Design, synthesis and evaluation of novel diaryl urea derivatives as potential antitumor agents

Chenshu Lu; Ke Tang; Yan Li; Peng Li; Ziyun Lin; Dali Yin; Xiaoguang Chen; Haihong Huang

doi:10.1016/j.ejmech.2014.03.020

Design, synthesis and evaluation of novel diaryl urea derivatives as potential antitumor agents

Eur J Med Chem. 2014 Apr 22:77:351-60. doi: 10.1016/j.ejmech.2014.03.020. Epub 2014 Mar 12.

Authors

Chenshu Lu¹, Ke Tang¹, Yan Li¹, Peng Li¹, Ziyun Lin¹, Dali Yin¹, Xiaoguang Chen², Haihong Huang³

Affiliations

¹ Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, China.
² Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, China. Electronic address: chxg@imm.ac.cn.
³ Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, China. Electronic address: joyce@imm.ac.cn.

PMID: 24675135
DOI: 10.1016/j.ejmech.2014.03.020

Abstract

A novel series of diaryl ureas containing different linker groups were designed and synthesized. Their in vitro antitumor activity against MX-1, A375, HepG2, Ketr3 and HT-29 was evaluated using the standard MTT assay. Compounds having a rigid linker group such as vinyl, ethynyl and phenyl showed significant inhibitory activity against a variety of cancer cell lines. Specifically, compound 23 with a phenyl linker group demonstrated broad-spectrum antitumor activity with IC50 values of 5.17-6.46 μM against five tested tumor cell lines. Compound 23 is more potent than reference drug sorafenib (8.27-15.2 μM), representing a promising lead for further optimization.

Keywords: Antitumor activity; Diaryl ureas; Linker; Sorafenib.

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
Hep G2 Cells
Humans
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
Proto-Oncogene Proteins B-raf / metabolism
Proto-Oncogene Proteins c-raf / antagonists & inhibitors*
Proto-Oncogene Proteins c-raf / metabolism
Structure-Activity Relationship
Urea / analogs & derivatives*
Urea / chemical synthesis
Urea / pharmacology*

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Urea
Proto-Oncogene Proteins B-raf
Proto-Oncogene Proteins c-raf