School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province, 710061, PR China.
Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, PR China.
Eur J Med Chem. 2017 Feb 15;127:275-285. doi: 10.1016/j.ejmech.2016.12.059. Epub 2017 Jan 2.
Angiogenesis is modulated by a multitude of pro-angiogenic factors including VEGFR-2, Tie-2, and EphB4. Moreover, their crosstalk also had been well elaborated. We have identified several diarylurea-based VEGFR-2 inhibitors as potential anti-angiogenesis agents. As a continuation to our previous research, two series of diaryl malonamide and diaryl thiourea derivatives have been developed as multiplex VEGFR-2/Tie-2/EphB4 inhibitors. Interestingly, the biological evaluation indicated that several compounds bearing trifluoromethyl or trifluoromethoxyl exhibited promising multiplex inhibition against angiogenesis-related VEGFR-2, Tie-2, and EphB4. The representative compound (18a) displayed both potent multi-targeted RTK inhibition and considerable antiproliferative activities against human umbilical vein endothelial cells (EA.hy926). These results will contribute to the discovery of novel muti-targeted anti-angiogenesis agents.
血管生成受多种促血管生成因子的调节，包括 VEGFR-2、Tie-2 和 EphB4。此外，它们的相互作用也得到了很好的阐述。我们已经鉴定出几种基于二芳基脲的 VEGFR-2 抑制剂作为潜在的抗血管生成剂。作为我们之前研究的延续，我们开发了两类二芳基丙二酰胺和二芳基硫脲衍生物作为多靶点 VEGFR-2/Tie-2/EphB4 抑制剂。有趣的是，生物学评价表明，一些含有三氟甲基或三氟甲氧基的化合物对与血管生成相关的 VEGFR-2、Tie-2 和 EphB4 具有有希望的多靶点抑制作用。代表性化合物（18a）对人脐静脉内皮细胞（EA.hy926）显示出强大的多靶点 RTK 抑制作用和显著的抗增殖活性。这些结果将有助于发现新型多靶点抗血管生成剂。
