Discovery of novel anti-angiogenesis agents. Part 8: Diaryl thiourea bearing 1H-indazole-3-amine as multi-target RTKs inhibitors

Ying Sun; Yuanyuan Shan; Chuansheng Li; Ru Si; Xiaoyan Pan; Binghe Wang; Jie Zhang

doi:10.1016/j.ejmech.2017.10.008

Discovery of novel anti-angiogenesis agents. Part 8: Diaryl thiourea bearing 1H-indazole-3-amine as multi-target RTKs inhibitors

Eur J Med Chem. 2017 Dec 1:141:373-385. doi: 10.1016/j.ejmech.2017.10.008. Epub 2017 Oct 6.

Authors

Ying Sun¹, Yuanyuan Shan², Chuansheng Li¹, Ru Si¹, Xiaoyan Pan¹, Binghe Wang³, Jie Zhang⁴

Affiliations

¹ School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, 710061, China.
² Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
³ Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, United States.
⁴ School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, 710061, China. Electronic address: zhj8623@xjtu.edu.cn.

PMID: 29032031
DOI: 10.1016/j.ejmech.2017.10.008

Abstract

VEGFR-2, TIE-2, and EphB4 are essential for both angiogenesis and tumorigenesis. Herein, we designed and prepared three classes of multi-target inhibitors based on the extensive sequence homology along the kinase domain of angiogenic RTKs. Biological evaluation indicated that these multi-target inhibitors exhibited considerable potential as novel anti-angiogeneic and anticancer agents. Among them, a diaryl thiourea bearing 1H-indazole-3-amine (16a) displayed the most potent RTK inhibition and excellent selectivity. It also showed inhibition on viability of human umbilical vein endothelial cells and anti-proliferation against a broad spectrum of cancer cells. Therefore, 1H-indazole-3-amine could serve as a promising hinge binding group for multi-target inhibitors of VEGFR-2, Tie-2, and EphB4.

Keywords: 1H-indazol-3-amine; Anti-angiogenesis agents; Hinge-binding group; Multi-target; RTK inhibitors.

MeSH terms

Angiogenesis Inhibitors / chemical synthesis
Angiogenesis Inhibitors / chemistry
Angiogenesis Inhibitors / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Human Umbilical Vein Endothelial Cells / drug effects
Humans
Indazoles / chemistry
Indazoles / pharmacology*
Molecular Docking Simulation
Molecular Structure
Neovascularization, Pathologic / drug therapy*
Neovascularization, Pathologic / metabolism
Neovascularization, Pathologic / pathology
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / metabolism
Structure-Activity Relationship
Thiourea / chemical synthesis
Thiourea / chemistry
Thiourea / pharmacology*

Substances

1H-indazol-3-amine
Angiogenesis Inhibitors
Antineoplastic Agents
Indazoles
Protein Kinase Inhibitors
Receptor Protein-Tyrosine Kinases
Thiourea