Design, synthesis and evaluation of novel 2-(1H-imidazol-2-yl) pyridine Sorafenib derivatives as potential BRAF inhibitors and anti-tumor agents

Yu Jiao; Bo-Tao Xin; Yanmin Zhang; Jianbing Wu; Xiaolin Lu; Ying Zheng; Weifang Tang; Xiang Zhou

doi:10.1016/j.ejmech.2014.11.008

Design, synthesis and evaluation of novel 2-(1H-imidazol-2-yl) pyridine Sorafenib derivatives as potential BRAF inhibitors and anti-tumor agents

Eur J Med Chem. 2015 Jan 27:90:170-83. doi: 10.1016/j.ejmech.2014.11.008. Epub 2014 Nov 6.

Authors

Yu Jiao¹, Bo-Tao Xin², Yanmin Zhang¹, Jianbing Wu¹, Xiaolin Lu¹, Ying Zheng¹, Weifang Tang¹, Xiang Zhou³

Affiliations

¹ Department of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198 Jiang Su, China.
² Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2300 RA Leiden, The Netherlands.
³ Department of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198 Jiang Su, China. Electronic address: stephanie055@163.com.

PMID: 25461318
DOI: 10.1016/j.ejmech.2014.11.008

Abstract

A series of 2-(1H-imidazol-2-yl) pyridine derivatives (CLW01-CLW31) have been designed and synthesized, and they were screened for BRAF kinase inhibitory activity. Besides, their biological activities were evaluated in vitro and in vivo. All the compounds were reported for the first time, and compounds CLW14 and CLW27 displayed the most potent antiproliferative activity against cell line A375 in vitro, with IC50 values of 4.26 and 2.93 μM, respectively, which were comparable with the positive control Sorafenib. Those two compounds were further evaluated for the in vivo efficacy using an A375 xenograft nude mice model. The results showed that the growth of A375 cancer cells xenografts was suppressed by factors of 35.68% and 42.50% (percent tumor growth inhibition values) after intragastric (ig) administration of compound CLW14 and CLW27 at concentration of 50 mg/kg. Thus they may be promising lead compounds to be developed as an alternative for current Sorafenib therapy.

Keywords: Antiproliferative activity; BRAF kinase; Cancer cell; In vivo efficacy; Sorafenib.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Hep G2 Cells
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry
Imidazoles / pharmacology*
MCF-7 Cells
Mice
Mice, Nude
Models, Molecular
Molecular Docking Simulation
Molecular Structure
Neoplasms, Experimental / drug therapy*
Neoplasms, Experimental / pathology
Niacinamide / analogs & derivatives*
Niacinamide / chemical synthesis
Niacinamide / chemistry
Niacinamide / pharmacology
Phenylurea Compounds / chemical synthesis
Phenylurea Compounds / chemistry
Phenylurea Compounds / pharmacology*
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
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Sorafenib
Structure-Activity Relationship

Substances

2-(1H-imidazol-2-yl)pyridine
Antineoplastic Agents
Imidazoles
Phenylurea Compounds
Protein Kinase Inhibitors
Pyridines
Niacinamide
Sorafenib
Proto-Oncogene Proteins B-raf