2-氯-9-(1-甲基乙基)-N-[4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)苯基]-9H-嘌呤-6-胺 | 1056016-74-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 中文名称: 2-氯-9-(1-甲基乙基)-N-[4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)苯基]-9H-嘌呤-6-胺
• 英文名称: 2-chloro-6-[4-(tetramethyldioxaborolanyl)phenylamino]-9-iso-propylpurine
• 英文别名: 2-Chloro-9-isopropyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-9H-purin-6-amine；2-chloro-9-propan-2-yl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]purin-6-amine
• CAS: 1056016-74-0
• 化学式: C₂₀H₂₅BClN₅O₂
• 分子量: 413.715
• InChiKey: AEMOONMOGAXRJW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  74.1
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-氯-9-(1-甲基乙基)-N-[4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)苯基]-9H-嘌呤-6-胺 在 四(三苯基膦)钯 、 sodium carbonate 、 三乙胺 作用下， 以 1,4-二氧六环 、 水 、 二甲基亚砜 为溶剂， 生成 (R)-2-(1-hydroxybut-2-ylamino)-6-[4-(2-pyrimidinyl)phenylamino]-9-isopropylpurine
  参考文献：
  名称：

  Synthesis and evaluation of new potent inhibitors of CK1 and CDK5, two kinases involved in Alzheimer’s disease

  摘要：

  Cyclin-dependent kinase 5 (CDK5) and Casein kinase 1 (CK1) are both involved in the hyperphosphorylation of the Tau protein and in the amyloid-beta production, the two major hallmarks of Alzheimer's disease. In the present paper, we describe the synthesis and biological evaluation of new series of 2,6,9-trisubstituted purines derived from DRF53, a dual specificity inhibitor of the kinase activity of CDK5 (IC50 = 80 nM) and CK1 (IC50 = 10 nM), and are able to prevent in a dose-dependent manner the CK1-dependent production of amyloid-beta in a cell model. Several molecules (e.g., 6e, 6g, 7c) displayed potent kinase inhibitory activities against CDK5 and CK1 (IC50 values ranging from 20 to 50 nM) among which a selective inhibitor of CK1 has been identified (5a, IC50 = 60 nM). In addition, some compounds exhibit sub-micromolar activities against DYRK1A (dual specificity, tyrosine phosphorylation regulated kinase 1A), a kinase involved in Down syndrome and Alzheimer's disease (6g, IC50 = 510 nM).

  DOI：

  10.1007/s00044-012-0334-1
• 作为产物：
  描述：

  2,6-二氯嘌呤 在 potassium carbonate 、 三乙胺 作用下， 以 二甲基亚砜 、 正丁醇 为溶剂， 生成 2-氯-9-(1-甲基乙基)-N-[4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)苯基]-9H-嘌呤-6-胺
  参考文献：
  名称：

  Several Human Cyclin-Dependent Kinase Inhibitors, Structurally Related to Roscovitine, As New Anti-Malarial Agents

  摘要：

  在非洲，疟疾每分钟导致一名儿童死亡。每年全球大约有一百万例死亡是由疟疾引起的。恶性疟原虫（Plasmodium falciparum）是导致这种病最致命形式的原虫，并且对现有的抗疟药物产生了抗药性。在新提议的抗疟疾靶点中，恶性疟原虫的细胞周期依赖性激酶（PfCDKs）引起了关注。它们参与原虫生长和发育的不同阶段，但与人类细胞周期依赖性激酶（CDKs）有很高的序列同源性。我们之前报道了合成结构上与（R）-罗索维丁相关的CDK抑制剂，这是一种2,6,9-三取代的嘌呤，它们显示出对神经系统疾病和癌症的活性。在这份报告中，我们描述了新型CDK抑制剂的合成及其表征，这些抑制剂在体外能有效降低恶性疟原虫（3D7和7G8株）的生长。有六种化合物的抑制效力比罗索维丁更强，其中三种对3D7和7G8株的IC50值接近1 µM。尽管这些分子确实能抑制恶性疟原虫的生长，但需要进一步研究以提高其对PfCDKs的选择性。

  DOI：

  10.3390/molecules190915237

文献信息

• Roscovitine-Derived, Dual-Specificity Inhibitors of Cyclin-Dependent Kinases and Casein Kinases 1
  作者：Nassima Oumata、Karima Bettayeb、Yoan Ferandin、Luc Demange、Angela Lopez-Giral、Marie-Lorène Goddard、Vassilios Myrianthopoulos、Emmanuel Mikros、Marc Flajolet、Paul Greengard、Laurent Meijer、Hervé Galons

  DOI：10.1021/jm800109e

  日期：2008.9.11

  Cyclin-dependent kinases (CDKs) and casein kinases 1 (CK 1) are involved in the two key molecular features of Alzheimer's disease, production of amyloid-beta peptides (extracellular plaques) and hyper-phosphorylation of Tau (intracellular neurofibrillary tangles). A series of 2,6,9-trisubstituted purines, structurally related to the CDK inhibitor roscovitine, have been synthesized. They mainly differ by the substituent on the C-6 position. These compounds were screened for kinase inhibitory activities and antiproliferative effects. Several biaryl derivatives displayed potent inhibition of both CDKs and CK1. In particular, derivative 13a was a potent inhibitor of CDK1/cyclin B (IC50: 220 nM), CDK5/p25 (IC50: 80 nM), and CK1 (IC50: 14 nM). Modeling of these molecules into the ATP-binding pocket of CK1 delta provided a rationale for the increased selectivity toward this kinase. 13a was able to prevent the CK1-dependent production of anyloid-beta in a cell model. CDK/CK1 dual-specificity inhibitors may have important applications in Alzheimer's disease and cancers.