4-chloro-1-(2-chloro-2-phenylethyl)-6-[(2-morpholin-4-ylethyl) thio]-1H-pyrazolo[3,4-d]pyrimidine | 1283727-43-4

• 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-1-(2-chloro-2-phenylethyl)-6-[(2-morpholin-4-ylethyl) thio]-1H-pyrazolo[3,4-d]pyrimidine
• 英文别名: 4-chloro-1-(2-chloro-2-phenylethyl)-6-[(2-morpholinoethyl)thio]-1H-pyrazolo[3,4-d]pyrimidine；4-[2-[4-Chloro-1-(2-chloro-2-phenylethyl)pyrazolo[3,4-d]pyrimidin-6-yl]sulfanylethyl]morpholine
• CAS: 1283727-43-4
• 化学式: C₁₉H₂₁Cl₂N₅OS
• 分子量: 438.381
• InChiKey: NEZWABBEAVQIIS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  81.4
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-chloro-1-(2-chloro-2-phenylethyl)-6-[(2-morpholin-4-ylethyl) thio]-1H-pyrazolo[3,4-d]pyrimidine 、 3-氨基苯酚 以 乙醇 为溶剂， 反应 8.0h， 以68%的产率得到3-({1-(2-chloro-2-phenylethyl)-6-[(2-morpholinoethyl)thio]-1H-pyrazolo[3,4-d]pyrimidin-4-yl}amino)phenol
  参考文献：
  名称：

  Efficient optimization of pyrazolo[3,4-d]pyrimidines derivatives as c-Src kinase inhibitors in neuroblastoma treatment

  摘要：

  The proto-oncogene c-Src is a non-receptor tyrosine kinase which is involved in the regulation of many cellular processes, such as differentiation, adhesion and survival. c-Src hyperactivation has been detected in many tumors, including neuroblastoma (NB), one of the major causes of death from neoplasia in infancy. We already reported a large family of pyrazolo[3,4-d]pyrimidines active as c-Src inhibitors. Interestingly, some of these derivatives resulted also active on SH-SY5Y NB cell line. Herein, starting from our previous Free Energy Perturbation/Monte Carlo calculations, we report an optimization study which led to the identification of a new series of derivatives endowed with nanomolar K-i values against c-Src, interesting antiproliferative activity on SH-SY5Y cells and a suitable ADME profile.

  DOI：

  10.1016/j.bmcl.2018.09.024
• 作为产物：
  描述：

  4-(2-氯乙基)吗啉 在 N,N-二甲基甲酰胺 、 sodium hydroxide 、 三氯氧磷 作用下， 以 乙醇 、 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 14.0h， 生成 4-chloro-1-(2-chloro-2-phenylethyl)-6-[(2-morpholin-4-ylethyl) thio]-1H-pyrazolo[3,4-d]pyrimidine
  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

• Novel pyrazolo[3,4-d]pyrimidines as dual Src/Bcr-Abl kinase inhibitors: Synthesis and biological evaluation for chronic myeloid leukemia treatment
  作者：Salvatore Di Maria、Francesca Picarazzi、Mattia Mori、Annarita Cianciusi、Anna Carbone、Emmanuele Crespan、Cecilia Perini、Samantha Sabetta、Serenella Deplano、Federica Poggialini、Alessio Molinari、Rossella Aronne、Elias Maccioni、Giovanni Maga、Adriano Angelucci、Silvia Schenone、Francesca Musumeci、Elena Dreassi

  DOI：10.1016/j.bioorg.2022.106071

  日期：2022.11

  molecules active as dual Src/Bcr-Abl inhibitors emerged as effective targeted therapies for CML and a few compounds are currently in clinical use. In this study, we applied a target-oriented approach to identify a family of pyrazolo[3,4-d]pyrimidines as dual Src/Bcr-Abl inhibitors as anti-leukemia agents. Considering the high homology between Src and Bcr-Abl, in-house Src inhibitors 8a-l and new analogue compounds

  Bcr-Abl 酪氨酸激酶 (TK) 是慢性粒细胞白血病 (CML) 的分子标志。Src 是另一种 TK 激酶，其参与 CML 已被广泛证实。作为双 Src/Bcr-Abl 抑制剂活性的小分子作为 CML 的有效靶向疗法出现，一些化合物目前正在临床使用。在这项研究中，我们应用了一种靶向方法来确定吡唑并[3,4- d ]嘧啶家族作为双 Src/Bcr-Abl 抑制剂作为抗白血病药物。考虑到 Src 和 Bcr-Abl 之间的高度同源性，内部Src 抑制剂8a-l和新的类似化合物9a-n被筛选为双重 Src/Bcr-Abl 抑制剂。确定了最有希望的化合物对 K562 CML 细胞的抗增殖活性和 ADME 谱。分子模型研究阐明了抑制剂与 Bcr-Abl (wt) 催化口袋的结合模式。化合物8j和8k在酶促和细胞测定中显示出纳摩尔活性，以及​​良好的 ADME 特性，成为 CML 治疗的有希望的候
• Identification and Biological Characterization of the Pyrazolo[3,4-d]pyrimidine Derivative SI388 Active as Src Inhibitor
  作者：Claudia Contadini、Claudia Cirotti、Anna Carbone、Mehrdad Norouzi、Annarita Cianciusi、Emmanuele Crespan、Cecilia Perini、Giovanni Maga、Daniela Barilà、Francesca Musumeci、Silvia Schenone

  DOI：10.3390/ph16070958

  日期：——

  including glioblastoma (GBM), has been extensively demonstrated. In this context, we started from our in-house library of pyrazolo[3,4-d]pyrimidines that are active as Src and/or Bcr-Abl TK inhibitors and performed a lead optimization study to discover a new generation derivative that is suitable for Src kinase targeting. We synthesized a library of 19 compounds, 2a-s. Among these, compound 2a (SI388)

  Src 是一种非受体酪氨酸激酶 (TK)，其与癌症（包括胶质母细胞瘤 (GBM)）的参与已被广泛证明。在这种情况下，我们从具有 Src 和/或 Bcr-Abl TK 抑制剂活性的吡唑并[3,4-d]嘧啶的内部库开始，进行了先导化合物优化研究，以发现适合的新一代衍生物用于 Src 激酶靶向。我们合成了 19 种化合物（2a-s）的库。其中，化合物 2a (SI388) 被确定为最有效的 Src 抑制剂。基于无细胞结果，我们研究了 SI388 在 2D 和 3D GBM 细胞模型中的作用。有趣的是，SI388 显着抑制 Src 激酶，从而影响细胞活力、致瘤性并增强癌细胞对电离辐射的敏感性。
• 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.
• Efficient optimization of pyrazolo[3,4-d]pyrimidines derivatives as c-Src kinase inhibitors in neuroblastoma treatment
  作者：Alessio Molinari、Anna Lucia Fallacara、Salvatore Di Maria、Claudio Zamperini、Federica Poggialini、Francesca Musumeci、Silvia Schenone、Adriano Angelucci、Alessandro Colapietro、Emmanuele Crespan、Miroslava Kissova、Giovanni Maga、Maurizio Botta

  DOI：10.1016/j.bmcl.2018.09.024

  日期：2018.11

  The proto-oncogene c-Src is a non-receptor tyrosine kinase which is involved in the regulation of many cellular processes, such as differentiation, adhesion and survival. c-Src hyperactivation has been detected in many tumors, including neuroblastoma (NB), one of the major causes of death from neoplasia in infancy. We already reported a large family of pyrazolo[3,4-d]pyrimidines active as c-Src inhibitors. Interestingly, some of these derivatives resulted also active on SH-SY5Y NB cell line. Herein, starting from our previous Free Energy Perturbation/Monte Carlo calculations, we report an optimization study which led to the identification of a new series of derivatives endowed with nanomolar K-i values against c-Src, interesting antiproliferative activity on SH-SY5Y cells and a suitable ADME profile.
• 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.