(2R)-2-[4-(bis-benzyloxy-phosphoryloxy)-benzyl]-N-methyl-succinamic acid | 397883-83-9

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 苯丙酸
• 英文名称: (2R)-2-[4-(bis-benzyloxy-phosphoryloxy)-benzyl]-N-methyl-succinamic acid
• 英文别名: 2-[4-(di(benzyloxy)phosphoryloxy)benzyl]-N-methylsuccinamic acid；(2R)-2-[4-(bis-benzyloxy-phosporyloxy)benzyl]-N-methylsuccinamic acid
• CAS: 397883-83-9
• 化学式: C₂₆H₂₈NO₇P
• 分子量: 497.485
• InChiKey: TYEOBMLDIYQBKH-HSZRJFAPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.99
• 重原子数：
  35.0
• 可旋转键数：
  13.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  111.16
• 氢给体数：
  2.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  (2R)-2-[4-(bis-benzyloxy-phosphoryloxy)-benzyl]-N-methyl-succinamic acid 在 palladium on activated charcoal 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 20.0 ℃ 、101.33 kPa 条件下， 反应 1.0h， 生成 (2S,3S)-2-[[(2S)-4-carboxy-2-[[(2S)-4-carboxy-2-[[(2R)-4-(methylamino)-4-oxo-2-[(4-phosphonooxyphenyl)methyl]butanoyl]amino]butanoyl]amino]butanoyl]amino]-3-methylpentanoic acid
  参考文献：
  名称：

  Calorimetric and Structural Studies of 1,2,3-Trisubstituted Cyclopropanes as Conformationally Constrained Peptide Inhibitors of Src SH2 Domain Binding

  摘要：

  Isothermal titration calorimetry and X-ray crystallography have been used to determine the structural and thermodynamic consequences associated with constraining the pTyr residue of the pYEE ligand for the Src Homology 2 domain of the Src kinase (Src SH2 domain). The conformation ally constrained peptide mimics that were used are cyclopropane-derived isosteres whereby a cyclopropane ring substitutes to the N-Ca-Cbeta atoms of the phosphotyrosine. Comparison of the thermodynamic data for the binding of the conformationally constrained peptide mimics relative to their equivalent flexible analogues as well as a native tetrapeptide revealed an entropic advantage of 5-9 cal mol(-1) K-1 for the binding of the conformationally constrained ligands. However, an unexpected drop in enthalpy for the binding of the conformationally constrained ligands relative to their flexible analogues was also observed. To evaluate whether these differences reflected conformational variations in peptide binding modes, we have determined the crystal structure of a complex of the Src SH2 domain bound to one of the conformationally constrained peptide mimics. Comparison of this new structure with that of the Src SH2 domain bound to a natural 11-mer peptide (Waksman et al. Cell 1993, 72, 779-790) revealed only very small differences. Hence, cyclopropane-derived peptides are excellent mimics of the bound state of their flexible analogues. However, a rigorous analysis of the structures and of the surface areas at the binding interface, and subsequent computational derivation of the energetic binding parameters, failed to predict the observed differences between the binding thermodynamics of the rigidified and flexible ligands, suggesting that the drop in enthalpy observed with the conformationally constrained peptide mimic arises from sources other than changes in buried surface areas, though the exact origin of the differences remains unclear.

  DOI：

  10.1021/ja011746f
• 作为产物：
  描述：

  3-(4-(tert-butoxy)phenyl)propanoic acid 在 palladium on activated charcoal N-甲基吗啉 、 四氮唑 、 叔丁基过氧化氢 、 氢气 、 sodium hexamethyldisilazane 、 三乙胺 、 三氟乙酸 、 lithium chloride 作用下， 以 乙醇 为溶剂， 生成 (2R)-2-[4-(bis-benzyloxy-phosphoryloxy)-benzyl]-N-methyl-succinamic acid
  参考文献：
  名称：

  Use of 1,2,3-trisubstituted cyclopropanes as conformationally constrained peptide mimics in SH2 antagonists

  摘要：

  Novel conformationally constrained phosphotyrosine pseudopeptide derivatives of the tetrapeptide pY-E-E-I were prepared and evaluated as SH2 binding antagonists. (C) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0040-4039(00)01611-7

文献信息

• Thermodynamic and Structural Effects of Conformational Constraints in Protein−Ligand Interactions. Entropic Paradoxy Associated with Ligand Preorganization
  作者：John E. DeLorbe、John H. Clements、Martin G. Teresk、Aaron P. Benfield、Hilary R. Plake、Laura E. Millspaugh、Stephen F. Martin

  DOI：10.1021/ja904698q

  日期：2009.11.25

  enthalpies. Unexpectedly, binding entropies of the constrained ligands were uniformly disfavored relative to their flexible controls, demonstrating that the widely held belief that ligand preorganization should result in an entropic advantage is not necessarily true. Crystallographic studies of complexes of several flexible and constrained ligands having the same amino acid at the pY+1 position revealed extensive

  琥珀酸和环丙烷衍生的磷酸酪氨酸 (pY) 置换被纳入一系列 Grb2 SH2 结合配体，其中 pY+1 残基发生变化，以确定配体预组织的变化如何影响结合能量学和结构。这些配体与 Grb2 SH2 结构域的配合物在一系列热力学和结构研究中使用等温滴定量热法和 X 射线晶体学进行了检查。所有配体的结合焓都是有利的，尽管在 pY+1 位点具有疏水残基的所有配体的结合熵是有利的，但在该位点具有亲水残基的那些的结合熵是不利的。与灵活的控制相比，预组织的配体通常与更有利的吉布斯能量结合，但这种增加的亲和力是相对更有利的结合焓的结果。出乎意料的是，相对于它们的灵活控制，受限配体的结合熵一致不受欢迎，这表明普遍认为配体预组织应该导致熵优势的观点不一定正确。对在 pY+1 位置具有相同氨基酸的几种柔性和受限配体的复合物的晶体学研究揭示了广泛的相似性，但存在一些显着的差异。在受限配体的复合物中有更多的直接极性
• Design and synthesis of conformationally constrained, extended and reverse turn pseudopeptides as Grb2-SH2 domain antagonists
  作者：Hilary R Plake、Thomas B Sundberg、Angela R Woodward、Stephen F Martin

  DOI：10.1016/s0040-4039(03)00013-3

  日期：2003.2

  A series of conformationally constrained and flexible pseudopeptide derivatives of the tripeptide pYVN were prepared as potential antagonists of interactions of phosphotyrosine peptides with the Grb2-SH2 domain. The conformation ally constrained compounds contained trans- and cis-cyclopropanes as replacements to enforce locally extended and reverse turn peptide conformations, respectively. (C) 2003 Elsevier Science Ltd. All rights reserved.
• Ligand Preorganization May Be Accompanied by Entropic Penalties in Protein–Ligand Interactions
  作者：Aaron P. Benfield、Martin G. Teresk、Hilary R. Plake、John E. DeLorbe、Laura E. Millspaugh、Stephen F. Martin

  DOI：10.1002/anie.200600844

  日期：2006.10.20