2,4-dichloro-6-(3-methylbutyl)-pyrimidine | 656822-35-4

• 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: 2,4-dichloro-6-(3-methylbutyl)-pyrimidine
• 英文别名: 2,4-Dichloro-6-(3-methylbutyl)pyrimidine
• CAS: 656822-35-4
• 化学式: C₉H₁₂Cl₂N₂
• 分子量: 219.114
• InChiKey: AKJREQZTJYZRCO-UHFFFAOYSA-N

物化性质

• 沸点：
  287.9±20.0 °C(Predicted)
• 密度：
  1.200±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  13
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  25.8
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  异丁硫醇 、 2,4-dichloro-6-(3-methylbutyl)-pyrimidine 在 sodium hydride 作用下， 以 四氢呋喃 为溶剂， 反应 16.33h， 以98%的产率得到2,4-bis-isobutylsulfanyl-6-(3-methyl-butyl)-pyrimidine
  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：

  乙基6-甲基-3-氧代庚酸酯 在 potassium carbonate 、 氯乙酸 、 三氯氧磷 作用下， 以 四氢呋喃 为溶剂， 反应 22.0h， 生成 2,4-dichloro-6-(3-methylbutyl)-pyrimidine
  参考文献：
  名称：

  设计，合成和体外生物学评估雌激素受体α共激活因子结合的小分子抑制剂。

  摘要：

  与激动剂配体复合的核受体（NRs）通过募集共激活蛋白复合物来激活转录。原则上，应该使用适当设计的共激活因子结合抑制剂（CBI）直接阻止这种转录关键受体-共激活因子的相互作用，从而抑制NRs的转录活性。为了指导我们各种CBI的设计，我们使用了激动剂结合的雌激素受体（ER）配体结合结构域（LBD）的晶体结构，该结构与含有LXXLL签名基元并结合到表面疏水槽的助活化剂肽复合的LBD。一组基于从外而内的设计方法的CBI，具有各种杂环核心（三氮烯，嘧啶，三硫杂环己烷，环己烷），它们模仿肽螺旋上三个亮氨酸的系链位点，在其上连接有亮氨酸残基样取代基。另一组基于“由内而外”的方法，具有一个萘核，该萘核模拟两个最深埋的亮氨酸，其取代基向外延伸，以模拟共活化剂螺旋肽的其他特征。开发了一种基于荧光各向异性的共激活剂竞争测定法，以测量这些CBI与ER激动剂复合物与共激活剂相互作用的凹槽位点的特异性结合。对照配体结

  DOI：

  10.1021/jm030404c

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.
• Design, Synthesis, and in Vitro Biological Evaluation of Small Molecule Inhibitors of Estrogen Receptor α Coactivator Binding
  作者：Alice L. Rodriguez、Anobel Tamrazi、Margaret L. Collins、John A. Katzenellenbogen

  DOI：10.1021/jm030404c

  日期：2004.1.1

  interaction was not with the ligand binding pocket. The most effective CBIs were those from the pyrimidine family, the best binding with K(i) values of ca. 30 microM. The trithiane- and cyclohexane-based CBIs appear to be poor structural mimics, because of equatorial vs axial conformational constraints, and the triazene-based CBIs are also conformationally constrained by amine-substituent-to-ring resonance

  与激动剂配体复合的核受体（NRs）通过募集共激活蛋白复合物来激活转录。原则上，应该使用适当设计的共激活因子结合抑制剂（CBI）直接阻止这种转录关键受体-共激活因子的相互作用，从而抑制NRs的转录活性。为了指导我们各种CBI的设计，我们使用了激动剂结合的雌激素受体（ER）配体结合结构域（LBD）的晶体结构，该结构与含有LXXLL签名基元并结合到表面疏水槽的助活化剂肽复合的LBD。一组基于从外而内的设计方法的CBI，具有各种杂环核心（三氮烯，嘧啶，三硫杂环己烷，环己烷），它们模仿肽螺旋上三个亮氨酸的系链位点，在其上连接有亮氨酸残基样取代基。另一组基于“由内而外”的方法，具有一个萘核，该萘核模拟两个最深埋的亮氨酸，其取代基向外延伸，以模拟共活化剂螺旋肽的其他特征。开发了一种基于荧光各向异性的共激活剂竞争测定法，以测量这些CBI与ER激动剂复合物与共激活剂相互作用的凹槽位点的特异性结合。对照配体结