(2,6-dichloro-pyrimidin-4-yl)-isobutyl-carbamic acid tert-butyl ester | 1067678-73-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: (2,6-dichloro-pyrimidin-4-yl)-isobutyl-carbamic acid tert-butyl ester
• 英文别名: Tert-butyl (2,6-dichloropyrimidin-4-yl)(isobutyl)carbamate；tert-butyl N-(2,6-dichloropyrimidin-4-yl)-N-(2-methylpropyl)carbamate
• CAS: 1067678-73-2
• 化学式: C₁₃H₁₉Cl₂N₃O₂
• 分子量: 320.219
• InChiKey: OSNXPHSCAGVEEU-UHFFFAOYSA-N

物化性质

• 沸点：
  404.9±30.0 °C(Predicted)
• 密度：
  1.244±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  20
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  55.3
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (2,6-dichloro-pyrimidin-4-yl)-isobutyl-carbamic acid tert-butyl ester 、 乙基溴化镁 在 iron(III)-acetylacetonate 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 乙醚 为溶剂， 反应 2.0h， 以45%的产率得到(2-chloro-6-ethyl-pyrimidin-4-yl)-isobutyl-carbamic acid tert-butyl ester
  参考文献：
  名称：

  Blocking Estrogen Signaling After the Hormone: Pyrimidine-Core Inhibitors of Estrogen Receptor-Coactivator Binding

  摘要：

  As an alternative approach to blocking estrogen action, we have developed small molecules that directly disrupt the key estrogen receptor (ER)/coactivator interaction necessary for gene activation. The more direct, protein-protein nature of this disruption might be effective even in hormone-refractory breast cancer. We have synthesized a pyrimidine-core library of moderate size, members of which act as a-helix mimics to block the ER alpha/coactivator interaction. Structure-activity relationships have been explored with various C-, N-, O-, and S-substituents on the pyrimidine core. Time-resolved fluorescence resonance energy transfer and cell-based reporter gene assays show that the most active members inhibit the ER alpha/steroid receptor coactivator interaction with Ki's in the low micromolar range. Through these studies, we have obtained a refined pharmacophore model for activity in this pyrimidine series. Furthermore, the favorable activities of several of these compounds support the feasibility that this coactivator binding inhibition mechanism for blocking estrogen action might provide a potential alternative approach to endocrine therapy.

  DOI：

  10.1021/jm800698b
• 作为产物：
  描述：

  2,4,6-三氯嘧啶 、 2-甲基-2-丙基异丁基氨基甲酸酯 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 以74%的产率得到(2,6-dichloro-pyrimidin-4-yl)-isobutyl-carbamic acid tert-butyl ester
  参考文献：
  名称：

  Blocking Estrogen Signaling After the Hormone: Pyrimidine-Core Inhibitors of Estrogen Receptor-Coactivator Binding

  摘要：

  As an alternative approach to blocking estrogen action, we have developed small molecules that directly disrupt the key estrogen receptor (ER)/coactivator interaction necessary for gene activation. The more direct, protein-protein nature of this disruption might be effective even in hormone-refractory breast cancer. We have synthesized a pyrimidine-core library of moderate size, members of which act as a-helix mimics to block the ER alpha/coactivator interaction. Structure-activity relationships have been explored with various C-, N-, O-, and S-substituents on the pyrimidine core. Time-resolved fluorescence resonance energy transfer and cell-based reporter gene assays show that the most active members inhibit the ER alpha/steroid receptor coactivator interaction with Ki's in the low micromolar range. Through these studies, we have obtained a refined pharmacophore model for activity in this pyrimidine series. Furthermore, the favorable activities of several of these compounds support the feasibility that this coactivator binding inhibition mechanism for blocking estrogen action might provide a potential alternative approach to endocrine therapy.

  DOI：

  10.1021/jm800698b

文献信息

• Blocking Estrogen Signaling After the Hormone: Pyrimidine-Core Inhibitors of Estrogen Receptor-Coactivator Binding
  作者：Alexander A. Parent、Jillian R. Gunther、John A. Katzenellenbogen

  DOI：10.1021/jm800698b

  日期：2008.10.23

  As an alternative approach to blocking estrogen action, we have developed small molecules that directly disrupt the key estrogen receptor (ER)/coactivator interaction necessary for gene activation. The more direct, protein-protein nature of this disruption might be effective even in hormone-refractory breast cancer. We have synthesized a pyrimidine-core library of moderate size, members of which act as a-helix mimics to block the ER alpha/coactivator interaction. Structure-activity relationships have been explored with various C-, N-, O-, and S-substituents on the pyrimidine core. Time-resolved fluorescence resonance energy transfer and cell-based reporter gene assays show that the most active members inhibit the ER alpha/steroid receptor coactivator interaction with Ki's in the low micromolar range. Through these studies, we have obtained a refined pharmacophore model for activity in this pyrimidine series. Furthermore, the favorable activities of several of these compounds support the feasibility that this coactivator binding inhibition mechanism for blocking estrogen action might provide a potential alternative approach to endocrine therapy.