Synthesis and biological evaluation of novel pazopanib derivatives as antitumor agents

Haofei Qi; Ligong Chen; Bingni Liu; Xinran Wang; Li Long; Dengke Liu

doi:10.1016/j.bmcl.2014.01.003

Synthesis and biological evaluation of novel pazopanib derivatives as antitumor agents

Bioorg Med Chem Lett. 2014 Feb 15;24(4):1108-10. doi: 10.1016/j.bmcl.2014.01.003. Epub 2014 Jan 13.

Authors

Haofei Qi¹, Ligong Chen¹, Bingni Liu², Xinran Wang¹, Li Long³, Dengke Liu⁴

Affiliations

¹ School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China.
² Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China.
³ School of Environmental and Chemical Engineering, Tianjin Polytechnic University, Tianjin 300387, China.
⁴ Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China. Electronic address: liudk_tjipr@163.com.

PMID: 24456902
DOI: 10.1016/j.bmcl.2014.01.003

Abstract

A series of novel pazopanib derivatives, 7a-m, were designed and synthesized by modification of terminal benzene and indazole rings in pazopanib. The structures of all the synthesized compounds were confirmed by (1)H NMR and MS. Their inhibitory activity against VEGFR-2, PDGFR-α and c-kit tyrosine kinases were evaluated. All the compounds exhibited definite kinase inhibition, in which compound 7l was most potent with IC50 values of 12 nM against VEGFR-2. Furthermore, compounds 7c, 7d and 7m demonstrated comparable inhibitory activity against three tyrosine kinases to pazopanib, and compound 7f showed superior inhibitory effects than that of pazopanib.

Keywords: Inhibitory activity; Pazopanib derivatives; Synthesis; Tyrosine kinase.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Crystallography, X-Ray
Dose-Response Relationship, Drug
Indazoles
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-kit / antagonists & inhibitors*
Proto-Oncogene Proteins c-kit / metabolism
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Receptor, Platelet-Derived Growth Factor alpha / antagonists & inhibitors*
Receptor, Platelet-Derived Growth Factor alpha / metabolism
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Antineoplastic Agents
Indazoles
Protein Kinase Inhibitors
Pyrimidines
Sulfonamides
pazopanib
KDR protein, human
Proto-Oncogene Proteins c-kit
Receptor, Platelet-Derived Growth Factor alpha
Vascular Endothelial Growth Factor Receptor-2