinase inhibitor for drug-sensitive and drug-resistant cancers treatment

Eur J Med Chem. 2019 Feb 1:163:10-27. doi: 10.1016/j.ejmech.2018.11.057. Epub 2018 Nov 23.

Authors

Baohui Qi¹, Ying Yang², Guowei Gong², Huan He², Xupeng Yue², Xin Xu², Yun Hu², Junming Li², Tao Chen², Xiaobing Wan², Anmian Zhang², Guobiao Zhou²

Affiliations

¹ Zhuhai Premier-Discipline Enhancement Scheme of Pharmacology, Zhuhai Key Laboratory of Basic and Applied Research in Chinese Medicine, Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai, 519041, Guangdong Province, China. Electronic address: bhqi@zmu.gd.cn.
² Zhuhai Premier-Discipline Enhancement Scheme of Pharmacology, Zhuhai Key Laboratory of Basic and Applied Research in Chinese Medicine, Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai, 519041, Guangdong Province, China.

PMID: 30503936
DOI: 10.1016/j.ejmech.2018.11.057

Abstract

A series of 21 novel N¹-(2-aryl-1,3-thiazolidin-4-one)-N³-aryl urea derivatives based on the previously identified lead compound I were synthesized and biologically characterized. The most promising compound 19a was identified as a multi-tyrosine kinase inhibitor, including c-Met, Ron, c-Kit, AXL and IGF-1R, etc. The results of real-time live-cell imaging indicated that compound 19a showed improved cytotoxicity and anti-proliferative activity against HT-29 cancer cells in a time- and dose-dependent manner, with an efficacy that was significantly greater than Cabozantinib. Flow cytometry and western blot analysis demonstrated the fact that anticancer activity was closely related with cancer cell apoptosis and the blockade of the phosphorylation of c-Met and its downstream signaling ERK and Akt. Furthermore, compound 19a also displayed slightly stronger effects on HT-29 cancer cells migration than that of Cabozantinib.

Keywords: 1; 3-Thiazolidin-4-one; Anticancer; Inhibitor; Tyrosine kinase; Urea.

MeSH terms

Apoptosis / drug effects
Cell Movement / drug effects
Cell Proliferation / drug effects
Drug Resistance, Neoplasm
Drug Screening Assays, Antitumor
HT29 Cells
Humans
Neoplasms / drug therapy*
Phosphorylation / drug effects
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / pharmacology
Protein-Tyrosine Kinases
Proto-Oncogene Proteins c-met / metabolism
Thiazolidines / chemistry*
Urea / chemistry
Urea / pharmacology*

Substances

Protein Kinase Inhibitors
Thiazolidines
Urea
MET protein, human
Protein-Tyrosine Kinases
Proto-Oncogene Proteins c-met