(4R,5S,6S)-2-{4-[2-(1-{2-carbamoyl-1-[3-(3S)-(5-{6-[5-(2-oxohexahydrothieno[3,4-d]imidazol-6-yl)pentanoylamino]hexanoyloxy}naphthalen-1-yl)propylcarbamoyl]ethylcarbamoyl}cyclohexylcarbamoyl)-2-(2S)-(oxalylamino)ethyl]phenyl}malonic acid tri-tert-butyl ester | 1084925-44-9

• 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: (4R,5S,6S)-2-{4-[2-(1-{2-carbamoyl-1-[3-(3S)-(5-{6-[5-(2-oxohexahydrothieno[3,4-d]imidazol-6-yl)pentanoylamino]hexanoyloxy}naphthalen-1-yl)propylcarbamoyl]ethylcarbamoyl}cyclohexylcarbamoyl)-2-(2S)-(oxalylamino)ethyl]phenyl}malonic acid tri-tert-butyl ester
• 英文别名: ditert-butyl 2-[4-[(2S)-3-[[1-[[(2S)-1-[3-[5-[6-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]hexanoyloxy]naphthalen-1-yl]propylamino]-4-amino-1,4-dioxobutan-2-yl]carbamoyl]cyclohexyl]amino]-2-[[2-[(2-methylpropan-2-yl)oxy]-2-oxoacetyl]amino]-3-oxopropyl]phenyl]propanedioate
• CAS: 1084925-44-9
• 化学式: C₆₆H₉₂N₈O₁₅S
• 分子量: 1269.57
• InChiKey: YXKBLNUBLDFINO-IDEBNZMXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.4
• 重原子数：
  90
• 可旋转键数：
  37
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  360
• 氢给体数：
  8
• 氢受体数：
  16

反应信息

• 作为反应物：
  描述：

  (4R,5S,6S)-2-{4-[2-(1-{2-carbamoyl-1-[3-(3S)-(5-{6-[5-(2-oxohexahydrothieno[3,4-d]imidazol-6-yl)pentanoylamino]hexanoyloxy}naphthalen-1-yl)propylcarbamoyl]ethylcarbamoyl}cyclohexylcarbamoyl)-2-(2S)-(oxalylamino)ethyl]phenyl}malonic acid tri-tert-butyl ester 在 水 、 1,2-乙二硫醇 、 三氟乙酸 作用下， 反应 1.0h， 以41%的产率得到(4R,5S,6S)-2-{4-[2-(1-{2-carbamoyl-1-[3-(3S)-(5-{6-[5-(2-oxohexahydrothieno[3,4-d]imidazol-6-yl)pentanoylamino]hexanoyloxy}naphthalen-1-yl)propylcarbamoyl]ethylcarbamoyl}cyclohexylcarbamoyl)-2-(2S)-(oxalylamino)ethyl]phenyl}malonic acid
  参考文献：
  名称：

  Selectivity and Mechanism of Action of a Growth Factor Receptor-Bound Protein 2 Src Homology 2 Domain Binding Antagonist

  摘要：

  We have shown previously that a potent synthetic antagonist of growth factor receptor-bound protein 2 (Grb2) Src homology 2 (SH2) domain binding (1) blocks growth factor stimulated motility, invasion, and angiogenesis in cultured cell models, as well as tumor metastasis in animals. To characterize the selectivity of I for the SH2 domain of Grb2 over other proteins containing similar structural binding motifs, we synthesized a biotinylated derivative (3) that retained high affinity Grb2 SH2 domain binding and potent biological activity. To investigate the selectivity of 1 and 3 for Grb2, the biotinylated antagonist 3 was used to immobilize target proteins from cell extracts for subsequent identification by mass spectrometry. Nonspecific binding was identified in parallel using a biotinylated analogue that lacked a single critical binding determinant. The mechanism of action of the antagonist was further characterized by immunoprecipitation, immunoblotting, and light microscopy. This approach to defining protein binding antagonist selectivity and molecular basis of action should be widely applicable in drug development.

  DOI：

  10.1021/jm800523u
• 作为产物：
  描述：

  6-biotinamidocaproic acid 、 2-{4-[2-(2S)-(tert-butoxyoxalylamino)-2-(1-(1S)-{2-carbamoyl-1-[3-(5-hydroxy-naphthalen-1-yl)propylcarbamoyl]ethylcarbamoyl}cyclohexylcarbamoyl)ethyl]phenyl}malonic acid di-tert-butyl ester 在 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以78%的产率得到(4R,5S,6S)-2-{4-[2-(1-{2-carbamoyl-1-[3-(3S)-(5-{6-[5-(2-oxohexahydrothieno[3,4-d]imidazol-6-yl)pentanoylamino]hexanoyloxy}naphthalen-1-yl)propylcarbamoyl]ethylcarbamoyl}cyclohexylcarbamoyl)-2-(2S)-(oxalylamino)ethyl]phenyl}malonic acid tri-tert-butyl ester
  参考文献：
  名称：

  Selectivity and Mechanism of Action of a Growth Factor Receptor-Bound Protein 2 Src Homology 2 Domain Binding Antagonist

  摘要：

  We have shown previously that a potent synthetic antagonist of growth factor receptor-bound protein 2 (Grb2) Src homology 2 (SH2) domain binding (1) blocks growth factor stimulated motility, invasion, and angiogenesis in cultured cell models, as well as tumor metastasis in animals. To characterize the selectivity of I for the SH2 domain of Grb2 over other proteins containing similar structural binding motifs, we synthesized a biotinylated derivative (3) that retained high affinity Grb2 SH2 domain binding and potent biological activity. To investigate the selectivity of 1 and 3 for Grb2, the biotinylated antagonist 3 was used to immobilize target proteins from cell extracts for subsequent identification by mass spectrometry. Nonspecific binding was identified in parallel using a biotinylated analogue that lacked a single critical binding determinant. The mechanism of action of the antagonist was further characterized by immunoprecipitation, immunoblotting, and light microscopy. This approach to defining protein binding antagonist selectivity and molecular basis of action should be widely applicable in drug development.

  DOI：

  10.1021/jm800523u