Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA.
Bioorg Med Chem. 2012 Apr 1;20(7):2444-54. doi: 10.1016/j.bmc.2012.01.029. Epub 2012 Feb 4.
With the goal of developing multitargeted receptor tyrosine kinase inhibitors that display potent inhibition against PDGFRβ and VEGFR-2 we designed and synthesized eleven N(4)-(3-bromophenyl)-7-(substitutedbenzyl) pyrrolo[2,3-d]pyrimidines 9a-19a. These compounds were obtained from the key intermediate N(4)-(3-bromophenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine 29. Various arylmethyl groups were regiospecifically attached at the N7 of 29 via sodium hydride induced alkylation with substituted arylmethyl halides. Compounds 11a and 19a were potent dual inhibitors of PDGFRβ and VEGFR-2. In a COLO-205, in vivo tumor mouse model 11a demonstrated inhibition of tumor growth, metastasis, and tumor angiogenesis that was better than or comparable to the standard compound TSU-68 (SU6668, 8).
我们的目标是开发具有多靶点受体酪氨酸激酶抑制作用的抑制剂，对 PDGFRβ 和 VEGFR-2 有很强的抑制作用，为此我们设计并合成了 11 种 N(4)-(3-溴苯基)-7-(取代苄基)吡咯并[2,3-d]嘧啶 9a-19a。这些化合物是由关键中间体 N(4)-(3-溴苯基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺 29 得到的。通过用取代的芳基卤化物在氢化钠诱导下进行区域特异性烷基化反应，将各种芳基甲基基团连接到 29 的 N7 上。化合物 11a 和 19a 是 PDGFRβ 和 VEGFR-2 的双重抑制剂。在 COLO-205 体内肿瘤小鼠模型中，化合物 11a 表现出对肿瘤生长、转移和肿瘤血管生成的抑制作用，优于或与标准化合物 TSU-68（SU6668，8）相当。
