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在 4-苯胺基取代的吡咯并[2,3-d]嘧啶中，2-氨基基团对受体酪氨酸激酶抑制和抗血管生成活性的贡献。

The contribution of a 2-amino group on receptor tyrosine kinase inhibition and antiangiogenic activity in 4-anilinosubstituted pyrrolo[2,3-d]pyrimidines.

机构信息

Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA.

出版信息

Bioorg Med Chem Lett. 2010 May 15;20(10):3177-81. doi: 10.1016/j.bmcl.2010.03.064. Epub 2010 Mar 24.

DOI:10.1016/j.bmcl.2010.03.064
PMID:20403693
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2866134/
Abstract

Comparison between a series of pyrrolo[2,3-d]pyrimidines with and without the 2-amino group is presented in order to determine the validity of our hypothesis that inclusion of this group improves potency against receptor tyrosine kinases (RTK). The 2-amino analogs were better against epidermal growth factor receptor (EGFR) and platelet derived growth factor-beta (PDGFR-beta) in whole cell inhibition assays and in the A431 cytotoxicity assay compared to the 2-desamino analogs. However, the 2-desamino analogs were more potent inhibitors against vascular endothelial growth factor-2 (VEGFR-2) than the corresponding 2-amino compounds. In addition, none of the 2-desamino compounds exhibited better anti-angiogenic activity in the chorioallantoic membrane (CAM) assay as compared to the standard and were only micromolar inhibitors. This study validates our original hypothesis that the inclusion of a 2-amino group in pyrrolo[2,3-d]pyrimidines improves multiple RTK inhibition and antiangiogenic activity.

摘要

为了确定我们的假设（即包含 2-氨基基团可以提高对受体酪氨酸激酶（RTK）的效力）的有效性，我们对一系列具有和不具有 2-氨基基团的吡咯并[2,3-d]嘧啶进行了比较。在全细胞抑制测定和 A431 细胞毒性测定中，2-氨基类似物比 2-去氨基类似物对表皮生长因子受体（EGFR）和血小板衍生生长因子-β（PDGFR-β）的抑制作用更好。然而，2-去氨基类似物对血管内皮生长因子-2（VEGFR-2）的抑制作用比相应的 2-氨基化合物更强。此外，与标准品相比，没有任何 2-去氨基化合物在鸡胚尿囊膜（CAM）测定中表现出更好的抗血管生成活性，并且仅为微摩尔抑制剂。这项研究验证了我们最初的假设，即在吡咯并[2,3-d]嘧啶中包含 2-氨基基团可以提高多种 RTK 抑制和抗血管生成活性。

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