Institut de Chimie Organique et Analytique, CNRS UMR 7311, B.P. 6759, 45067 Orléans Cedex 2, France; Equipe de Chimie Bioorganique & Analytique, URAC 22, Université Hassan II Mohammedia-Casablanca, BP 146, 28800 Mohammedia, Morocco.
Institut de Chimie Organique et Analytique, CNRS UMR 7311, B.P. 6759, 45067 Orléans Cedex 2, France.
Eur J Med Chem. 2014 Jun 10;80:352-63. doi: 10.1016/j.ejmech.2014.04.055. Epub 2014 Apr 22.
We here report the synthesis and biological evaluation of an original collection of 4,7-disubstituted pyrido[3,2-d]pyrimidines designed as potential kinase inhibitors. The collection was generated from a single starting material, 4,7-dichloropyrido[3,2-d]pyrimidine, which afforded the final compounds after two steps: a sequential or one-pot sequence including selective cross coupling reactions in C-4, followed by the second cross-coupling in C-7. In position C-4, a Suzuki-Miyaura type reaction led to monosubstituted derivatives whereas in position C-7, synthesis was achieved via a Suzuki or a Buchwald type reaction using commercially available or undescribed boron derivatives. The biological activity of the V-shaped family was measured in protein kinase assays. The structure activity relationship (SAR) revealed that some compounds selectively inhibited DYRK1A and CDK5 without affecting GSK3. Docking studies furnished possible explanations that correlate with the SAR data. The most active compound on the two biological targets was 27 which exhibited the following IC50: 110 nM for CDK5, 24 nM for DYRK1A and only 1.2 μM for GSK3. In the C-7 amino subfamily, the best derivative was indubitably compound 48 which led to a near selective action on DYRK1A and a remarkable IC50 of 60 nM.
我们在此报告了一系列 4,7-二取代的吡啶并[3,2-d]嘧啶的合成和生物评价，这些化合物被设计为潜在的激酶抑制剂。该系列化合物由单一起始原料 4,7-二氯吡啶并[3,2-d]嘧啶合成，经过两步反应得到最终化合物：在 C-4 位进行选择性交叉偶联反应的顺序或一锅法序列，然后在 C-7 位进行第二次交叉偶联。在 C-4 位，Suzuki-Miyaura 型反应得到单取代衍生物，而在 C-7 位，通过Suzuki 或 Buchwald 型反应使用商业上可获得的或未描述的硼衍生物合成。V 形家族的生物活性在蛋白激酶测定中进行了测量。构效关系（SAR）表明，一些化合物选择性地抑制 DYRK1A 和 CDK5，而不影响 GSK3。对接研究提供了可能与 SAR 数据相关的解释。在两个生物学靶标上最活跃的化合物是 27，其对 CDK5 的 IC50 为 110 nM，对 DYRK1A 的 IC50 为 24 nM，对 GSK3 的 IC50 仅为 1.2 μM。在 C-7 氨基亚家族中，最好的衍生物无疑是化合物 48，它对 DYRK1A 具有近乎选择性的作用，IC50 为 60 nM。
