4-chloro-1-(2-chloro-2-phenylethyl)-6-(methylthio)-4H-pyrazolo[3,4-d]pyrimidin-4-one | 679805-51-7

• 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: 4-chloro-1-(2-chloro-2-phenylethyl)-6-(methylthio)-4H-pyrazolo[3,4-d]pyrimidin-4-one
• 英文别名: 4-chloro-1-(2-chloro-2-phenylethyl)-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine；4-chloro-1-(2-chloro-2-phenylethyl)-6-methylsulfanylpyrazolo[3,4-d]pyrimidine
• CAS: 679805-51-7
• 化学式: C₁₄H₁₂Cl₂N₄S
• 分子量: 339.248
• InChiKey: NMBNNXLZYQVIFR-UHFFFAOYSA-N

物化性质

• 熔点：
  95-96 °C
• 沸点：
  528.9±60.0 °C(Predicted)
• 密度：
  1.47±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  68.9
• 氢给体数：
  0
• 氢受体数：
  4

安全信息

• 海关编码：
  2933990090

反应信息

• 作为反应物：
  描述：

  4-chloro-1-(2-chloro-2-phenylethyl)-6-(methylthio)-4H-pyrazolo[3,4-d]pyrimidin-4-one 在 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 甲苯 为溶剂， 反应 32.0h， 生成 2,6-dimethyl-4-[6-methylsulfanyl-1-[(E)-2-phenylethenyl]pyrazolo[3,4-d]pyrimidin-4-yl]morpholine
  参考文献：
  名称：

  Pyrazolo[3,4-d]pyrimidines as Potent Antiproliferative and Proapoptotic Agents toward A431 and 8701-BC Cells in Culture via Inhibition of c-Src Phosphorylation

  摘要：

  We report here the synthesis of new pyrazolo[3,4-d]pyrimidine derivatives along with their biological properties as inhibitors of isolated Src and cell line proliferation (A431 and 8701-BC cells). Such compounds block the growth of cancer cells by interfering with the phosphorylation of Src, and they act as proapoptotic agents through the inhibition of the anti apoptotic gene BCL2. Several of them were found to be more active than the reference compound (1-(tert-butyl)-3-(4-chlorophenyl)-4-aminopyrazolo[3,4-d]pyrimidine, PP2) in inhibiting cell proliferation and in inducing apoptosis, and as active as PP2 in the inhibition of the phosphorylation of isolated Src. Moreover, molecular modeling simulations have been performed to hypothesize the way, at the molecular level, by which the inhibitors were able to act as antiproliferative agents.

  DOI：

  10.1021/jm050603r
• 作为产物：
  描述：

  5-氨基-1-(2-羟基-2-苯基乙基)-1H-吡唑-4-羧酸乙酯 在 sodium hydroxide 、 溶剂黄146 、 N,N-二甲基甲酰胺 、 三氯氧磷 作用下， 以 四氢呋喃 、 氯仿 为溶剂， 反应 28.17h， 生成 4-chloro-1-(2-chloro-2-phenylethyl)-6-(methylthio)-4H-pyrazolo[3,4-d]pyrimidin-4-one
  参考文献：
  名称：

  1-（2-氯-2-苯基乙基）-6-甲硫基-1H-吡唑并[3,4-d]嘧啶4-氨基取代基的合成及其生物学评价。

  摘要：

  合成了一系列新的4-氨基-6-甲硫基-1H-吡唑并[3,4-d]嘧啶（2a-m），在N1位带有2-氯-2-苯基乙基链。测量了这些化合物对A1腺苷受体（A1AR）的亲和力。化合物显示出较差的亲和力。通过2a，2d，2g获得了更有趣的结果，该结果显示了对上皮生长因子（EGF）刺激的A-431细胞系的细胞增殖和EGF受体酪氨酸激酶（EGFR-TK）磷酸化的抑制活性。

  DOI：

  10.1016/j.ejmech.2003.11.007

文献信息

• 4-Substituted derivatives of pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine and uses thereof
  申请人：Bondavalli Francesco

  公开号：US20070010510A1

  公开（公告）日：2007-01-11

  4-Substituted derivatives of pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine are described. Compounds are active as antitumoural agents.

  本文描述了嘧唑并[3,4-d]嘧啶和吡咯并[2,3-d]嘧啶的4-取代衍生物。这些化合物作为抗肿瘤剂具有活性。
• 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。
• Identification of a Novel Pyrazolo[3,4-<i>d</i>]pyrimidine Able To Inhibit Cell Proliferation of a Human Osteogenic Sarcoma in Vitro and in a Xenograft Model in Mice
  作者：Fabrizio Manetti、Annalisa Santucci、Giada A. Locatelli、Giovanni Maga、Adriano Spreafico、Tommaso Serchi、Maurizio Orlandini、Giulia Bernardini、Nicola P. Caradonna、Andrea Spallarossa、Chiara Brullo、Silvia Schenone、Olga Bruno、Angelo Ranise、Francesco Bondavalli、Oskar Hoffmann、Mauro Bologna、Adriano Angelucci、Maurizio Botta

  DOI：10.1021/jm061449r

  日期：2007.11.1

  New pyrazolo[3,4-d]pyrimidines were synthesized and found to inhibit Src phosphorylation in a cell-free assay. Some of them significantly reduced the growth of human osteogenic sarcoma (SaOS-2) cells. The best compound, in terms of inhibitory properties toward both Src and SaOS-2 cells, was further investigated and found to reduce bone resorption when used to treat mouse osteoclasts, without interfering with normal osteoblast growth. Moreover, its metabolic stability prompted its study on a human SaOS-2 xenograft tumor model in nude mice, where the compound reduced significantly both the volume and weight of the tumor. These experimental findings make the new compound an interesting hit in the field of bone-related diseases.
• Studies on the ATP Binding Site of Fyn Kinase for the Identification of New Inhibitors and Their Evaluation as Potential Agents against Tauopathies and Tumors
  作者：Cristina Tintori、Giuseppina La Sala、Giulia Vignaroli、Lorenzo Botta、Anna Lucia Fallacara、Federico Falchi、Marco Radi、Claudio Zamperini、Elena Dreassi、Lucia Dello Iacono、Donata Orioli、Giuseppe Biamonti、Mirko Garbelli、Andrea Lossani、Francesca Gasparrini、Tiziano Tuccinardi、Ilaria Laurenzana、Adriano Angelucci、Giovanni Maga、Silvia Schenone、Chiara Brullo、Francesca Musumeci、Andrea Desogus、Emmanuele Crespan、Maurizio Botta

  DOI：10.1021/acs.jmedchem.5b00140

  日期：2015.6.11

  Fyn is a member of the Src-family of nonreceptor protein-tyrosine kinases. Its abnormal activity has been shown to be related to various human cancers as well as to severe pathologies,; such as Alzheimer's and Parkinson's diseases. Herein, a structure-based drug design protocol was employed aimed at identifying novel Fyn inhibitors. Two hits from commercial sources (1, 2) were found active against Fyn with K-i of about 2 mu M, while derivative 4a, derived from our internal library, showed a K-i of 0.9 mu M. A hit-to-lead optimization effort was then initiated on derivative 4a to improve its potency. Slightly modifications rapidly determine an increase in the binding affinity, with the best inhibitors 4c and 44 having K(i)s of 70 and 95 nM, respectively. Both compounds were found able to inhibit the phosphorylation of : the protein Tau in an Alzheimer's model cell line and showed antiproliferative activities against different cancer cell lines.