N-[(9H-芴-9-基甲氧基)羰基]-L-酪氨酸 O-丙二酸二叔丁酯 | 168135-77-1

• 物质功能分类: 生物化工 - 氨基酸及其衍生物 - 酪氨酸类衍生物
• 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
• 中文名称: N-[(9H-芴-9-基甲氧基)羰基]-L-酪氨酸 O-丙二酸二叔丁酯
• 中文别名: N-[(9H-芴-9-基甲氧基)羰基]-L-酪氨酸O-丙二酸二叔丁酯
• 英文名称: Fmoc-OMT(t-Bu)2-OH
• 英文别名: N^α-Fmoc-L-O-(2-malonyl)tyrosine-O,O-(tert-butyl)2；N^α-Fmoc-O'-(O'',O''-di-tert-butyl-2-malonyl)tyrosine；N^α-Fmoc(t-BuO)2-OMT-OH；Fmoc-Tyr(Malonyl-Di-Otbu)-OH；(2S)-3-[4-[1,3-bis[(2-methylpropan-2-yl)oxy]-1,3-dioxopropan-2-yl]oxyphenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid
• CAS: 168135-77-1
• 化学式: C₃₅H₃₉NO₉
• 分子量: 617.696
• InChiKey: MBSLNORFSWIPLG-NDEPHWFRSA-N

物化性质

• 沸点：
  744.6±60.0 °C(Predicted)
• 密度：
  1.235

计算性质

• 辛醇/水分配系数(LogP)：
  6.6
• 重原子数：
  45
• 可旋转键数：
  15
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  138
• 氢给体数：
  2
• 氢受体数：
  9

安全信息

• 储存条件：
  -15°C

反应信息

• 作为反应物：
  描述：

  N-[(9H-芴-9-基甲氧基)羰基]-L-酪氨酸 O-丙二酸二叔丁酯 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 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 4.17h， 生成 2-[4-((S)-2-Acetylamino-2-{1-[(S)-2-carbamoyl-1-(3-naphthalen-1-yl-propylcarbamoyl)-ethylcarbamoyl]-cyclohexylcarbamoyl}-ethyl)-phenoxy]-malonic acid
  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：

  L-酪氨酸 在 盐酸 、 lithium hydroxide 、 Rh(AcO)2 、 sodium carbonate 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 、 苯 为溶剂， 反应 48.5h， 生成 N-[(9H-芴-9-基甲氧基)羰基]-L-酪氨酸 O-丙二酸二叔丁酯
  参考文献：
  名称：

  LO-（2-丙二酰基）酪氨酸：一种新的磷酸酪氨酸模拟物，用于制备Src同源性2域抑制肽。

  摘要：

  Src同源性2（SH2）域结合相互作用的抑制提供了一种潜在的手段来调节蛋白质酪氨酸激酶依赖性信号传导。含小磷酪氨酰（pTyr）的肽能够与SH2结构域结合并与较大的pTyr肽或天然的含pTyr的蛋白质配体竞争。这种含pTyr的肽在体内作为SH2结构域抑制剂的用途受到限制，因为它们对蛋白质酪氨酸磷酸酶（PTP）的水解能力和离子化磷酸盐部分的不良细胞渗透能力。SH2域抑制剂设计的一个重要方面是创建对PTP稳定并具有合理生物利用度的pTyr模拟物。迄今为止，大多数与SH2域结合的抗PTP的pTyr模拟物都是膦酸酯，例如（膦酰基甲基）苯丙氨酸（Pmp，2），[（单氟膦酰基）甲基]苯丙氨酸（FPmp，3）或[（二氟膦酰基）甲基]-苯丙氨酸（F2Pmp，4）。在此，我们报道了使用受保护的类似物LNα-Fmoc-O'-（）将新的不含磷的pTyr模拟物LO-（2-丙二酰基）酪氨酸（L-OMT，5）掺入SH2域抑制肽中。

  DOI：

  10.1021/jm00021a016

文献信息

• L-O-(2-malonyl)tyrosine (L-OMT) a new phosphotyrosyl mimic suitably protected for solid-phase synthesis of signal transduction inhibitory peptides
  作者：Bin Ye、Terrence R Burke

  DOI：10.1016/0040-4039(95)00890-o

  日期：1995.7

  A new phosphotyrosyl (pTyr) mimic L-O-(2-malonyl)tyrosine (L-OMT, 4) utilizes a malonyl structure in place of the parent phosphate group. This compound is stable to protein-tyrosine phosphatases and has advantages over phosphonate-based pTyr mimics in that protection of the malonyl group as its diester allows passage of the OMT across cell membranes, with subsequent esterase-mediated liberation of the free diacid once inside cells. Herein is reported the synthesis of N-alpha-Fmoc-L-OMT-O,O-(tert-butyl)(2) (5) for the solid-phase synthesis of L-OMT containing peptides as modulators of cellular signal transduction. Additionally included is the preparation of N-alpha-Fmoc-L-OMT-O,O-(n-butyl)(2) (6) for the direct solid-phase synthesis of OMT-peptide diester prodrugs for use in cell-based studies.
• New syntheses of tetrazolylmethylphenylalanine and O-malonyltyrosine as pTyr mimetics for the design of STAT3 dimerization inhibitors
  作者：Jennifer Dourlat、Bruno Valentin、Wang-Qing Liu、Christiane Garbay

  DOI：10.1016/j.bmcl.2007.04.107

  日期：2007.7

  Investigation within the pTyr-binding pocket of the STAT3 SH2 domain led us to develop a novel synthesis of two pTyr mimetics, L-tetrazolylmethylphenylalanine (L-Tmp) and L-O-malonyltyrosine (L-OMT), that were next incorporated in a high affinity ligand of STAT3 SH2 domain. Biological evaluation of peptidomimetics on STAT3 dimerization identified L-OMT as the first non-phosphorus pTyr mimetic so far reported against STAT3 SH2 domain, harboring an activity similar to that of the Pmp-containing reference peptidomimetic. (C) 2007 Elsevier Ltd. All rights reserved.
• 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.
• A one-step synthesis of Nα-Fmoc-4-O-[O′,O″-di-tert-butyl-2-(2-fluoromalonyl)]-l-tyrosine from commercially available starting material
  作者：Sang Uk Kang、Terrence R. Burke

  DOI：10.1016/j.tetlet.2004.09.163

  日期：2004.11

  A one-step high yield synthesis from commercially available starting material is reported for the novel phosphotyrosyl mimetic, N-alpha-Fmoc-4-O-[O',O"-di-tert-butyl-2-(2-fluoromalonyl)]-L-tyrosine. The conditions employed for this transformation may also be applicable for the direct electrophilic fluorination of other N-alpha-Fmoc-protected amino acids. Published by Elsevier Ltd.
• Potent inhibition of protein-tyrosine phosphatase by phosphotyrosine-mimic containing cyclic peptides
  作者：Miki Akamatsu、Peter P. Roller、Li Chen、Zhong-Yin Zhang、Bin Ye、Terrence R. Burke

  DOI：10.1016/s0968-0896(96)00195-2

  日期：1997.1

  In an effort to derive potent and bioavailable protein-tyrosine phosphatase inhibitors, we have previously reported hexameric peptides based on the epidermal growth factor receptor sequence EGFR(988-993) (Asp-Ala-Asp-Glu-Xxx-Leu, where Xxx = Tyr), in which the tyrosyl residue has been replaced by the non-hydrolyzable phosphotyrosyl mimics phosphonomethylphenylalanine (Pmp), difluorophosphsnomethylphenylalanine (F(2)Pmp) and O-malonyltyrosine (OMT) Inhibitory potencies (IC50 values) of these peptides against the tyrosine phosphatase PTP 1B were 200, 0.2 and 10 mu M, respectively. Since cellular penetration of peptides containing highly charged phosphonate residues is compromised, and good bioreversible protection strategies for the F(2)Pmp residue have not yet been reported, the OMT residue is of particular interest in that it affords potential new prodrug approaches. In the current study we have prepared cyclized versions of the OMT-containing EGFR(988-993) peptide in order to increase its proteolytic stability and restrain conformational flexibility. Three different cyclic analogues were synthesized. Two of these were cyclized through the peptide backbone ('head to tail') using in one case a single glycine spacer (heptamer peptide) and in the second instance, two glycines (octamer peptide). In a PTP1-based assay the cyclic heptamer experienced a two-fold loss of potency (K-i = 25.2+/-3.9 mu M) relative to the linear hexamer parent (K-i = 13+/-0.9 mu M), while the cyclic octamer demonstrated a five-fold increase in potency (K-i = 2.60+/-0.11 mu M). The third peptide was cyclized by means of a sulfide bridge between the side chain of a C-terminally added cysteine residue and the beta-carbon of a N-terminal acetyl residue. Although the overall size of this ring was identical to that exhibited by the preceding backbone-cyclized octamer, it displayed a three-fold enhancement in potency (K-i = 0.73+/-0.03 mu M). The structural basis for the observed results are discussed. Conformational restrictions induced by cyclization could aid in defining geometries for peptidomimetic design. Finally, it can be speculated that cyclization of other linear PTP-inhibitoly peptides, such as the F(2)Pmp-containing hexamer, may also increase their potency. Published by Elsevier Science Ltd. Science Ltd.