2-chloro-9-propan-2-yl-N-pyrazin-2-ylpurin-6-amine | 1416987-18-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: 2-chloro-9-propan-2-yl-N-pyrazin-2-ylpurin-6-amine
• CAS: 1416987-18-2
• 化学式: C₁₂H₁₂ClN₇
• 分子量: 289.727
• InChiKey: PVYDTGBTJLOFKH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  81.4
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-氨基丁醇 、 2-chloro-9-propan-2-yl-N-pyrazin-2-ylpurin-6-amine 在 三乙胺 作用下， 以 二甲基亚砜 为溶剂， 以61%的产率得到(2R)-2-[[9-propan-2-yl-6-(pyrazin-2-ylamino)purin-2-yl]amino]butan-1-ol
  参考文献：
  名称：

  Potent inhibitors of CDK5 derived from roscovitine: Synthesis, biological evaluation and molecular modelling

  摘要：

  Cyclin dependent kinase 5 (CDK5) is a serine/threonine kinase belonging to the cyclin dependent kinase (CDK) family. CDK5 is involved in numerous neuronal diseases (including Alzheimer's or Parkinson's diseases, stroke, traumatic brain injury), pain signaling and cell migration. In the present Letter, we describe syntheses and biological evaluations of new 2,6,9-trisubstituted purines, structurally related to roscovitine, a promising CDK inhibitor currently in clinical trials (CDK1/Cyclin B, IC50 = 350 nM; CDK5/p25, IC50 = 200 nM). These new molecules were synthesized using an original Buchwald-Hartwig catalytic procedure; several compounds (3j, 3k, 3l, 3e, 4k, 6b, 6c) displayed potent kinase inhibitory potencies against CDK5 (IC50 values ranging from 17 to 50 nM) and showed significant cell death inducing activities (IC50 values ranging from 2 to 9 mu M on SH-SY5Y). The docking of the inhibitors into the ATP binding domain of the CDK5 catalytic site highlighted the discriminatory effect of a hydrogen bond involving the CDK5 Lys-89. In addition, the calculated final energy balances for complexation measured for several inhibitors is consistent with the ranking of the IC50 values. Lastly, we observed that several compounds exhibit submicromolar activities against DYRK1A (dual specificity, tyrosine phosphorylation regulated kinase 1A), a kinase involved in Down syndrome and Alzheimer's disease (3g, 3h, 4m; IC50 values ranging from 300 to 400 nM). (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.10.141
• 作为产物：
  描述：

  2,6-二氯嘌呤 在 palladium diacetate 、 potassium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 作用下， 以 二甲基亚砜 、 甲苯 为溶剂， 反应 24.34h， 生成 2-chloro-9-propan-2-yl-N-pyrazin-2-ylpurin-6-amine
  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

• Potent inhibitors of CDK5 derived from roscovitine: Synthesis, biological evaluation and molecular modelling
  作者：Luc Demange、Fatma Nait Abdellah、Olivier Lozach、Yoan Ferandin、Nohad Gresh、Laurent Meijer、Hervé Galons

  DOI：10.1016/j.bmcl.2012.10.141

  日期：2013.1

  Cyclin dependent kinase 5 (CDK5) is a serine/threonine kinase belonging to the cyclin dependent kinase (CDK) family. CDK5 is involved in numerous neuronal diseases (including Alzheimer's or Parkinson's diseases, stroke, traumatic brain injury), pain signaling and cell migration. In the present Letter, we describe syntheses and biological evaluations of new 2,6,9-trisubstituted purines, structurally related to roscovitine, a promising CDK inhibitor currently in clinical trials (CDK1/Cyclin B, IC50 = 350 nM; CDK5/p25, IC50 = 200 nM). These new molecules were synthesized using an original Buchwald-Hartwig catalytic procedure; several compounds (3j, 3k, 3l, 3e, 4k, 6b, 6c) displayed potent kinase inhibitory potencies against CDK5 (IC50 values ranging from 17 to 50 nM) and showed significant cell death inducing activities (IC50 values ranging from 2 to 9 mu M on SH-SY5Y). The docking of the inhibitors into the ATP binding domain of the CDK5 catalytic site highlighted the discriminatory effect of a hydrogen bond involving the CDK5 Lys-89. In addition, the calculated final energy balances for complexation measured for several inhibitors is consistent with the ranking of the IC50 values. Lastly, we observed that several compounds exhibit submicromolar activities against DYRK1A (dual specificity, tyrosine phosphorylation regulated kinase 1A), a kinase involved in Down syndrome and Alzheimer's disease (3g, 3h, 4m; IC50 values ranging from 300 to 400 nM). (C) 2012 Elsevier Ltd. All rights reserved.
• Several Human Cyclin-Dependent Kinase Inhibitors, Structurally Related to Roscovitine, As New Anti-Malarial Agents
  作者：Sandrine Houzé、Nha-Thu Hoang、Olivier Lozach、Jacques Le Bras、Laurent Meijer、Hervé Galons、Luc Demange

  DOI：10.3390/molecules190915237

  日期：——

  In Africa, malaria kills one child each minute. It is also responsible for about one million deaths worldwide each year. Plasmodium falciparum, is the protozoan responsible for the most lethal form of the disease, with resistance developing against the available anti-malarial drugs. Among newly proposed anti-malaria targets, are the P. falciparum cyclin-dependent kinases (PfCDKs). There are involved in different stages of the protozoan growth and development but share high sequence homology with human cyclin-dependent kinases (CDKs). We previously reported the synthesis of CDKs inhibitors that are structurally-related to (R)-roscovitine, a 2,6,9-trisubstituted purine, and they showed activity against neuronal diseases and cancers. In this report, we describe the synthesis and the characterization of new CDK inhibitors, active in reducing the in vitro growth of P. falciparum (3D7 and 7G8 strains). Six compounds are more potent inhibitors than roscovitine, and three exhibited IC50 values close to 1 µM for both 3D7 and 7G8 strains. Although, such molecules do inhibit P. falciparum growth, they require further studies to improve their selectivity for PfCDKs.

  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。