4-chloro-1-(2-chloro-2-phenylethyl)-1H-pyrazolo[3,4-d]pyrimidine | 805227-62-7

• 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)-1H-pyrazolo[3,4-d]pyrimidine
• 英文别名: 4-chloro-1-(2-chloro-2-phenylethyl)-pyrazolo[3,4-d]pyrimidine；4-Chloro-1-(2-chloro-2-phenylethyl)pyrazolo[3,4-d]pyrimidine
• CAS: 805227-62-7
• 化学式: C₁₃H₁₀Cl₂N₄
• 分子量: 293.155
• InChiKey: BCQPWCIXZSKCPK-UHFFFAOYSA-N

物化性质

• 熔点：
  105-106 °C
• 沸点：
  446.4±45.0 °C(Predicted)
• 密度：
  1.46±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  43.6
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  环丙胺 、 4-chloro-1-(2-chloro-2-phenylethyl)-1H-pyrazolo[3,4-d]pyrimidine 以 甲苯 为溶剂， 反应 36.0h， 以90%的产率得到1-(2-chloro-2-phenylethyl)-N-cyclopropylpyrazolo[3,4-d]pyrimidin-4-amine
  参考文献：
  名称：

  Antiproliferative activity of new 1-aryl-4-amino-1H-pyrazolo[3,4-d]pyrimidine derivatives toward the human epidermoid carcinoma A431 cell line

  摘要：

  Synthesis and biological evaluation of a new class of 1-aryl-4-amino-1H-pyrazolo[3,4-d]pyrimidine derivatives are reported. A preliminary cellular assay system using the tumor cell line A431 responding to epidermal growth factor (EGF) for its growth, shows that the new compounds are potent inhibitors of cell growth. The inhibition of tumor cell proliferation is not associated with blockage of EGF receptor (EGFR), but substantially due to the interference with the signalling pathway at the level of Src tyrosine kinase and at the level of the downstream effector signal mitogen activated protein kinases (MAPKs), ERK1-2. (C) 2004 Elsevier SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2004.07.010
• 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 N,N-二甲基甲酰胺二甲基缩醛 、 三氯氧磷 作用下， 以 氯仿 为溶剂， 反应 11.5h， 生成 4-chloro-1-(2-chloro-2-phenylethyl)-1H-pyrazolo[3,4-d]pyrimidine
  参考文献：
  名称：

  新型吡唑并[3,4-d]嘧啶作为双 Src/Bcr-Abl 激酶抑制剂：慢性粒细胞白血病治疗的合成和生物学评价

  摘要：

  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

  DOI：

  10.1016/j.bioorg.2022.106071

文献信息

• Design, Synthesis, and Biological Evaluation of Pyrazolo[3,4-<i>d</i>]pyrimidines Active in Vivo on the Bcr-Abl T315I Mutant
  作者：Marco Radi、Cristina Tintori、Francesca Musumeci、Chiara Brullo、Claudio Zamperini、Elena Dreassi、Anna Lucia Fallacara、Giulia Vignaroli、Emmanuele Crespan、Samantha Zanoli、Ilaria Laurenzana、Irene Filippi、Giovanni Maga、Silvia Schenone、Adriano Angelucci、Maurizio Botta

  DOI：10.1021/jm400233w

  日期：2013.7.11

  Starting from our in-house library of pyrazolo, [3,4-d]pyrimidines, a cross-docking simulation was conducted, on Bcr-Abl T315I mutant. Among the selected, compounds; (2a-e), the 4-bromo derivative 2b showed the best activity against the Bcr-Abl T315I mutant. Deeper computational studies highlighted the importance of the bromine atom in the para position of the NI side chain phenyl,ring for the interaction with the T315I mutant. A series of 4;bromo derivatives was thin synthesized and biologically evaluated.: Compound 2j showed a good balance of different ADME properties, high activity in cell-free assays, and a submicromolar potency against T315I Bcr-Abl expressing cells. In addition, it was converted into a water-soluble formulation by liposome encapsulation, preserving a good activity on leukemic T315I cells and avoiding the use of DMSO as solubilizing agent. In vivo studies on mice inoculated with 32D-T315I cells and treated with 2j showed a more than 50% reduction in tumor volumes.
• 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.
• Structure-Based Optimization of Pyrazolo[3,4-<i>d</i>]pyrimidines as Abl Inhibitors and Antiproliferative Agents toward Human Leukemia Cell Lines
  作者：Fabrizio Manetti、Chiara Brullo、Matteo Magnani、Francesca Mosci、Beatrice Chelli、Emmanuele Crespan、Silvia Schenone、Antonella Naldini、Olga Bruno、Maria Letizia Trincavelli、Giovanni Maga、Fabio Carraro、Claudia Martini、Francesco Bondavalli、Maurizio Botta

  DOI：10.1021/jm701240c

  日期：2008.3.13

  Results from molecular docking calculations and Grid mapping laid the foundations for a structure-based optimization approach to improve the biological properties of pyrazolo-pyrimidine derivatives in terms of inhibition of Abl enzymatic activity and anti proliferative properties toward human leukemia cells. Insertion of halogen substituents with various substitution patterns, suggested by simulations, led to a significant improvement of leukemia cell growth inhibition and to an increase up to 1 order of magnitude of the affinity toward Abl.
• 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.
• [EN] 4-SUBSTITUTED DERIVATIVES OF PYRAZOLO [3,4-d] PYRIMIDINE AND PYRROLO [2,3-d] PYRIMIDINE AND USES THEREOF<br/>[FR] DERIVES SUBSTITUES EN 4 DE PYRAZOLO[3,4-D]PYRIMIDINE ET DE PYRROLO[2,3-D]PYRIMIDINE ET LEURS UTILISATIONS
  申请人：UNIV SIENA

  公开号：WO2004106339A3

  公开（公告）日：2005-02-17