Discovery of multi-target receptor tyrosine kinase inhibitors as novel anti-angiogenesis agents.
Discovery of multi-target receptor tyrosine kinase inhibitors as novel anti-angiogenesis agents.
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发现多靶点受体酪氨酸激酶抑制剂作为新型抗血管生成剂
DOI：
10.1038/srep45145
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发表时间：
2017-03-23
影响因子：
4.6
通讯作者：
Zhang J
中科院分区：
文献类型：
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作者：
Wang J;Zhang L;Pan X;Dai B;Sun Y;Li C;Zhang J
最近，我们发现了一种结合水杨醛肟（BPS-7）的联苯芳基尿素作为抗血管生成剂。本研究通过二脲类化合物与n-吡啶-2-基环丙烷甲酰胺的结合，公开了一系列以bps -7为先导化合物的新型抗血管生成药物。几种标题化合物对三种促血管生成rtk （VEGFR-2、TIE-2和EphB4）同时具有抑制作用。其中部分对人血管内皮细胞具有较强的抗增殖活性（EA.hy926）。特别是，两种有效的化合物（caud1和caud2）可以被认为是有前途的抗血管生成药物，具有三重抑制谱。生物学评价和分子对接结果表明，n-吡啶-2-基环丙烷羧酰胺可作为一种铰链结合基团（HBG），用于发现多靶点抗血管生成药物。在血管生成的组织模型中，caud2也显示出有希望的抗血管生成效力。
Recently, we have identified a biphenyl-aryl urea incorporated with salicylaldoxime (BPS-7) as an anti-angiogenesis agent. Herein, we disclosed a series of novel anti-angiogenesis agents withBPS-7as lead compound through combining diarylureas withN-pyridin-2-ylcyclopropane carboxamide. Several title compounds exhibited simultaneous inhibition effects against three pro-angiogenic RTKs (VEGFR-2, TIE-2 and EphB4). Some of them displayed potent anti-proliferative activity against human vascular endothelial cell (EA.hy926). In particular, two potent compounds (CDAU-1 and CDAU-2) could be considered as promising anti-angiogenesis agents with triplet inhibition profile. The biological evaluation and molecular docking results indicate thatN-pyridin-2-ylcyclopropane carboxamide could serve as a hinge-binding group (HBG) for the discovery of multi-target anti-angiogenesis agents. CDAU-2 also exhibited promising anti-angiogenic potency in a tissue model for angiogenesis.