N^α-Fmoc-4-(bis((tert-butyl)oxycarbonyl)fluoromethyl)-L-phenylalanine | 264131-62-6

• 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: N^α-Fmoc-4-(bis((tert-butyl)oxycarbonyl)fluoromethyl)-L-phenylalanine
• 英文别名: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-[4-[2-fluoro-1,3-bis[(2-methylpropan-2-yl)oxy]-1,3-dioxopropan-2-yl]phenyl]propanoic acid
• CAS: 264131-62-6
• 化学式: C₃₅H₃₈FNO₈
• 分子量: 619.687
• InChiKey: IGLIBCNFSHGDHJ-NDEPHWFRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.8
• 重原子数：
  45
• 可旋转键数：
  14
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  128
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  N^α-Fmoc-4-(bis((tert-butyl)oxycarbonyl)fluoromethyl)-L-phenylalanine 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 3.17h， 生成 2-[4-((S)-2-Amino-2-{1-[(S)-2-carbamoyl-1-(3-naphthalen-1-yl-propylcarbamoyl)-ethylcarbamoyl]-cyclohexylcarbamoyl}-ethyl)-phenyl]-2-fluoro-malonic acid di-tert-butyl ester
  参考文献：
  名称：

  Inhibition of Grb2 SH2 Domain Binding by Non-Phosphate-Containing Ligands. 2. 4-(2-Malonyl)phenylalanine as a Potent Phosphotyrosyl Mimetic

  摘要：

  Nonhydrolyzable phosphotyrosyl (pTyr) mimetics serve as important components of many competitive Grb2 SH2 domain inhibitors. To date, the most potent of these inhibitors have relied on phosphonate-based structures to replace the 4-phosphoryl group of the parent pTyr residue. Reported herein is the design and evaluation of a new pTyr mimetic, p-malonylphenylalanine (Pmf), which does not contain phosphorus yet, in Grb2 SH2 domain binding systems, approaches the potency of phosphonate-based pTyr mimetics. When incorporated into high affinity Grb2 SH2 domain-directed platforms, Pmf is 15-20 times more potent than the closely related previously reported pTyr mimetic, O-malonyltyrosine (OMT). Pmf-containing inhibitors show inhibition constants as low as 8 nM in extracellular Grb2 binding assays and in whole cell systems, effective blockade of both endogenous Grb2 binding to cognate erbB-2, and downstream MAP kinase activation. Evidence is provided that use of an N-alpha-oxalyl auxiliary enhances effectiveness of Pmf and other inhibitors in both extracellular and intracellular contexts. As one of the most potent Grb2 SH2 domain-directed pTyr mimetics yet disclosed, Pmf may potentially have utility in the design of new chemotherapeutics for the treatment of various proliferative diseases, including breast cancer.

  DOI：

  10.1021/jm9904248
• 作为产物：
  描述：

  benzyl (3S,5S,6R)-3-[4-(bis((tert-butyl)oxycarbonyl)fluoromethyl)phenylmethyl]-(-)-6-oxo-5,6-diphenyl-4-morpholine-carboxylate 在 钯 氢气 、 溶剂黄146 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 水 为溶剂， 20.0 ℃ 、310.27 kPa 条件下， 反应 5.0h， 生成 N^α-Fmoc-4-(bis((tert-butyl)oxycarbonyl)fluoromethyl)-L-phenylalanine
  参考文献：
  名称：

  Inhibition of Grb2 SH2 Domain Binding by Non-Phosphate-Containing Ligands. 2. 4-(2-Malonyl)phenylalanine as a Potent Phosphotyrosyl Mimetic

  摘要：

  Nonhydrolyzable phosphotyrosyl (pTyr) mimetics serve as important components of many competitive Grb2 SH2 domain inhibitors. To date, the most potent of these inhibitors have relied on phosphonate-based structures to replace the 4-phosphoryl group of the parent pTyr residue. Reported herein is the design and evaluation of a new pTyr mimetic, p-malonylphenylalanine (Pmf), which does not contain phosphorus yet, in Grb2 SH2 domain binding systems, approaches the potency of phosphonate-based pTyr mimetics. When incorporated into high affinity Grb2 SH2 domain-directed platforms, Pmf is 15-20 times more potent than the closely related previously reported pTyr mimetic, O-malonyltyrosine (OMT). Pmf-containing inhibitors show inhibition constants as low as 8 nM in extracellular Grb2 binding assays and in whole cell systems, effective blockade of both endogenous Grb2 binding to cognate erbB-2, and downstream MAP kinase activation. Evidence is provided that use of an N-alpha-oxalyl auxiliary enhances effectiveness of Pmf and other inhibitors in both extracellular and intracellular contexts. As one of the most potent Grb2 SH2 domain-directed pTyr mimetics yet disclosed, Pmf may potentially have utility in the design of new chemotherapeutics for the treatment of various proliferative diseases, including breast cancer.

  DOI：

  10.1021/jm9904248

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.
• Inhibition of Grb2 SH2 Domain Binding by Non-Phosphate-Containing Ligands. 2. 4-(2-Malonyl)phenylalanine as a Potent Phosphotyrosyl Mimetic
  作者：Yang Gao、Juliet Luo、Zhu-Jun Yao、Ribo Guo、Hong Zou、James Kelley、Johannes H. Voigt、Dajun Yang、Terrence R. Burke

  DOI：10.1021/jm9904248

  日期：2000.3.1

  Nonhydrolyzable phosphotyrosyl (pTyr) mimetics serve as important components of many competitive Grb2 SH2 domain inhibitors. To date, the most potent of these inhibitors have relied on phosphonate-based structures to replace the 4-phosphoryl group of the parent pTyr residue. Reported herein is the design and evaluation of a new pTyr mimetic, p-malonylphenylalanine (Pmf), which does not contain phosphorus yet, in Grb2 SH2 domain binding systems, approaches the potency of phosphonate-based pTyr mimetics. When incorporated into high affinity Grb2 SH2 domain-directed platforms, Pmf is 15-20 times more potent than the closely related previously reported pTyr mimetic, O-malonyltyrosine (OMT). Pmf-containing inhibitors show inhibition constants as low as 8 nM in extracellular Grb2 binding assays and in whole cell systems, effective blockade of both endogenous Grb2 binding to cognate erbB-2, and downstream MAP kinase activation. Evidence is provided that use of an N-alpha-oxalyl auxiliary enhances effectiveness of Pmf and other inhibitors in both extracellular and intracellular contexts. As one of the most potent Grb2 SH2 domain-directed pTyr mimetics yet disclosed, Pmf may potentially have utility in the design of new chemotherapeutics for the treatment of various proliferative diseases, including breast cancer.