(3-bromo-phenyl)-[6-methylsulfanyl-1-(2-phenyl-propyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amine | 1338789-34-6

• 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: (3-bromo-phenyl)-[6-methylsulfanyl-1-(2-phenyl-propyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amine
• 英文别名: N-(3-bromophenyl)-6-(methylthio)-1-(2-phenylpropyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine；N-(3-bromophenyl)-6-methylsulfanyl-1-(2-phenylpropyl)pyrazolo[3,4-d]pyrimidin-4-amine
• CAS: 1338789-34-6
• 化学式: C₂₁H₂₀BrN₅S
• 分子量: 454.393
• InChiKey: JSXXDWHFXXQDDJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  80.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (3-bromo-phenyl)-[6-methylsulfanyl-1-(2-phenyl-propyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amine 在 碳酸氢钠 作用下， 以 二氯甲烷 为溶剂， 反应 19.0h， 生成 2-(4-methylpiperazin-1-yl)ethyl 3-bromophenyl(6-(methylthio)-1-(2-phenylpropyl)-1Hpyrazolo[3,4-d]pyrimidin-4-yl)carbamate
  参考文献：
  名称：

  吡唑并[3,4- d ]嘧啶的前药：从文库合成到原位成胶质母细胞瘤模型中潜在抗癌药的评价

  摘要：

  吡唑并[3,4- d ]嘧啶是有效的蛋白激酶抑制剂，具有有希望的抗肿瘤活性，但水溶性较差，因此值得进一步优化。在这里，我们提出了一锅两步程序，用于合成一组具有较高水溶性和增强的药代动力学和治疗特性的吡唑并[3,4- d ]嘧啶前药（1a - 8a和9a - e）。ADME研究表明，最有前途的前药具有更好的水溶性，在人和鼠血清中具有良好的水解作用，并且相对于母体药物而言，其跨细胞膜的能力增强，这说明了它们在体外24小时的性能更好对人胶质母细胞瘤U87细胞系的细胞毒性。最后，还对体内的4–4a药物/前药进行了评估，揭示了前药具有良好疗效的有利的药代动力学特征。事实证明，前药方法的应用是提高母体药物水溶性的成功策略，对它们的生物学功效也产生了积极影响。

  DOI：

  10.1021/acs.jmedchem.7b00637
• 作为产物：
  描述：

  β-溴代异丙基苯 在 一水合肼 、 N,N-二甲基甲酰胺 、 sodium hydroxide 、 三氯氧磷 作用下， 以 四氢呋喃 、 乙醇 、 氯仿 、 水 为溶剂， 反应 79.17h， 生成 (3-bromo-phenyl)-[6-methylsulfanyl-1-(2-phenyl-propyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amine
  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

• Pyrazolo[3,4-<i>d</i>]pyrimidine Prodrugs: Strategic Optimization of the Aqueous Solubility of Dual Src/Abl Inhibitors
  作者：Giulia Vignaroli、Claudio Zamperini、Elena Dreassi、Marco Radi、Adriano Angelucci、Patrizia Sanità、Emmanuele Crespan、Miroslava Kissova、Giovanni Maga、Silvia Schenone、Francesca Musumeci、Maurizio Botta

  DOI：10.1021/ml4000782

  日期：2013.7.11

  Design and synthesis of prodrugs of promising drug candidates represents a valid strategy to overcome the lack of favorable ADME properties, in particular aqueous solubility and bioavailability. We report herein the successful application of this strategy with two representative pyrazolo[3,4-d]pyrimidine derivatives (1 and 2), which led to the development of the corresponding and highly water-soluble

  设计和合成有前景的候选药物的前药代表了克服缺乏有利的 ADME 特性，特别是水溶性和生物利用度的有效策略。我们在此报告了该策略与两种代表性吡唑并[3,4- d ]嘧啶衍生物（1和2）的成功应用，这导致了相应的高水溶性抗肿瘤前药（7和8）的开发。体外研究证实了水溶性的显着改善，并且对于化合物8 而言，具有良好的血浆稳定性，表明其具有优异的体内生物利用度。正如预期的那样，未裂解的水溶性前药7和8对酶靶标（c-Src 和 c-Abl）没有活性，但在骨髓细胞系中显示出有希望的抗增殖活性，这是由于所选增溶部分的体外水解，随后释放活性化合物（1和2）。
• COMPOUNDS AND USES THEREOF
  申请人：LEAD DISCOVERY SIENA S.R.L.

  公开号：US20180186796A1

  公开（公告）日：2018-07-05

  The present invention refers to 4-amino-substituted pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine derivatives of formula I and IV able to target the Src family kinases (SFKs) such as Src, Fyn and Hck tyrosine kinases as well as Abl tyrosine kinase and uses and method of preparation thereof. In particular, the compounds of the invention are for use in the treatment and/or prevention of cancer, such as neuroblastoma (NB) or glioblastoma multiforme (GBM) or for use in the treatment and/or prevention of neurodegenerative diseases such as taupathies.
• Prodrugs of Pyrazolo[3,4-<i>d</i>]pyrimidines: From Library Synthesis to Evaluation as Potential Anticancer Agents in an Orthotopic Glioblastoma Model
  作者：Giulia Vignaroli、Giulia Iovenitti、Claudio Zamperini、Federica Coniglio、Pierpaolo Calandro、Alessio Molinari、Anna Lucia Fallacara、Andrea Sartucci、Alessia Calgani、David Colecchia、Andrea Mancini、Claudio Festuccia、Elena Dreassi、Massimo Valoti、Francesca Musumeci、Mario Chiariello、Adriano Angelucci、Maurizio Botta、Silvia Schenone

  DOI：10.1021/acs.jmedchem.7b00637

  日期：2017.7.27

  Pyrazolo[3,4-d]pyrimidines are potent protein kinase inhibitors with promising antitumor activity but suboptimal aqueous solubility, consequently worth being further optimized. Herein, we present the one-pot two-step procedure for the synthesis of a set of pyrazolo[3,4-d]pyrimidine prodrugs (1a−8a and 9a−e) with higher aqueous solubility and enhanced pharmacokinetic and therapeutic properties. ADME

  吡唑并[3,4- d ]嘧啶是有效的蛋白激酶抑制剂，具有有希望的抗肿瘤活性，但水溶性较差，因此值得进一步优化。在这里，我们提出了一锅两步程序，用于合成一组具有较高水溶性和增强的药代动力学和治疗特性的吡唑并[3,4- d ]嘧啶前药（1a - 8a和9a - e）。ADME研究表明，最有前途的前药具有更好的水溶性，在人和鼠血清中具有良好的水解作用，并且相对于母体药物而言，其跨细胞膜的能力增强，这说明了它们在体外24小时的性能更好对人胶质母细胞瘤U87细胞系的细胞毒性。最后，还对体内的4–4a药物/前药进行了评估，揭示了前药具有良好疗效的有利的药代动力学特征。事实证明，前药方法的应用是提高母体药物水溶性的成功策略，对它们的生物学功效也产生了积极影响。
• 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.