4-chloro-1-(2-chloro-2-(4-fluorophenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine | 1013930-73-8

• 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-(4-fluorophenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine
• 英文别名: 4-Chloro-1-[2-chloro-2-(4-fluorophenyl)ethyl]pyrazolo[3,4-d]pyrimidine
• CAS: 1013930-73-8
• 化学式: C₁₃H₉Cl₂FN₄
• 分子量: 311.146
• InChiKey: JZUBIVKNMKKITJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  20
• 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：
  4

反应信息

• 作为反应物：
  描述：

  4-chloro-1-(2-chloro-2-(4-fluorophenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine 、 pyridoxamine dihydrochloride 在 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.17h， 以58%的产率得到(Z)-4-((1-(4-fluorostyryl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)methyl)-5-(hydroxymethyl)-2-methylpyridin-3-ol
  参考文献：
  名称：

  合成生物学上相关的1,4-二取代的吡唑并[3,4- d ]嘧啶的另一种合成方法

  摘要：

  已经开发了一种通用的合成1，4-二取代的吡唑并[3，4- d ]嘧啶的方法。从商业上可获得的别嘌呤醇开始，TBAF介导的N1官能化和随后的C4亲核取代，在微波辅助或标准加热条件下，可得到具有潜在生物学意义的高度官能化的吡唑并[3,4- d ]嘧啶。

  DOI：

  10.1016/j.tetlet.2013.07.069
• 作为产物：
  描述：

  2-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-(4-fluorophenyl)ethanol 在 三氯氧磷 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以60%的产率得到4-chloro-1-(2-chloro-2-(4-fluorophenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine
  参考文献：
  名称：

  合成生物学上相关的1,4-二取代的吡唑并[3,4- d ]嘧啶的另一种合成方法

  摘要：

  已经开发了一种通用的合成1，4-二取代的吡唑并[3，4- d ]嘧啶的方法。从商业上可获得的别嘌呤醇开始，TBAF介导的N1官能化和随后的C4亲核取代，在微波辅助或标准加热条件下，可得到具有潜在生物学意义的高度官能化的吡唑并[3,4- d ]嘧啶。

  DOI：

  10.1016/j.tetlet.2013.07.069

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.
• 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.
• 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.
• A cascade screening approach for the identification of Bcr-Abl myristate pocket binders active against wild type and T315I mutant
  作者：Marco Radi、Ralf Schneider、Anna Lucia Fallacara、Lorenzo Botta、Emmanuele Crespan、Cristina Tintori、Giovanni Maga、Miroslava Kissova、Alessia Calgani、André Richters、Franesca Musumeci、Daniel Rauh、Silvia Schenone

  DOI：10.1016/j.bmcl.2016.06.051

  日期：2016.8

  The major clinical challenge in drug-resistant chronic myelogenous leukemia (CML) is currently represented by the Bcr-Abl T315I mutant, which is unresponsive to treatment with common first and second generation ATP-competitive tyrosine kinase inhibitors (TKIs). Allosteric inhibition of Bcr-Abl represent a new frontier in the fight against resistant leukemia and few candidates have been identified in the last few years. Among these, myristate pocket (MP) binders discovered by Novartis (e.g. GNF2/5) showed promising results, although they proved to be active against the T315I mutant only in combination with first and second generation ATP-competitive inhibitors. Here we used a cascade screening approach based on sequential fluorescence polarization (FP) screening, in silico docking/dynamics studies and kinetic-enzymatic studies to identify novel MP binders. A pyrazolo[3,4-d]pyrimidine derivative (6) has been identified as a promising allosteric inhibitor active on 32D leukemia cell lines (expressing Bcr-Abl WT and T315I) with no need of combination with any ATP-competitive inhibitor. (C) 2016 Elsevier Ltd. All rights reserved.
• Dual Src and Abl inhibitors target wild type Abl and the AblT315I Imatinib-resistant mutant with different mechanisms
  作者：Emmanuele Crespan、Marco Radi、Samantha Zanoli、Silvia Schenone、Maurizio Botta、Giovanni Maga

  DOI：10.1016/j.bmc.2010.04.024

  日期：2010.6.1

  The tyrosine kinase Src and its close homolog Abl, both play important roles in chronic myelogenous leukemia (CML) progression and Imatinib resistance. No clinically approved inhibitors of the drug-resistant AblT315I exist to date. Here, we present a thorough kinetic analysis of two potent dual Src-Abl inhibitors towards wild type Src and Abl, and the AblT315I mutant. Our results show that the most potent compound BO1 shows only a modest loss of potency (fourfold) towards the AblT315I mutant in vitro and was an ATP-competitive inhibitor of wild type Abl but it acted as a non-competitive inhibitor in the case of AblT315I. (C) 2010 Elsevier Ltd. All rights reserved.