4-Chloro-1-[2-chloro-2-(4-chlorophenyl)ethyl]-6-methylsulfanylpyrazolo[3,4-d]pyrimidine | 959772-34-0

• 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-chlorophenyl)ethyl]-6-methylsulfanylpyrazolo[3,4-d]pyrimidine
• CAS: 959772-34-0
• 化学式: C₁₄H₁₁Cl₃N₄S
• 分子量: 373.693
• InChiKey: AMMUATSAZCRTNU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  22
• 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

反应信息

• 作为反应物：
  描述：

  4-Chloro-1-[2-chloro-2-(4-chlorophenyl)ethyl]-6-methylsulfanylpyrazolo[3,4-d]pyrimidine 、 二乙胺 以 甲苯 为溶剂， 以66%的产率得到1-(2-chloro-2-(4-chlorophenyl)ethyl)-N,N-diethyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
  参考文献：
  名称：

  Synthesis, biological evaluation and docking studies of 4-amino substituted 1H-pyrazolo[3,4-d]pyrimidines

  摘要：

  The synthesis of new 4-amino substituted pyrazolo[3,4-d]pyrimidines along with their activity in cell-free enzymatic assays on Src and Abl tyrosine kinases is reported. Some compounds emerged as good dual inhibitors of the two enzymes, showed antiproliferative effects on two Bcr-Abl positive leukemia cell lines K-562 and KU-812, and induced apoptosis, as demonstrated by the PARP assay. Docking studies have been also performed to analyze the binding mode of compounds under study and to identify the structural determinants of their interaction with both Src and Abl. (C) 2008 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2008.01.034
• 作为产物：
  描述：

  1-[2-(4-chlorophenyl)-2-hydroxyethyl]-6-methylsulfanyl-5H-pyrazolo[3,4-d]pyrimidin-4-one 在 N,N-二甲基甲酰胺 、 三氯氧磷 作用下， 以 氯仿 为溶剂， 反应 4.0h， 以60%的产率得到4-Chloro-1-[2-chloro-2-(4-chlorophenyl)ethyl]-6-methylsulfanylpyrazolo[3,4-d]pyrimidine
  参考文献：
  名称：

  Identification of a Novel Pyrazolo[3,4-d]pyrimidine Able To Inhibit Cell Proliferation of a Human Osteogenic Sarcoma in Vitro and in a Xenograft Model in Mice

  摘要：

  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.

  DOI：

  10.1021/jm061449r

文献信息

• 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.
• 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.
• Synthesis, biological evaluation and docking studies of 4-amino substituted 1H-pyrazolo[3,4-d]pyrimidines
  作者：Silvia Schenone、Chiara Brullo、Olga Bruno、Francesco Bondavalli、Luisa Mosti、Giovanni Maga、Emmanuele Crespan、Fabio Carraro、Fabrizio Manetti、Cristina Tintori、Maurizio Botta

  DOI：10.1016/j.ejmech.2008.01.034

  日期：2008.12

  The synthesis of new 4-amino substituted pyrazolo[3,4-d]pyrimidines along with their activity in cell-free enzymatic assays on Src and Abl tyrosine kinases is reported. Some compounds emerged as good dual inhibitors of the two enzymes, showed antiproliferative effects on two Bcr-Abl positive leukemia cell lines K-562 and KU-812, and induced apoptosis, as demonstrated by the PARP assay. Docking studies have been also performed to analyze the binding mode of compounds under study and to identify the structural determinants of their interaction with both Src and Abl. (C) 2008 Elsevier Masson SAS. All rights reserved.