N-(3-chlorophenyl)-1-(2-phenylpropyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine | 1283727-55-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡唑并嘧啶类
• 英文名称: N-(3-chlorophenyl)-1-(2-phenylpropyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
• 英文别名: N-(3-chlorophenyl)-1-(2-phenylpropyl)pyrazolo[3,4-d]pyrimidin-4-amine
• CAS: 1283727-55-8
• 化学式: C₂₀H₁₈ClN₅
• 分子量: 363.849
• InChiKey: XFCBZNMZGGDLOU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  55.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  (2-溴丙基)苯 在 N,N-二甲基甲酰胺 、 肼 、 三氯氧磷 作用下， 以 乙醇 、 氯仿 为溶剂， 反应 47.0h， 生成 N-(3-chlorophenyl)-1-(2-phenylpropyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
  参考文献：
  名称：

  Design, Synthesis, Biological Activity, and ADME Properties of Pyrazolo[3,4-d]pyrimidines Active in Hypoxic Human Leukemia Cells: A Lead Optimization Study

  摘要：

  A family of dual Src/Abl inhibitors characterized by a substituted pyrazolo[3,4-d]pyrimidine scaffold was previously reported by us and proved to be active against several tumor cell lines. Among these compounds, a promising antileukemia lead (1) has been recently identified, but, unfortunately, it suffers from substandard pharmaceutical properties. Accordingly, an approach for the optimization of the lead 1 is described in the present work. A series of more soluble pyrazolo[3,4-d]pyrimidine derivatives were rationally designed and proved to maintain the dual Src/Abl activity of the lead. Selected compounds showed an interesting activity profile against three different leukemic cells also in hypoxic conditions, which are usually characterized by imatinib-resistance. Finally, in vitro ADME properties (PAMPA permeation, water solubility, microsomal stability) for the most promising inhibitors were also evaluated, thus allowing the identification of a few optimized analogues of lead 1 as promising antileukemia agents.

  DOI：

  10.1021/jm1012819

文献信息

• Identification of potent c-Src inhibitors strongly affecting the proliferation of human neuroblastoma cells
  作者：Marco Radi、Chiara Brullo、Emmanuele Crespan、Cristina Tintori、Francesca Musumeci、Mariangela Biava、Silvia Schenone、Elena Dreassi、Claudio Zamperini、Giovanni Maga、Dafne Pagano、Adriano Angelucci、Mauro Bologna、Maurizio Botta

  DOI：10.1016/j.bmcl.2011.07.079

  日期：2011.10

  Neuroblastoma (NB) represents the most common extracranial paediatric solid tumor for which no specific FDA-approved treatment is currently available. The tyrosine kinase c-Src has been reported to play an important role in the differentiation, cell-adhesion and survival of NB cells. Starting from dual Src/Abl inhibitors previously found active in NB cell lines (1-3), small modification of the original structures almost abolished the Abl activity with a contemporary improvement of affinity and specificity for cSrc. Among the synthesized compounds, the most potent c-Src inhibitor (10a) showed a very interesting antiproliferative activity in SH-SY5Y cells with an IC50 of 80 nM and a favourable ADME profile. A 3D SAR analysis was also attempted and may guide the design of more potent c-Src inhibitors as potential agents for NB treatment. (C) 2011 Elsevier Ltd. All rights reserved.
• Design, Synthesis, Biological Activity, and ADME Properties of Pyrazolo[3,4-<i>d</i>]pyrimidines Active in Hypoxic Human Leukemia Cells: A Lead Optimization Study
  作者：Marco Radi、Elena Dreassi、Chiara Brullo、Emmanuele Crespan、Cristina Tintori、Vincenzo Bernardo、Massimo Valoti、Claudio Zamperini、Henry Daigl、Francesca Musumeci、Fabio Carraro、Antonella Naldini、Irene Filippi、Giovanni Maga、Silvia Schenone、Maurizio Botta

  DOI：10.1021/jm1012819

  日期：2011.4.28

  A family of dual Src/Abl inhibitors characterized by a substituted pyrazolo[3,4-d]pyrimidine scaffold was previously reported by us and proved to be active against several tumor cell lines. Among these compounds, a promising antileukemia lead (1) has been recently identified, but, unfortunately, it suffers from substandard pharmaceutical properties. Accordingly, an approach for the optimization of the lead 1 is described in the present work. A series of more soluble pyrazolo[3,4-d]pyrimidine derivatives were rationally designed and proved to maintain the dual Src/Abl activity of the lead. Selected compounds showed an interesting activity profile against three different leukemic cells also in hypoxic conditions, which are usually characterized by imatinib-resistance. Finally, in vitro ADME properties (PAMPA permeation, water solubility, microsomal stability) for the most promising inhibitors were also evaluated, thus allowing the identification of a few optimized analogues of lead 1 as promising antileukemia agents.