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.
• Synthesis and evaluation of new potent inhibitors of CK1 and CDK5, two kinases involved in Alzheimer’s disease
  作者：Luc Demange、Olivier Lozach、Yoan Ferandin、Nha Thu Hoang、Laurent Meijer、Hervé Galons

  DOI：10.1007/s00044-012-0334-1

  日期：2013.7

  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).
• 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。