methyl N^α-Fmoc-O'-(O'',O''-di-tert-butyl-2-malonyl)tyrosinate | 168135-78-2

• 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: methyl N^α-Fmoc-O'-(O'',O''-di-tert-butyl-2-malonyl)tyrosinate
• 英文别名: methyl N^α-Fmoc-4-O-tyrosinate；ditert-butyl 2-[4-[(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methoxy-3-oxopropyl]phenoxy]propanedioate
• CAS: 168135-78-2
• 化学式: C₃₆H₄₁NO₉
• 分子量: 631.723
• InChiKey: WJRNEGBFTPHORL-LJAQVGFWSA-N

物化性质

• 沸点：
  730.5±60.0 °C(Predicted)
• 密度：
  1.202±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  7
• 重原子数：
  46
• 可旋转键数：
  16
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  127
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  methyl N^α-Fmoc-O'-(O'',O''-di-tert-butyl-2-malonyl)tyrosinate 在 lithium hydroxide 作用下， 以 四氢呋喃 为溶剂， 反应 0.5h， 以88%的产率得到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
• 作为产物：
  描述：

  L-酪氨酸 在 盐酸 、 Rh(AcO)2 、 sodium carbonate 作用下， 以 1,4-二氧六环 、 水 、 苯 为溶剂， 反应 48.0h， 生成 methyl N^α-Fmoc-O'-(O'',O''-di-tert-butyl-2-malonyl)tyrosinate
  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.
• 4‘-<i>O</i>-[2-(2-Fluoromalonyl)]-<scp>l</scp>-tyrosine:  A Phosphotyrosyl Mimic for the Preparation of Signal Transduction Inhibitory Peptides
  作者：Terrence R. Burke,、Bin Ye、Miki Akamatsu、Harry Ford,、Xinjian Yan、Hemanta K. Kole、Gert Wolf、Steven E. Shoelson、Peter P. Roller

  DOI：10.1021/jm950621g

  日期：1996.1.1

  Development of phosphotyrosyl (pTyr) mimetics which are stable to protein-tyrosine phosphatases (PTPs), yet can retain biological potency when incorporated into peptides, is an active area of drug development. Since a majority of pTyr mimetics derive their ''phosphofunctionality'' from phosphorus-containing moieties, such as phosphonates, evolution of new inhibitors and modes of prodrug derivatization have been restricted to chemistries appropriate for phosphorus-containing moieties. A new, nonphosphorus-containing pTyr mimetic has recently been reported, L-O-(2-malonyl)tyrosine (OMT, 5), which can be incorporated into peptides that exhibit good PTP and Src homology 2 (SH2) domain inhibitory potency. For phosphonate-based pTyr mimetics such as phosphonomethyl phenylalanine (Pmp, 2), introduction of fluorines a to the phosphorus has provided higher affinity pTyr mimetics. This strategy has now been applied to OR IT, and herein is reported 4'-O-[2-(2-fluoromalonyl)]-L-tyrosine (FOMT) 6), a new fluorine-containing nonphosphorus pTyr mimetic. Incorporation of FOMT into appropriate peptides results in good inhibition of both PTP and SH2 domains. In an assay measuring the inhibition of PTP 1B-mediated dephosphorylation of phosphorylated insulin receptor, the peptide Ac-DA-D-E-X-L-amide exhibited a 10-fold enhancement in inhibitory potency for X = FOMT (19) (IC50 = 1 mu M) relative to the unfluorinated peptide, X = OMT (18) (IC50 = 10 mu M). Molecular modeling indicated that this increased affinity may be attributable to new hydrogen-bonding interactions between the fluorine and the enzyme catalytic site, and not due to lowering of pK(a) values. In a competition binding assay using the p85 PI 3-kinase C-terminal SH2 domain GST fusion construct, the inhibitory peptide, Ac-D-X-V-P-M-L-amide, showed no enhancement of inhibitory potency for X = FOMT (22) (IC50 = 18 mu M) relative to the unfluorinated peptide, X = OMT (21) (IC50 = 14 mu M). The use of FOMT would therefore appear to have particular potential for the development of PTP inhibitors.
• 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.