2-(4-iodo-2-methoxycarbonylphenyl)propanedioic acid, 1,3-bis(1,1-dimethylethyl)ester | 439904-24-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-(4-iodo-2-methoxycarbonylphenyl)propanedioic acid, 1,3-bis(1,1-dimethylethyl)ester
• 英文别名: [4-iodo-2-(methoxycarbonyl)phenyl]propanedioic acid 1,3-bis(1,1-dimethylethyl) ester；methyl 2-di-tert-butylmalonate-5-iodobenzoate；Ditert-butyl 2-(4-iodo-2-methoxycarbonylphenyl)propanedioate
• CAS: 439904-24-2
• 化学式: C₁₉H₂₅IO₆
• 分子量: 476.308
• InChiKey: KEZBVZZUJKZSEX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  26
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  78.9
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-(4-iodo-2-methoxycarbonylphenyl)propanedioic acid, 1,3-bis(1,1-dimethylethyl)ester 在 10percent Pd/C palladium diacetate 、 lithium hydroxide 、 sodium hydroxide 、 氢气 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 三(邻甲基苯基)磷 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 20.0~50.0 ℃ 、176.0 kPa 条件下， 反应 153.5h， 生成 2-[4-[2-acetamido-3-oxo-3-[[(3S)-2-oxo-1-[(4-phenylphenyl)methyl]azepan-3-yl]amino]propyl]-2-carboxyphenyl]propanedioic acid
  参考文献：
  名称：

  SAR和X射线。一种结合基于片段的筛选和合理药物设计的新方法：应用于Src SH2纳摩尔抑制剂的发现。

  摘要：

  （pp60）Src是一种参与信号转导的蛋白质，主要在神经元，血小板和破骨细胞中表达。最近在Soriano的KO实验中发现了其确切的生物学作用，除了骨质疏松症外没有其他明显的表型，这种疾病导致骨形成过多。Src家族的SH2结构域特异性识别在+1和+3位置具有磷酸酪氨酸和亲脂氨基酸特征的四肽序列。最近，我们通过该四肽的模块化肽模拟来寻找SH2配体。这产生了数个纳摩尔抑制剂家族。最好的是结合己内酰胺支架，联苯部分和磷酸酪氨酸。但是，这些抑制剂仍然结合了磷酸基团，赋予了与蛋白质良好的结合亲和力。磷酸盐对于候选药物具有不良的特征，即磷酸酶使磷酸基团的高水解速率和高电荷含量阻止了细胞渗透。因此，在寻找Src SH2的最佳非肽配体时，我们寻找了磷酸盐替代物。为此，我们通过碎片晶体学方法设计了SAR。这项工作的开始源于两个实验观察。首先，磷酸苯酯本身对Src SH2表现出可检测的结合亲和力，这一事实使我们

  DOI：

  10.1021/jm010927p
• 作为产物：
  描述：

  2,5-二碘苯甲酸 在 氯化亚砜 、 sodium hydride 作用下， 以 1,4-二氧六环 为溶剂， 反应 39.75h， 生成 2-(4-iodo-2-methoxycarbonylphenyl)propanedioic acid, 1,3-bis(1,1-dimethylethyl)ester
  参考文献：
  名称：

  SAR和X射线。一种结合基于片段的筛选和合理药物设计的新方法：应用于Src SH2纳摩尔抑制剂的发现。

  摘要：

  （pp60）Src是一种参与信号转导的蛋白质，主要在神经元，血小板和破骨细胞中表达。最近在Soriano的KO实验中发现了其确切的生物学作用，除了骨质疏松症外没有其他明显的表型，这种疾病导致骨形成过多。Src家族的SH2结构域特异性识别在+1和+3位置具有磷酸酪氨酸和亲脂氨基酸特征的四肽序列。最近，我们通过该四肽的模块化肽模拟来寻找SH2配体。这产生了数个纳摩尔抑制剂家族。最好的是结合己内酰胺支架，联苯部分和磷酸酪氨酸。但是，这些抑制剂仍然结合了磷酸基团，赋予了与蛋白质良好的结合亲和力。磷酸盐对于候选药物具有不良的特征，即磷酸酶使磷酸基团的高水解速率和高电荷含量阻止了细胞渗透。因此，在寻找Src SH2的最佳非肽配体时，我们寻找了磷酸盐替代物。为此，我们通过碎片晶体学方法设计了SAR。这项工作的开始源于两个实验观察。首先，磷酸苯酯本身对Src SH2表现出可检测的结合亲和力，这一事实使我们

  DOI：

  10.1021/jm010927p

文献信息

• Requirements for Specific Binding of Low Affinity Inhibitor Fragments to the SH2 Domain of ^pp60Src Are Identical to Those for High Affinity Binding of Full Length Inhibitors
  作者：Gudrun Lange、Dominique Lesuisse、Pierre Deprez、Bernard Schoot、Petra Loenze、Didier Bénard、Jean-Pierre Marquette、Pierre Broto、Edoardo Sarubbi、Eliane Mandine

  DOI：10.1021/jm020970s

  日期：2003.11.1

  Results from a novel approach which uses protein crystallography for the screening of a low affinity inhibitor fragment library are analyzed by comparing the X-ray structures with bound fragments to the structures with the corresponding full length inhibitors. The screen for new phospho-tyrosine mimics binding to the SH2 domain of (pp60)src was initiated because of the limited cell penetration of phosphates. Fragments in our library typically had between 6 and 30 atoms and included compounds which had either millimolar activity in a Biacore assay or were suggested by the ab initio design program LUDI but had no measurable affinity. All identified fragments were located in the phospho-tyrosine pocket. The most promising fragments were successfully used to replace the phospho-tyrosine and resulted in novel nonpeptidic high affinity inhibitors. The significant diversity of successful fragments is reflected in the high flexibility of the phospho-tyrosine pocket. Comparison of the X-ray structures shows that the presence of the H-bond acceptors and not their relative position within the pharmacophore are essential for fragment binding and/or high affinity binding of full length inhibitors. The X-ray data show that the fragments are recognized by forming a complex H-bond network within the phospho-tyrosine pocket of SH2. No fragment structure was found in which this H-bond network was incomplete, and any uncompensated H-bond within the H-bond network leads to a significant decrease in the affinity of full length inhibitors. No correlation between affinity and fragment binding was found for these polar fragments and hence affinity-based screening would have overlooked some interesting starting points for inhibitor design. In contrast, we were unable to identify electron density for hydrophobic fragments, confirming that hydrophobic interactions are important for inhibitor affinity but of minor importance for ligand recognition. Our results suggest that a screening approach using protein crystallography is particularly useful to identify universal fragments for the conserved hydrophilic recognition sites found in target families such as SH2 domains, phosphatases, kinases, proteases, and esterases.