Fmoc-[HTY](tBu)-OH

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: Fmoc-[HTY](tBu)-OH
• 英文别名: Fmoc-hTyr(tBu)-OH；(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-(4-(tert-butoxy)phenyl)butanoic acid；(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-[4-[(2-methylpropan-2-yl)oxy]phenyl]butanoic acid
• 化学式: C₂₉H₃₁NO₅
• 分子量: 473.569
• InChiKey: FKUBPXDMQFEPGP-SANMLTNESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  35
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  84.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  Fmoc-[HTY](tBu)-OH 在 N-甲基吗啉 、 hydroxylamine Wang resin 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 哌啶 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 、 二氯甲烷 为溶剂， 反应 1.17h， 生成 (S)-2-amino-N-hydroxy-4-(4-hydroxyphenyl)butanamide
  参考文献：
  名称：

  Design and Evaluation of Hydroxamate Derivatives as Metal-Mediated Inhibitors of a Protein Tyrosine Kinase

  摘要：

  Protein tyrosine kinases use two Mg2+ ions as cofactors in catalysis, one as the ATP-Mg complex (M1) and the other as an essential activator (M2). The M2-binding site has high affinity for transition metal cations such as cobalt and zinc. Taking advantage of this high affinity, we examined hydroxamates as metal-mediated inhibitors against C-terminal Src kinase (Csk), a protein tyrosine kinase. Of a small group of amino acid hydroxamates, tyrosine and phenylalanine hydroxamates inhibited Csk activity only in the presence of Co2+. Four classes of phenylalanine and tyrosine hydroxamate derivatives were synthesized and evaluated as metal-mediated inhibitors of Csk, leading to improved inhibition and a better understanding of the structure-activity relationships. This study suggests that hydroxamates may serve as a general scaffold for developing metal-mediated inhibitors against protein tyrosine kinases. To the best of our knowledge, this is the first report of designing metal-mediated inhibitors against a protein tyrosine kinase by targeting a metal binding site.

  DOI：

  10.1021/jm061058c
• 作为产物：
  描述：

  methyl (2S)-4-(4-tert-butoxyphenyl)-2-([(9H-fluoren-9-ylmethoxy)carbonyl]amino)butanoate 在 水 、 calcium chloride 、 sodium hydroxide 作用下， 以 异丙醇 为溶剂， 以66 %的产率得到Fmoc-[HTY](tBu)-OH
  参考文献：
  名称：

  金属光氧化还原催化合成Fmoc-高酪氨酸的便捷途径及其在鱼腥肽环肽全合成中的应用

  摘要：

  在此，我们报告了天然环肽anabaenopeptin F的首次固相全合成，并使用金属光氧化还原催化来克服与制备这些肽中包含的非蛋白氨基酸高酪氨酸相关的关键挑战。从L-高丝氨酸开始，用N -Fmoc-( S )-2-氨基-4-溴丁酸和4-叔丁氧基溴苯伴侣通过金属光氧化还原催化以简单的方式制备对映体纯Fmoc保护的高酪氨酸。将制备的保护氨基酸用于固相肽合成，实现了anabaenopeptin F的全合成，并建立了异亮氨酸残基的立体化学。合成的鱼腥肽 F 的蛋白酶抑制研究表明，在低纳摩尔范围内对羧肽酶 B 具有抑制活性。合成方法的高度收敛性为快速获得N -Fmoc保护的非蛋白和非天然氨基酸以及包含这些氨基酸的复杂生物活性肽的全合成铺平了道路。

  DOI：

  10.1039/d3ob01608k

文献信息

• χ-Conopeptide Pharmacophore Development: Toward a Novel Class of Norepinephrine Transporter Inhibitor (Xen2174) for Pain
  作者：Andreas Brust、Elka Palant、Daniel E. Croker、Barbara Colless、Roger Drinkwater、Brad Patterson、Christina I. Schroeder、David Wilson、Carsten K. Nielsen、Maree T. Smith、Dianne Alewood、Paul F. Alewood、Richard J. Lewis

  DOI：10.1021/jm9003413

  日期：2009.11.26

  Norepinephrine (NE) amplifies the strength of descending pain inhibition, giving inhibitors of spinal NET clinical utility in the management of pain. χ-MrIA isolated from the venom of a predatory marine snail noncompetitively inhibits NET and reverses allodynia in rat models of neuropathic pain. An analogue of χ-MrIA has been found to be a suitable drug candidate. On the basis of the NMR solution structure

  去甲肾上腺素（NE）增强了向下疼痛抑制的强度，使脊髓NET抑制剂在疼痛控制中具有临床应用价值。从掠食性海洋蜗牛毒液中分离得到的χ-MrIA非竞争性抑制NET并逆转神经性疼痛大鼠模型的异常性疼痛。已经发现χ-MrIA的类似物是合适的候选药物。基于该相关肽，Xen2174（3）的NMR溶液结构以及类似物的构效关系，提出了3与NET的变构结合的药效团模型。如图所示3NET主要通过第一个环中的氨基酸与NET相互作用，形成紧密的反向旋转，以允许与NET高亲和力相互作用的方向呈现氨基酸Tyr7，Lys8和Leu9。第二环与转运蛋白内的大疏水口袋相互作用。基于药效基团的类似物证明了支持所提出模型的活性。基于改善的化学稳定性和广泛的治疗指数，选择了3种药物进行进一步开发，目前处于II期临床试验中。
• Synthesis and evaluation of novel macrocyclic antifungal peptides
  作者：Monique P.C. Mulder、John A.W. Kruijtzer、Eefjan J. Breukink、Johan Kemmink、Roland J. Pieters、Rob M.J. Liskamp

  DOI：10.1016/j.bmc.2011.08.034

  日期：2011.11

  Echinocandins are a novel class of macrocyclic antifungal peptides that act by inhibiting the beta-(1,3)-D-glucan synthase complex, which is not present in mammalian cells. Due to the large number of hydroxyl groups present in these complex macrocyclic lipopeptides, most structure-activity relationship studies have relied upon semisynthetic derivatives. In order to probe the influence of the cyclic peptide backbone on the antifungal activity we developed a successful strategy for the synthesis of novel echinocandins analogues by on-resin ring closing metathesis or disulfide formation. The specific minimum inhibitory activity of each mimic was determined against Candida albicans. Our results indicate that ring size is an important factor for antifungal activity. (C) 2011 Elsevier Ltd. All rights reserved.
• Design and Evaluation of Hydroxamate Derivatives as Metal-Mediated Inhibitors of a Protein Tyrosine Kinase
  作者：Xianfeng Gu、Yuehao Wang、Anil Kumar、Guofeng Ye、Keykavous Parang、Gongqin Sun

  DOI：10.1021/jm061058c

  日期：2006.12.1

  Protein tyrosine kinases use two Mg2+ ions as cofactors in catalysis, one as the ATP-Mg complex (M1) and the other as an essential activator (M2). The M2-binding site has high affinity for transition metal cations such as cobalt and zinc. Taking advantage of this high affinity, we examined hydroxamates as metal-mediated inhibitors against C-terminal Src kinase (Csk), a protein tyrosine kinase. Of a small group of amino acid hydroxamates, tyrosine and phenylalanine hydroxamates inhibited Csk activity only in the presence of Co2+. Four classes of phenylalanine and tyrosine hydroxamate derivatives were synthesized and evaluated as metal-mediated inhibitors of Csk, leading to improved inhibition and a better understanding of the structure-activity relationships. This study suggests that hydroxamates may serve as a general scaffold for developing metal-mediated inhibitors against protein tyrosine kinases. To the best of our knowledge, this is the first report of designing metal-mediated inhibitors against a protein tyrosine kinase by targeting a metal binding site.
• Convenient route to Fmoc-homotyrosine <i>via</i> metallaphotoredox catalysis and its use in the total synthesis of anabaenopeptin cyclic peptides
  作者：Christopher Bérubé、Louis-David Guay、Tommy Fraser、Victor Lapointe、Sébastien Cardinal、Éric Biron

  DOI：10.1039/d3ob01608k

  日期：——

  metallaphotoredox catalysis with N-Fmoc-(S)-2-amino-4-bromobutanoic acid and 4-tert-butoxybromobenzene partners. The prepared protected amino acid was used in solid-phase peptide synthesis to achieve the total synthesis of anabaenopeptin F and establish the stereochemistry of the isoleucine residue. Protease inhibition studies with the synthesized anabaenopeptin F showed inhibitory activities against

  在此，我们报告了天然环肽anabaenopeptin F的首次固相全合成，并使用金属光氧化还原催化来克服与制备这些肽中包含的非蛋白氨基酸高酪氨酸相关的关键挑战。从L-高丝氨酸开始，用N -Fmoc-( S )-2-氨基-4-溴丁酸和4-叔丁氧基溴苯伴侣通过金属光氧化还原催化以简单的方式制备对映体纯Fmoc保护的高酪氨酸。将制备的保护氨基酸用于固相肽合成，实现了anabaenopeptin F的全合成，并建立了异亮氨酸残基的立体化学。合成的鱼腥肽 F 的蛋白酶抑制研究表明，在低纳摩尔范围内对羧肽酶 B 具有抑制活性。合成方法的高度收敛性为快速获得N -Fmoc保护的非蛋白和非天然氨基酸以及包含这些氨基酸的复杂生物活性肽的全合成铺平了道路。