{1-[(S)-2-Carbamoyl-1-(3-naphthalen-1-yl-propylcarbamoyl)-ethylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester | 220193-51-1

• 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: {1-[(S)-2-Carbamoyl-1-(3-naphthalen-1-yl-propylcarbamoyl)-ethylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester
• 英文别名: tert-butyl N-[1-[[(2S)-4-amino-1-(3-naphthalen-1-ylpropylamino)-1,4-dioxobutan-2-yl]carbamoyl]cyclohexyl]carbamate
• CAS: 220193-51-1
• 化学式: C₂₉H₄₀N₄O₅
• 分子量: 524.66
• InChiKey: VJWGTVLVUJGBGG-QHCPKHFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  38
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  140
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  {1-[(S)-2-Carbamoyl-1-(3-naphthalen-1-yl-propylcarbamoyl)-ethylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester 在 哌啶 、 三乙基硅烷 、 N,N′-二叔丁基碳二亚胺 、 1-羟基苯并三唑 、 三氟乙酸 作用下， 以 乙腈 为溶剂， 反应 2.17h， 生成 2-trimethylsilylethyl 5-[(2S)-3-[[1-[[(2S)-4-amino-1-(3-naphthalen-1-ylpropylamino)-1,4-dioxobutan-2-yl]carbamoyl]cyclohexyl]amino]-2-[[2-[(2-methylpropan-2-yl)oxy]-2-oxoacetyl]amino]-3-oxopropyl]-2-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]benzoate
  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：

  1-(N-叔丁氧羰基氨基)环己烷甲酸 、 [(2S)-4-amino-1-(3-naphthalen-1-ylpropylamino)-1,4-dioxobutan-2-yl]azanium;2,2,2-trifluoroacetate 在 1-羟基苯并三唑一水物 、 N,N'-二异丙基碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 4.5h， 生成 {1-[(S)-2-Carbamoyl-1-(3-naphthalen-1-yl-propylcarbamoyl)-ethylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester
  参考文献：
  名称：

  细胞渗透性、不含磷酸盐的 GRB2 SH2 结构域抑制剂的大规模制备

  摘要：

  细胞信号转导抑制剂正在成为包括癌症和糖尿病在内的多种疾病的重要新疗法。异常蛋白酪氨酸激酶依赖性信号传导的拮抗剂特别令人感兴趣 7，其中类似物 14 和 2s 代表了两个值得注意的例子，最近据报道它们在细胞外测定和全细胞制备中均能有效抑制 Grb2 SH2 结构域结合。Grb2 SH2 结构域在多种癌症（包括乳腺癌和白血病）中发挥的核心作用，使 1 和 2 成为有用的药理学工具和治疗剂的潜在价值。以前 1 和 2 都仅以毫克级制备。然而，由于需要显着更大的数量，本文报道了它们通过适用于相关信号转导抑制剂放大的技术在数百毫克规模上的合成。特别值得注意的是应用径向压缩技术以实现近 1 g 规模的最终产品 HPLC 纯化。

  DOI：

  10.1080/00304940009356287