4-chloro-6-(methylthio)-1-(2-phenylethyl)-1H-pyrazolo[3,4-d]-pyrimidine | 1338789-21-1

• 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: 4-chloro-6-(methylthio)-1-(2-phenylethyl)-1H-pyrazolo[3,4-d]-pyrimidine
• 英文别名: 4-chloro-6-(methylthio)-1-phenethyl-1H-pyrazolo[3,4-d]pyrimidine
• CAS: 1338789-21-1
• 化学式: C₁₄H₁₃ClN₄S
• 分子量: 304.803
• InChiKey: PYESRJWMZUKXQP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.44
• 重原子数：
  20.0
• 可旋转键数：
  4.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  43.6
• 氢给体数：
  0.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  4-chloro-6-(methylthio)-1-(2-phenylethyl)-1H-pyrazolo[3,4-d]-pyrimidine 在 10 wt% Pd(OH)2 on carbon 、 氢气 作用下， 以 甲醇 、 乙醇 为溶剂， 反应 14.0h， 生成 N-(3-chlorophenyl)-1-(2-phenylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
  参考文献：
  名称：

  探索特权吡唑并[3,4- d ]嘧啶支架周围的化学空间：寻求新型的T315I突变型Abl的变构抑制剂

  摘要：

  具有高水平分子多样性的吡唑并[3,4- d ]嘧啶文库已通过应用允许C3，N1，C4和C6取代的合成序列开发而成。对这种基于“特权支架”的化合物集合的酶促筛选，证实了在以目标为导向的合成为特征的领域中，以多样性为导向的方法的使用。实际上，几种化合物对选定的激酶表现出高活性（即Src，Abl wt和T315I突变形式），而且有趣的是，新化合物作为A315的T315I突变形式的变构抑制剂出现了，打开了大门。开发新型非竞争性Abl抑制剂（T315I）的新机会。

  DOI：

  10.1021/co500004e
• 作为产物：
  描述：

  6-(methylthio)-1-(2-phenylethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]-pyrimidin-4-one 在 N,N-二甲基甲酰胺 、 三氯氧磷 作用下， 以 氯仿 为溶剂， 反应 8.0h， 以83%的产率得到4-chloro-6-(methylthio)-1-(2-phenylethyl)-1H-pyrazolo[3,4-d]-pyrimidine
  参考文献：
  名称：

  Identification of potent c-Src inhibitors strongly affecting the proliferation of human neuroblastoma cells

  摘要：

  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.

  DOI：

  10.1016/j.bmcl.2011.07.079

文献信息

• Combining X-ray Crystallography and Molecular Modeling toward the Optimization of Pyrazolo[3,4-<i>d</i>]pyrimidines as Potent c-Src Inhibitors Active in Vivo against Neuroblastoma
  作者：Cristina Tintori、Anna Lucia Fallacara、Marco Radi、Claudio Zamperini、Elena Dreassi、Emmanuele Crespan、Giovanni Maga、Silvia Schenone、Francesca Musumeci、Chiara Brullo、André Richters、Francesca Gasparrini、Adriano Angelucci、Claudio Festuccia、Simona Delle Monache、Daniel Rauh、Maurizio Botta

  DOI：10.1021/jm5013159

  日期：2015.1.8

  c-Src is a tyrosine kinase belonging to the Src-family kinases. It is overexpressed and/or hyperactivated in a variety of cancer cells, thus its inhibition has been predicted to have therapeutic effects in solid tumors. Recently, the pyrazolo[3,4-d]pyrimidine 3 was reported as a dual c-Src/Abl inhibitor. Herein we describe a multidisciplinary drug discovery approach for the optimization of the lead 3 against c-Src. Starting from the X-ray crystal structure of c-Src in complex with 3, Monte Carlo free energy perturbation calculations were applied to guide the design of c-Src inhibitors with improved activities. As a result, the introduction of a meta hydroxyl group on the C4 anilino ring was computed to be particularly favorable. The potency of the synthesized inhibitors was increased with respect to the starting lead 3. The best identified compounds were also found active in the inhibition of neuroblastoma cell proliferation. Furthermore, compound 29 also showed in vivo activity in xenograft model using SH-SY5Y cells.