(3S)-3-(4-{[bis(tert-butoxy)phosphono]methyl}phenyl)hex-5-enoic acid | 495403-75-3

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 苯丙酸
• 英文名称: (3S)-3-(4-{[bis(tert-butoxy)phosphono]methyl}phenyl)hex-5-enoic acid
• 英文别名: (3S)-3-[4-[bis[(2-methylpropan-2-yl)oxy]phosphorylmethyl]phenyl]hex-5-enoic acid
• CAS: 495403-75-3
• 化学式: C₂₁H₃₃O₅P
• 分子量: 396.464
• InChiKey: JXGIGONRWOLQOS-SFHVURJKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  27
• 可旋转键数：
  11
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  72.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (3S)-3-(4-{[bis(tert-butoxy)phosphono]methyl}phenyl)hex-5-enoic acid 在 Grubbs catalyst first generation 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 60.0h， 生成 2-[(9S,13S,18S)-8,11,21-triaza-18-(4-{[bis(tert-butoxy)phosphono]methyl}phenyl)-13-(naphthylmethyl)-7,10,20-trioxospiro[5.15]henicos-15-en-9-yl]acetamide
  参考文献：
  名称：

  Macrocyclization in the Design of Grb2 SH2 Domain-Binding Ligands Exhibiting High Potency in Whole-Cell Systems

  摘要：

  While most SH2 domains bind phosphotyrosyl (pTyr) containing peptides in extended fashion, the growth factor receptor-bound protein 2 (Grb2) SH2 domain preferentially binds ligands in bend conformations. Accordingly, incorporation of bend-inducing functionality into synthetic ligands could potentially enhance their affinity for this SH2 domain. A macrocyclic tripeptide mimetic that contains a simplified pTyr surrogate lacking an alpha-nitrogen has recently been shown to exhibit high Grb2 SH2 domain-binding affinity in extracellular ELISA-based assays. However, the same compound is largely ineffective in whole-cell assays. It is known that acidic functionality originating from the alpha-nitrogen of pTyr residues or from the alpha-position of P-0 pTyr mimetics not only increases binding affinity of peptides to Grb2 SH2 domains in extracellular assays but also enhances potency in cell-based systems. Such functionality is absent from the previously reported macrocycle. Therefore, the current study was undertaken to examine the effects of introducing carboxylic functionality at the pTyr mimetic alpha-position of macrocyclic ligands. It was found that such a modification not only enhanced Grb2 SH2 domain binding in extracellular assays but also conferred high efficacy in whole-cell systems. The most potent compound of the current study exhibited an IC50 value of 0.002 muM in an extracellular ELISA-based assay, and in MDA-MB-453 cells, it both inhibited the association of Grb2 with p185(erbB-2) and exhibited antimitogenic effects with submicromolar IC50 values.

  DOI：

  10.1021/jm0203635
• 作为产物：
  描述：

  (4S)-3-[(3S)-3-(4-{[bis(tert-butoxy)phosphono]methyl}phenyl)hex-5-enoyl]-4-phenyl-1,3-oxazolidin-2-one 在 lithium hydroxide 、 双氧水 作用下， 以 四氢呋喃 为溶剂， 以90%的产率得到(3S)-3-(4-{[bis(tert-butoxy)phosphono]methyl}phenyl)hex-5-enoic acid
  参考文献：
  名称：

  Macrocyclization in the Design of Grb2 SH2 Domain-Binding Ligands Exhibiting High Potency in Whole-Cell Systems

  摘要：

  While most SH2 domains bind phosphotyrosyl (pTyr) containing peptides in extended fashion, the growth factor receptor-bound protein 2 (Grb2) SH2 domain preferentially binds ligands in bend conformations. Accordingly, incorporation of bend-inducing functionality into synthetic ligands could potentially enhance their affinity for this SH2 domain. A macrocyclic tripeptide mimetic that contains a simplified pTyr surrogate lacking an alpha-nitrogen has recently been shown to exhibit high Grb2 SH2 domain-binding affinity in extracellular ELISA-based assays. However, the same compound is largely ineffective in whole-cell assays. It is known that acidic functionality originating from the alpha-nitrogen of pTyr residues or from the alpha-position of P-0 pTyr mimetics not only increases binding affinity of peptides to Grb2 SH2 domains in extracellular assays but also enhances potency in cell-based systems. Such functionality is absent from the previously reported macrocycle. Therefore, the current study was undertaken to examine the effects of introducing carboxylic functionality at the pTyr mimetic alpha-position of macrocyclic ligands. It was found that such a modification not only enhanced Grb2 SH2 domain binding in extracellular assays but also conferred high efficacy in whole-cell systems. The most potent compound of the current study exhibited an IC50 value of 0.002 muM in an extracellular ELISA-based assay, and in MDA-MB-453 cells, it both inhibited the association of Grb2 with p185(erbB-2) and exhibited antimitogenic effects with submicromolar IC50 values.

  DOI：

  10.1021/jm0203635

文献信息

• Sh2 domain binding inhibitors
  申请人：Burke R. Terrence

  公开号：US20060167222A1

  公开（公告）日：2006-07-27

  Disclosed are compounds for SH2 domain binding inhibition, for example, a compound of formula (I), wherein R 1 is a lipophile; R 2 , in combination with the phenyl ring, is a phenylphosphate mimic group or a protected phenylphosphate mimic group; R 3 is hydrogen, azido, amino, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, or alkylcarbonylamino, wherein the alkyl portion of R 3 may be optionally substituted with a substituent selected from the group consisting of halo, hydroxy, carboxyl, amino, aminoalkyl, alkyl, alkoxy, and keto; R 6 is a linker; AA is an amino acid; and n is 1 to 6; or a salt thereof. The conformationally compounds provide enhanced binding affinity with SH2 domain protein. Also disclosed are a pharmaceutical compositions and a method for inhibiting an SH2 domain from binding with a phosphoprotein.

  本发明揭示了用于SH2结构域结合抑制的化合物，例如，式(I)的化合物，其中R1是一个疏水基；R2与苯环结合，是苯基磷酸酯类似物基团或受保护的苯基磷酸酯类似物基团；R3是氢、叠氮基、氨基、羧基烷基、烷氧羰基烷基、氨基羰基烷基或烷基羰基氨基，其中R3的烷基部分可以选择地用来自卤素、羟基、羧基、氨基、氨基烷基、烷基、烷氧基和酮的取代基进行取代；R6是一个连接基；AA是一种氨基酸；n为1至6；或其盐。这些构象化合物提供了与SH2结构域蛋白的增强结合亲和力。本发明还揭示了一种制药组合物和一种抑制SH2结构域与磷酸化蛋白结合的方法。
• US7425537B2
  申请人：——

  公开号：US7425537B2

  公开（公告）日：2008-09-16
• [EN] SH2 DOMAIN BINDING INHIBITORS<br/>[FR] INHIBITEURS DE LIAISON AU DOMAINE SH2
  申请人：US GOV HEALTH & HUMAN SERV

  公开号：WO2004003005A2

  公开（公告）日：2004-01-08

  Disclosed are compounds for SH2 domain binding inhibition, for example, a compound of formula (I), wherein R1 is a lipophile; R2, in combination with the phenyl ring, is a phenylphosphate mimic group or a protected phenylphosphate mimic group; R3 is hydrogen, azido, amino, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, or alkylcarbonylamino, wherein the alkyl portion of R3 may be optionally substituted with a substituent selected from the group consisting of halo, hydroxy, carboxyl, amino, aminoalkyl, alkyl, alkoxy, and keto; R6 is a linker; AA is an amino acid; and n is 1 to 6; or a salt thereof. The conformationally compounds provide enhanced binding affinity with SH2 domain protein. Also disclosed are a pharmaceutical compositions and a method for inhibiting an SH2 domain from binding with a phosphoprotein.
• Macrocyclization in the Design of Grb2 SH2 Domain-Binding Ligands Exhibiting High Potency in Whole-Cell Systems
  作者：Chang-Qing Wei、Yang Gao、Kyeong Lee、Ribo Guo、Bihua Li、Manchao Zhang、Dajun Yang、Terrence R. Burke

  DOI：10.1021/jm0203635

  日期：2003.1.1

  While most SH2 domains bind phosphotyrosyl (pTyr) containing peptides in extended fashion, the growth factor receptor-bound protein 2 (Grb2) SH2 domain preferentially binds ligands in bend conformations. Accordingly, incorporation of bend-inducing functionality into synthetic ligands could potentially enhance their affinity for this SH2 domain. A macrocyclic tripeptide mimetic that contains a simplified pTyr surrogate lacking an alpha-nitrogen has recently been shown to exhibit high Grb2 SH2 domain-binding affinity in extracellular ELISA-based assays. However, the same compound is largely ineffective in whole-cell assays. It is known that acidic functionality originating from the alpha-nitrogen of pTyr residues or from the alpha-position of P-0 pTyr mimetics not only increases binding affinity of peptides to Grb2 SH2 domains in extracellular assays but also enhances potency in cell-based systems. Such functionality is absent from the previously reported macrocycle. Therefore, the current study was undertaken to examine the effects of introducing carboxylic functionality at the pTyr mimetic alpha-position of macrocyclic ligands. It was found that such a modification not only enhanced Grb2 SH2 domain binding in extracellular assays but also conferred high efficacy in whole-cell systems. The most potent compound of the current study exhibited an IC50 value of 0.002 muM in an extracellular ELISA-based assay, and in MDA-MB-453 cells, it both inhibited the association of Grb2 with p185(erbB-2) and exhibited antimitogenic effects with submicromolar IC50 values.