Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 175, Issue -, Pages 349-356Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.04.015
Keywords
VEGFR-2 inhibition; Dioxinoquinazoline derivatives; Anti-Tumor; Toxicity assay
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Funding
- Beijing Scitech-MQ Pharmaceuticals Limited [SITG002]
- Beijing Key Laboratory for Green Catalysis and Separation
- Beijing Key Laboratory of Environmental Viral Oncology
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Twelve 2,3-dihydro-[1,4]-dioxino(2,3-flguinazoline derivatives were designed and evaluated as vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitors. The most half-maximal inhibitory concentration (IC50) values of them were less than 10 nM. Among these compounds, 13d displayed highly effective inhibitory activity against VEGFR-2 (IC50 = 2.4 nM) and excellent antiproliferative activities against human umbilical vein endothelial cells (HUVECs) (IC50 =1.2 nM). When anti-tumor animal experiments were carried out in mice, the tumor almost disappeared (TGI = 133.0%) after six days of administration of 13d. Therefore, 13d was a potential and effective anticancer agent. The binding conformations were respectively compared between VEGFR-2 with 13d and leading compound lenvatinib, and shows that they have similar binding modes. (C) 2019 Elsevier Masson SAS. All rights reserved.
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