ethyl 2-(2-((tert-butoxycarbonyl)(4-cyclohexylbenzyl)amino)-6-(isobutylamino)-9H-purin-9-yl)acetate | 1255652-42-6

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: ethyl 2-(2-((tert-butoxycarbonyl)(4-cyclohexylbenzyl)amino)-6-(isobutylamino)-9H-purin-9-yl)acetate
• 英文别名: ethyl 2-{2-[(tert-butoxycarbonyl)(4-cyclohexylbenzyl)amino]-6-(isobutylamino)-9H-purin-9-yl}acetate；Ethyl 2-[2-[(4-cyclohexylphenyl)methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]-6-(2-methylpropylamino)purin-9-yl]acetate
• CAS: 1255652-42-6
• 化学式: C₃₁H₄₄N₆O₄
• 分子量: 564.728
• InChiKey: JNCCOVBHVWLCPR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.2
• 重原子数：
  41
• 可旋转键数：
  13
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  112
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  ethyl 2-(2-((tert-butoxycarbonyl)(4-cyclohexylbenzyl)amino)-6-(isobutylamino)-9H-purin-9-yl)acetate 在 水 、 N,N-二异丙基乙胺 、 三氟乙酸 、 lithium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 17.5h， 生成 {2-[2-((4-cyclohexylbenzyl)amino)-6-(isobutylamino)-9H-purin-9-yl]acetoxy}methyl pivalate
  参考文献：
  名称：

  A 2,6,9-hetero-trisubstituted purine inhibitor exhibits potent biological effects against multiple myeloma cells

  摘要：

  A focused library of hetero-trisubstituted purines was developed for improving the cell penetrating and biological efficacy of a series of anti-Stat3 protein inhibitors. From this SAR study, lead agent 22e was identified as being a promising inhibitor of MM tumour cells (IC50's <5 mu M). Surprisingly, biophysical and biochemical characterization proved that 22e was not a Stat3 inhibitor. Initial screening against the kinome, prompted by the purine scaffold's history for targeting ATP binding pockets, suggests possible targeting of the JAK family kinases, as well for ABL1 (nonphosphorylated F317L) and AAK1. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.04.080
• 作为产物：
  描述：

  2-amino-9-tert-butoxycarbonyl-6-chloropurine 在 sodium hydride 、 N,N-二异丙基乙胺 、 三苯基膦 作用下， 以 四氢呋喃 、 二甲基亚砜 、 mineral oil 为溶剂， 反应 2.95h， 生成 ethyl 2-(2-((tert-butoxycarbonyl)(4-cyclohexylbenzyl)amino)-6-(isobutylamino)-9H-purin-9-yl)acetate
  参考文献：
  名称：

  A 2,6,9-hetero-trisubstituted purine inhibitor exhibits potent biological effects against multiple myeloma cells

  摘要：

  A focused library of hetero-trisubstituted purines was developed for improving the cell penetrating and biological efficacy of a series of anti-Stat3 protein inhibitors. From this SAR study, lead agent 22e was identified as being a promising inhibitor of MM tumour cells (IC50's <5 mu M). Surprisingly, biophysical and biochemical characterization proved that 22e was not a Stat3 inhibitor. Initial screening against the kinome, prompted by the purine scaffold's history for targeting ATP binding pockets, suggests possible targeting of the JAK family kinases, as well for ABL1 (nonphosphorylated F317L) and AAK1. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.04.080

文献信息

• Identification of Purine-Scaffold Small-Molecule Inhibitors of Stat3 Activation by QSAR Studies
  作者：Vijay M. Shahani、Peibin Yue、Sina Haftchenary、Wei Zhao、Julie L. Lukkarila、Xiaolei Zhang、Daniel Ball、Christina Nona、Patrick T. Gunning、James Turkson

  DOI：10.1021/ml100224d

  日期：2011.1.13

  useful Stat3 inhibitors, computational analysis of the binding to Stat3 of the existing Stat3 dimerization disruptors and quantitative structure−activity relationships (QSAR) were pursued, by which a pharmacophore model was derived for predicting optimized Stat3 dimerization inhibitors. The 2,6,9-trisubstituted-purine scaffold was functionalized in order to access the three subpockets of the Stat3 SH2

  为了促进临床上有用的 Stat3 抑制剂的发现，对现有 Stat3 二聚化干扰物与 Stat3 的结合和定量构效关系 (QSAR) 进行了计算分析，由此衍生了药效团模型来预测优化的 Stat3 二聚化抑制剂。对 2,6,9-三取代嘌呤支架进行功能化，以便进入 Stat3 SH2 结构域表面的三个亚袋并衍生出有效的 Stat3 结合抑制剂。选择的嘌呤支架对纯化的非磷酸化 Stat3 表现出良好的亲和力（KD ，0.8−12 μM） ，并在体外抑制 Stat3 DNA 结合活性，并在 20−60 μM 时抑制细胞内磷酸化。此外，药物选择性抑制人类前列腺癌细胞、乳腺癌细胞和胰腺癌细胞以及具有异常 Stat3 活性的 v-Src 转化小鼠成纤维细胞的活力。本文的研究确定了新型小分子三取代嘌呤作为持续活性 Stat3 和 Stat3 依赖性肿瘤细胞活力的有效抑制剂，并且首次验证了使用嘌呤碱基作为构建新型
• SUBSTITUTED 2-(9H-PURIN-9-YL) ACETIC ACID ANALOGUES AS INHIBITORS OF STAT3
  申请人：Turkson James

  公开号：US20130172340A1

  公开（公告）日：2013-07-04

  In one aspect, the invention relates to substituted purine analogs, derivatives thereof, and related compounds, which are useful as inhibitors of STAT protein activity; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating disorders of uncontrolled cellular proliferation associated with a STAT protein activity dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  在某个方面，本发明涉及取代嘌呤类似物、其衍生物和相关化合物，这些化合物可用作STAT蛋白活性的抑制剂；制备这些化合物的合成方法；包含这些化合物的药物组合物；以及使用这些化合物和组合物治疗与STAT蛋白活性功能障碍相关的细胞无控制增殖疾病的方法。本摘要旨在作为搜索特定技术领域的扫描工具，不旨在限制本发明。
• [EN] SUBSTITUTED 2-(9H-PURIN-9-YL) ACETIC ACID ANALOGUES AS INHIBITORS OF STAT3<br/>[FR] ANALOGUES D'ACIDE 2-(9H-PURIN-9-YL)ACÉTIQUE SUBSTITUÉS EN TANT QU'INHIBITEURS DE STAT3
  申请人：UNIV CENTRAL FLORIDA RES FOUND

  公开号：WO2011163424A2

  公开（公告）日：2011-12-29

  In one aspect, the invention relates to substituted purine analogs, derivatives thereof, and related compounds, which are useful as inhibitors of STAT protein activity; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating disorders of uncontrolled cellular proliferation associated with a STAT protein activity dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.