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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 ( IF 6.7 ) Pub Date : 2020-12-04 , DOI: 10.1016/j.ejmech.2020.113083
De-pu Wang , Kai-li Liu , Xin-yang Li , Guo-qing Lu , Wen-han Xue , Xin-hua Qian , Kamara Mohamed O , Fan-hao Meng

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.



中文翻译:

基于1,2,3-三唑支架的新型血管内皮生长因子受体2(VEGFR-2)抑制剂的设计,合成以及体内外抗血管生成研究

在过去的五年中,我们的团队一直致力于点击化学研究,通过合成不同的目标抑制剂来探索1,2,3-三唑的生物活性。本研究首次合成了基于1,2,3-三唑骨架的一系列新型吲哚-2-酮衍生物,并测试了它们对血管内皮生长因子受体2(VEGFR-2)的抑制作用。 。大多数化合物在VEGFR-2激酶测定中显示出有希望的活性,并且对人脐静脉内皮细胞(HUVEC)毒性低。化合物13d(IC 50  = 26.38 nM)具有比舒尼替尼(IC 50)更好的激酶活性抑制能力 = 83.20 nM),对HUVEC的毒性较小。而且,它对HT-29和MKN-45细胞具有优异的抑制作用。一方面,通过试管形成分析,transwell和Western blot分析,化合物13d可以抑制HUVEC上的VEGFR-2蛋白磷酸化,从而抑制HUVEC的迁移和管形成。在体内研究中,带有VEGFR-2标记的斑马鱼模型还证实了化合物13d比舒尼替尼具有更高的抗血管生成能力。另一方面,分子对接和分子动力学(MD)模拟结果表明,化合物13d可以稳定地结合VEGFR-2的活性位点。根据以上发现,化合物13d 可以被认为是一种有效的抗血管生成药物,并且比舒尼替尼具有更高的开发价值。

更新日期:2020-12-16
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