PUBLICATION
Design, synthesis, and in vitro and in vivo anti-angiogenesis study of a novel vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor based on 1,2,3-triazole scaffold
- Authors
- Wang, D.P., Liu, K.L., Li, X.Y., Lu, G.Q., Xue, W.H., Qian, X.H., Mohamed O, K., Meng, F.H.
- ID
- ZDB-PUB-201220-5
- Date
- 2020
- Source
- European Journal of Medicinal Chemistry 211: 113083 (Journal)
- Registered Authors
- Keywords
- 1,2,3-Triazole, Anti-angiogenesis, VEGFR-2, Zebrafish
- MeSH Terms
-
- Angiogenesis Inhibitors/pharmacology
- Angiogenesis Inhibitors/therapeutic use*
- Animals
- Cell Proliferation
- Drug Design
- Humans
- Molecular Structure
- Triazoles/pharmacology
- Triazoles/therapeutic use*
- Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors*
- Zebrafish
- PubMed
- 33340911 Full text @ Eur. J. Med. Chem.
Citation
Wang, D.P., Liu, K.L., Li, X.Y., Lu, G.Q., Xue, W.H., Qian, X.H., Mohamed O, K., Meng, F.H. (2020) Design, synthesis, and in vitro and in vivo anti-angiogenesis study of a novel vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor based on 1,2,3-triazole scaffold. European Journal of Medicinal Chemistry. 211:113083.
Abstract
In the past five years, our team had been committed to click chemistry research, exploring the biological activity of 1,2,3-triazole by synthesizing different target inhibitors. In this study, a series of novel indole-2-one derivatives based on 1,2,3-triazole scaffolds were synthesized for the first time, and their inhibitory activity on vascular endothelial growth factor receptor-2 (VEGFR-2) was tested. Most of the compounds had shown promising activity in the VEGFR-2 kinase assay and had low toxicity to human umbilical vein endothelial cells (HUVECs). The compound 13d (IC50 = 26.38 nM) had better kinase activity inhibition ability than sunitinib (IC50 = 83.20 nM) and was less toxic to HUVECs. Moreover, it had an excellent inhibitory effect on HT-29 and MKN-45 cells. On the one hand, by tube formation assay, transwell, and Western blot analysis, compound 13d could inhibit VEGFR-2 protein phosphorylate on HUVECs, thereby inhibiting HUVECs migration and tube formation. In vivo study, the zebrafish model with VEGFR-2 labeling also verified that compound 13d had more anti-angiogenesis ability than sunitinib. On the other hand, molecular docking and molecular dynamics (MD) simulation results showed that compound 13d could stably bind to the active site of VEGFR-2. Based on the above findings, compound 13d could be considered an effective anti-angiogenesis drug and has more development value than sunitinib.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping