(S)-2-({1-[(S)-2-Acetylamino-3-(4-tert-butoxy-phenyl)-propionylamino]-cyclohexanecarbonyl}-amino)-N¹-(3-naphthalen-1-yl-propyl)-succinamide | 220193-67-9

• 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: (S)-2-({1-[(S)-2-Acetylamino-3-(4-tert-butoxy-phenyl)-propionylamino]-cyclohexanecarbonyl}-amino)-N¹-(3-naphthalen-1-yl-propyl)-succinamide
• 英文别名: (2S)-2-[[1-[[(2S)-2-acetamido-3-[4-[(2-methylpropan-2-yl)oxy]phenyl]propanoyl]amino]cyclohexanecarbonyl]amino]-N-(3-naphthalen-1-ylpropyl)butanediamide
• CAS: 220193-67-9
• 化学式: C₃₉H₅₁N₅O₆
• 分子量: 685.864
• InChiKey: CADBGCUJCWPMKH-LQJZCPKCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  50
• 可旋转键数：
  16
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  169
• 氢给体数：
  5
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (S)-2-({1-[(S)-2-Acetylamino-3-(4-tert-butoxy-phenyl)-propionylamino]-cyclohexanecarbonyl}-amino)-N¹-(3-naphthalen-1-yl-propyl)-succinamide 在 三乙基硅烷 、 三氟乙酸 作用下， 反应 1.0h， 以88%的产率得到(S)-2-({1-[(S)-2-Acetylamino-3-(4-hydroxy-phenyl)-propionylamino]-cyclohexanecarbonyl}-amino)-N¹-(3-naphthalen-1-yl-propyl)-succinamide
  参考文献：
  名称：

  Potent Inhibition of Grb2 SH2 Domain Binding by Non-Phosphate-Containing Ligands

  摘要：

  Development of Grb2 Src homology 2 (SH2) domain binding inhibitors has important implications for treatment of a variety of diseases, including several cancers. In cellular studies, inhibitors of Grb2 SH2 domain binding have to date been large, highly charged peptides which relied on special transport devices for cell membrane penetration. Work presented in the current study examines a variety of pTyr mimetics in the context of a high-affinity Grb2 binding platform. Among the analogues studied are new norm-phosphorus-containing pTyr mimetics 23a and 23b which, when incorporated into tripeptide structures 18f and 20f, are able to inhibit Grb2 SH2 domain binding with affinities among the best yet reported for non-phosphorus-containing SH2 domain inhibitors (IC50 values of 6.7 and 1.3 mu M, respectively). The present study has also demonstrated the usefulness of the Na-oxalyl group as an auxiliary which enhances the binding potency of both phosphorus- and non-phosphorus-containing pTyr mimetics. When combined with the (phosphonomethyl)phenylalanine (Pmp) residue to give analogues such as L-20d, potent inhibition of Grb2 SH2 domain binding can be achieved both in extracellular assays using isolated Grb2 SH2 domain protein and in intracellular systems measuring the association of endogenous Grb2 with its cognate p185(erbB-2) ligand. These latter effects can be achieved at micromolar to submicromolar concentrations without prodrug derivatization. The oxalyl-containing pTyr mimetics presented in this study should be of general usefulness for the development of other Grb2 SH2 domain antagonists, independent of the beta-bend-mimicking platform utilized for their display.

  DOI：

  10.1021/jm980388x
• 作为产物：
  描述：

  ((S)-2-(4-tert-Butoxy-phenyl)-1-{1-[(S)-2-carbamoyl-1-(3-naphthalen-1-yl-propylcarbamoyl)-ethylcarbamoyl]-cyclohexylcarbamoyl}-ethyl)-carbamic acid 9H-fluoren-9-ylmethyl ester 在 哌啶 作用下， 以 乙腈 为溶剂， 反应 1.0h， 生成 (S)-2-({1-[(S)-2-Acetylamino-3-(4-tert-butoxy-phenyl)-propionylamino]-cyclohexanecarbonyl}-amino)-N¹-(3-naphthalen-1-yl-propyl)-succinamide
  参考文献：
  名称：

  Potent Inhibition of Grb2 SH2 Domain Binding by Non-Phosphate-Containing Ligands

  摘要：

  Development of Grb2 Src homology 2 (SH2) domain binding inhibitors has important implications for treatment of a variety of diseases, including several cancers. In cellular studies, inhibitors of Grb2 SH2 domain binding have to date been large, highly charged peptides which relied on special transport devices for cell membrane penetration. Work presented in the current study examines a variety of pTyr mimetics in the context of a high-affinity Grb2 binding platform. Among the analogues studied are new norm-phosphorus-containing pTyr mimetics 23a and 23b which, when incorporated into tripeptide structures 18f and 20f, are able to inhibit Grb2 SH2 domain binding with affinities among the best yet reported for non-phosphorus-containing SH2 domain inhibitors (IC50 values of 6.7 and 1.3 mu M, respectively). The present study has also demonstrated the usefulness of the Na-oxalyl group as an auxiliary which enhances the binding potency of both phosphorus- and non-phosphorus-containing pTyr mimetics. When combined with the (phosphonomethyl)phenylalanine (Pmp) residue to give analogues such as L-20d, potent inhibition of Grb2 SH2 domain binding can be achieved both in extracellular assays using isolated Grb2 SH2 domain protein and in intracellular systems measuring the association of endogenous Grb2 with its cognate p185(erbB-2) ligand. These latter effects can be achieved at micromolar to submicromolar concentrations without prodrug derivatization. The oxalyl-containing pTyr mimetics presented in this study should be of general usefulness for the development of other Grb2 SH2 domain antagonists, independent of the beta-bend-mimicking platform utilized for their display.

  DOI：

  10.1021/jm980388x