(3R)-N-{[N-((1S)-1-{N-[(2S)-2-(naphthylmethyl)pent-4-enyl]carbamoyl}-2-carbamoylethyl)carbamoyl]isopropyl}-3-(4-{[bis(tert-butoxy)phosphono]methyl}phenyl)pent-4-enamide | 495404-18-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (3R)-N-{[N-((1S)-1-{N-[(2S)-2-(naphthylmethyl)pent-4-enyl]carbamoyl}-2-carbamoylethyl)carbamoyl]isopropyl}-3-(4-{[bis(tert-butoxy)phosphono]methyl}phenyl)pent-4-enamide
• 英文别名: (2S)-2-[[2-[[(3R)-3-[4-[bis[(2-methylpropan-2-yl)oxy]phosphorylmethyl]phenyl]pent-4-enoyl]amino]-2-methylpropanoyl]amino]-N-[(2S)-2-(naphthalen-1-ylmethyl)pent-4-enyl]butanediamide
• CAS: 495404-18-7
• 化学式: C₄₄H₆₁N₄O₇P
• 分子量: 788.965
• InChiKey: NUSHXWADWBRRBD-WXLVEAMESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  56
• 可旋转键数：
  22
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  166
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (3R)-N-{[N-((1S)-1-{N-[(2S)-2-(naphthylmethyl)pent-4-enyl]carbamoyl}-2-carbamoylethyl)carbamoyl]isopropyl}-3-(4-{[bis(tert-butoxy)phosphono]methyl}phenyl)pent-4-enamide 在 Grubbs catalyst first generation 作用下， 以 二氯甲烷 为溶剂， 以63%的产率得到2-[(1S,5S,9R)-3,12,15-triaza-9-(4-{[bis(tert-butoxy)phosphono]methyl}phenyl)-13,13-dimethyl-5-(naphthylmethyl)-2,11,14-trioxocyclopentadec-7-enyl]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：

  (S)-2-amino-N¹-((S)-2-(naphthalen-1-ylmethyl)pent-4-en-1-yl)succinamide 在 哌啶 、 N,N′-二叔丁基碳二亚胺 、 1-羟基苯并三唑 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 2.0h， 生成 (3R)-N-{[N-((1S)-1-{N-[(2S)-2-(naphthylmethyl)pent-4-enyl]carbamoyl}-2-carbamoylethyl)carbamoyl]isopropyl}-3-(4-{[bis(tert-butoxy)phosphono]methyl}phenyl)pent-4-enamide
  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

• 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.