6-(methylthio)-1-(2-phenylethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]-pyrimidin-4-one | 1338789-19-7

• 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: 6-(methylthio)-1-(2-phenylethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]-pyrimidin-4-one
• CAS: 1338789-19-7
• 化学式: C₁₄H₁₄N₄OS
• 分子量: 286.357
• InChiKey: VNQDWNDLYDTYSC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.08
• 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：
  63.57
• 氢给体数：
  1.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  6-(methylthio)-1-(2-phenylethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]-pyrimidin-4-one 在 三氯氧磷 作用下， 以 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 3-(6-(methylthio)-1-phenethyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenol
  参考文献：
  名称：

  Combining X-ray Crystallography and Molecular Modeling toward the Optimization of Pyrazolo[3,4-d]pyrimidines as Potent c-Src Inhibitors Active in Vivo against Neuroblastoma

  摘要：

  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.

  DOI：

  10.1021/jm5013159
• 作为产物：
  描述：

  5-氨基-1-苯乙基吡唑-4-甲酸乙酯 在 sodium hydroxide 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 42.17h， 生成 6-(methylthio)-1-(2-phenylethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]-pyrimidin-4-one
  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