2-tert-Butoxycarbonylmethoxy-5-[(S)-2-carboxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-ethyl]-benzoic acid 2-trimethylsilanyl-ethyl ester | 213757-71-2

• 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: 2-tert-Butoxycarbonylmethoxy-5-[(S)-2-carboxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-ethyl]-benzoic acid 2-trimethylsilanyl-ethyl ester
• 英文别名: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-[4-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]-3-(2-trimethylsilylethoxycarbonyl)phenyl]propanoic acid
• CAS: 213757-71-2
• 化学式: C₃₆H₄₃NO₉Si
• 分子量: 661.824
• InChiKey: JJKMECNGNWILGZ-PMERELPUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.44
• 重原子数：
  47
• 可旋转键数：
  17
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  138
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  2-tert-Butoxycarbonylmethoxy-5-[(S)-2-carboxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-ethyl]-benzoic acid 2-trimethylsilanyl-ethyl ester 、 (2S)-2-amino-N1-[3-(1-naphthalenyl)propyl]butanediamide 在 N,N′-二叔丁基碳二亚胺 、 1-羟基苯并三唑 作用下， 生成 2-tert-Butoxycarbonylmethoxy-5-[(S)-2-{1-[(S)-2-carbamoyl-1-(3-naphthalen-1-yl-propylcarbamoyl)-ethylcarbamoyl]-cyclohexylcarbamoyl}-2-(9H-fluoren-9-ylmethoxycarbonylamino)-ethyl]-benzoic acid 2-trimethylsilanyl-ethyl ester
  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：

  9-芴甲基-N-琥珀酰亚胺基碳酸酯 、 5-((S)-2-Amino-2-carboxy-ethyl)-2-tert-butoxycarbonylmethoxy-benzoic acid 2-trimethylsilanyl-ethyl ester 在 碳酸氢钠 作用下， 以 1,4-二氧六环 、 水 为溶剂， 以89%的产率得到2-tert-Butoxycarbonylmethoxy-5-[(S)-2-carboxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-ethyl]-benzoic acid 2-trimethylsilanyl-ethyl ester
  参考文献：
  名称：

  非含磷磷酸酪氨酸模拟物的对映选择性合成及其在酪氨酸磷酸酶抑制肽制备中的应用

  摘要：

  三个新的L-氨基酸类似物12,18和25都在适于掺入到通过使用Fmoc协议固相合成肽保护形式被制备。这些试剂代表不含磷的磷酸酪氨酰基（pTyr）模拟物，其利用羧基提供通常由pTyr磷酸基团提供的官能度。为了证明这些类似物的效用，制备了模拟酪氨酸的蛋白酪氨酸磷酸酶定向肽Ac-DADE- X -L-酰胺（28-30）。在（8）a K i的情况下针对PTP1的取值为3.6μM，等于母体含pTyr的肽的Km。除了酪氨酸磷酸酶，这些类似物在许多情况下可能有用，包括SH2结构域和磷酸酪氨酸结合结构域系统。

  DOI：

  10.1016/s0040-4020(98)00590-0

文献信息

• Tripeptide inhibitors of Yersinia protein-tyrosine phosphatase
  作者：Kyeong Lee、Yang Gao、Zhu-Jun Yao、Jason Phan、Li Wu、Jiao Liang、David S Waugh、Zhong-Yin Zhang、Terrence R Burke

  DOI：10.1016/s0960-894x(03)00481-5

  日期：2003.8

  The protein-tyrosine phosphatase (PTP) 'YopH' is a virulence factor of Yersinia pestis, the causative agent of plague. Potential use of Yersinia as a bioterrorism agent renders YopH inhibitors of therapeutic importance. Previously, we had examined the inhibitory potencies of a variety of phosphotyrosyl (pTyr) mimetics against the human PTP1B enzyme by displaying them in the EGFR-derived hexapeptide sequence, 'Ac-Asp-Ala-Asp-Glu-Xxx-Leu-amide', where Xxx=pTyr mimetic. The poor inhibitory potencies of certain of these pTyr mimetics were attributed to restricted orientation within the PTP1B catalytic pocket incurred by extensive peripheral interaction of the hexapeptide platform. Utilizing the smaller tripeptide platform. 'Fmoc-Glu-Xxx-Leu-amide' we demonstrate herein that several of the low affinity hexapeptide-expressed pTyr mimetics exhibit high PTP1B affinity within the context of the tripeptide platform. Of particular note, the mono-anionic 4(carboxydifluoroinethyl)Phe residue exhibits affinity equivalent to the di-anionic F(2)Pmp residue, which had previously been among the most potent PTP-binding motifs. Against YopH, it was found that all tripeptides having Gin residues with an unprotected side chain carboxyl were inactive. Alternatively, in their Glu-OBn ester forms, several of the tripeptides exhibited good YopH affinity with the mono-anionic peptide, Fmoc-Glu(OBn)-Xxx-Leu-amide, where Xxx = 4-(carboxymethyloxy)Phe providing an IC50 value of 2.8 muM. One concern with such inhibitors is that they may potentially function by non-specific mechanisms. Studies with representative inhibitors. while failing to provide evidence of a non-specific promiscuous mode of inhibition, did indicate that non-classical inhibition may be involved. (C) 2003 Elsevier Ltd. All rights reserved.
• Potent Inhibition of Grb2 SH2 Domain Binding by Non-Phosphate-Containing Ligands
  作者：Zhu-Jun Yao、C. Richter King、Tin Cao、James Kelley、George W. A. Milne、Johannes H. Voigt、Terrence R. Burke

  DOI：10.1021/jm980388x

  日期：1999.1.1

  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.
• Enantioselective synthesis of nonphosphorus-containing phosphotyrosyl mimetics and their use in the preparation of tyrosine phosphatase inhibitory peptides
  作者：Terrence R Burke、Zhu-Jun Yao、He Zhao、George W.A Milne、Li Wu、Zhong-Yin Zhang、Johannes H Voigt

  DOI：10.1016/s0040-4020(98)00590-0

  日期：1998.8

  Three new L-amino acid analogues 12, 18 and 25 have been prepared in protected form suitable for incorporation into peptides by solid-phase synthesis using Fmoc protocols. These agents represent nonphosphorus-containing phosphotyrosyl (pTyr) mimetics, which utilize carboxylic groups to provide functionality normally afforded by the pTyr phosphate group. To demonstrate the utility of these analogues

  三个新的L-氨基酸类似物12,18和25都在适于掺入到通过使用Fmoc协议固相合成肽保护形式被制备。这些试剂代表不含磷的磷酸酪氨酰基（pTyr）模拟物，其利用羧基提供通常由pTyr磷酸基团提供的官能度。为了证明这些类似物的效用，制备了模拟酪氨酸的蛋白酪氨酸磷酸酶定向肽Ac-DADE- X -L-酰胺（28-30）。在（8）a K i的情况下针对PTP1的取值为3.6μM，等于母体含pTyr的肽的Km。除了酪氨酸磷酸酶，这些类似物在许多情况下可能有用，包括SH2结构域和磷酸酪氨酸结合结构域系统。