Fmoc-Arg(NO2)-OH

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: Fmoc-Arg(NO2)-OH
• 英文别名: Fmoc-L-Arg^NO2；(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-5-[[(E)-N'-nitrocarbamimidoyl]amino]pentanoic acid
• 化学式: C₂₁H₂₃N₅O₆
• mdl: MFCD00065617
• 分子量: 441.444
• InChiKey: RXMHIKWOZKQXCJ-SFHVURJKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  32
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.285
• 拓扑面积：
  172
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  Fmoc-Arg(NO2)-OH 在 哌啶 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.01h， 生成 L-Arg NO2-L-Dbu-OC(CH3)3
  参考文献：
  名称：

  Synthesis and Evaluation of Peptidomimetics as Selective Inhibitors and Active Site Probes of Nitric Oxide Synthases

  摘要：

  Nitric oxide synthase (NOS) catalyzes the conversion of L-arginine to L-citrilline and nitric oxide (NO). Selective inhibition of the isoforms of NOS could have great therapeutic potential in the treatment of certain disease states arising from pathologically elevated synthesis of NO. Recently, we reported dipeptide amides containing a basic amine side chain as potent and selective inhibitors of neuronal NOS (Huang, H.; Martasek, P.; Roman, L. J.; Masters, B. S. S.; Silverman, R. B. J. Med. Chem. 1999, 42, 3147). The mast potent nNOS inhibitor among these compounds is L-Arg(NO2)-L-Dbu-NH2 (1) (K-i = 130 nM), which also exhibits the highest selectivity over eNOS (>1500-fold) with excellent selectivity over iNOS (190-fold). Here we describe the design and synthesis of a series of peptidomimetic analogues of this dipeptide as potential selective inhibitors of nNOS. The biochemical evaluation of these compounds also revealed the binding requirements of the dipeptide inhibitors with NOS. Incorporation of protecting groups at the N-terminus of the dipeptide amide 1 (compounds 4 and 5) resulted in dramatic decreases in the inhibitory potency of nNOS. Masking the NH group of the peptide bond (peptoids 6-8 and N-methylated compounds 9-11) also gave much poorer nNOS inhibitors than I. Both of the results demonstrate the importance of the cl-amine of the dipeptide and the NH moiety of the peptide bond for binding at the active site. Modifications at the C-terminus of the peptide included converting the amide to the methyl ester (12), tert-butyl ester (13), and carboxylic acid (14) and also descarboxamide analogues (15-17), which revealed less restricted binding requirements for the C-terminus of the dipeptide. Further optimization should be possible when we learn more about the binding requirements at the active sites of NOSs.

  DOI：

  10.1021/jm000127z

文献信息

• Methods for the production of peptide derivatives
  申请人：Tovi Avi

  公开号：US20060276626A1

  公开（公告）日：2006-12-07

  The invention relates to methods for the preparation of peptides which are a C-terminal amide derivatives by a combination of solid-phase synthesis and post assembly solution phase synthesis. The peptides which are a C-terminal amide derivatives are further converted to peptide acetates. The invention also relates to pure peptide acetates and to protected peptide precursors.

  这项发明涉及一种通过固相合成和后组装溶液相合成相结合的方法制备C-末端酰胺衍生物的肽。这些C-末端酰胺衍生物的肽进一步转化为肽醋酸酯。该发明还涉及纯肽醋酸酯和受保护的肽前体。
• Cooperative Stapling of Native Peptides at Lysine and Tyrosine or Arginine with Formaldehyde
  作者：Bo Li、Hong Tang、Aneta Turlik、Zhao Wan、Xiao‐Song Xue、Li Li、Xiaoxiao Yang、Jiuyuan Li、Gang He、Kendall N. Houk、Gong Chen

  DOI：10.1002/anie.202016267

  日期：2021.3.15

  stapling native peptides at lysine residues with formaldehyde by the cooperation of nearby tyrosine or arginine residues. The stapling reactions can proceed with high efficiency and residue selectivity under mild conditions, and generate linchpins with distinct physiochemical properties. The new method for peptide stapling enables unique control of position‐selectivity for substrates bearing multiple

  通过两个相邻氨基酸侧链的分子内交联来对肽进行装订提供了调节肽的结构和性质的重要工具。与人工修饰的肽底物的装订相比，用于装订天然肽的方法更易于获得和遗传可编码。然而，在天然肽的装订中用于选择性控制的现有策略是相对有限的：锚定位点通常由Cys控制，并且缺乏用于在不同位置处的相同类型的残基之间实现位置选择性的手段。我们已经开发了一种简单而有效的策略，可以通过附近的酪氨酸或精氨酸残基的协作，在赖氨酸残基上用甲醛缝合天然肽。装订反应可以在温和的条件下以高效率和残基选择性进行，并生成具有独特理化特性的小片段。肽装订的新方法可以通过易于在肽序列中建立的反应性，对带有多个反应位点的底物进行位置选择性的独特控制。
• Structure-Based Design and Synthesis of <i>N</i>^ω-Nitro-<scp>l</scp>-Arginine-Containing Peptidomimetics as Selective Inhibitors of Neuronal Nitric Oxide Synthase. Displacement of the Heme Structural Water
  作者：Jiwon Seo、Jotato Igarashi、Huiying Li、Pavel Martásek、Linda J. Roman、Thomas L. Poulos、Richard B. Silverman

  DOI：10.1021/jm061305c

  日期：2007.5.1

  The neuronal isoform of nitric oxide synthase (nNOS), the enzyme responsible for the production of nitric oxide in the central nervous system, represents an attractive target for the treatment of various neurodegenerative disorders. X-ray crystal structures of complexes of nNOS with two nNOS-selective inhibitors, (4S)-N-4-amino-5-[(2-aminoethylamino]pentyl}-N'-nitroguanidine (1) and 4-N-(Nomega-n

  一氧化氮合酶（nNOS）的神经元亚型是负责在中枢神经系统中产生一氧化氮的酶，是治疗各种神经退行性疾病的诱人靶标。nNOS与两种nNOS选择性抑制剂（4S）-N- 4-氨基-5-[（2-氨基乙基氨基]戊基} -N'-硝基胍（1）和4-N- （Nomega-硝基-1-精氨酸）-trans-4-氨基-1-脯氨酸酰胺（2）导致了一个保守的结构水分子的发现，该分子被氢键合在两个血红素丙酸酯和抑制剂之间（图2）。根据这一观察，我们假设通过将氢键供体基团连接到酰胺氮2或仲胺氮1上，抑制剂分子可以取代结构水分子并获得与血红素辅因子的直接相互作用。为了检验该假设，设计并合成了具有N-羟基（3和5）或N-氨基（4）供体基团的拟肽类似物3-5。结合了抑制剂3和5的nNOS的X射线晶体结构证实，N-羟基确实取代了结构水分子，并提供了与丙酸血红素部分的直接相互作用（图5和6）。出乎意料的是，体外活性测定结果表明，
• Selection of DNA‐Encoded Dynamic Chemical Libraries for Direct Inhibitor Discovery
  作者：Yuqing Deng、Jianzhao Peng、Feng Xiong、Yinan Song、Yu Zhou、Jianfu Zhang、Fong Sang Lam、Chao Xie、Wenyin Shen、Yiran Huang、Ling Meng、Xiaoyu Li

  DOI：10.1002/anie.202005070

  日期：2020.8.24

  that can identify full ligand structures from large‐scale DEDLs. This method is also able to convert unbiased libraries into focused ones targeting specific protein classes. We demonstrated this method by selecting DEDLs against five proteins, and novel inhibitors were identified for all targets. Notably, several selective BD1/BD2 inhibitors were identified from the selections against bromodomain 4 (BRD4)

  动态组合库（DCL）是生物医学研究中配体发现的强大工具。但是，DCL的低多样性阻碍了它们的应用。最近，DCL中已经采用了DNA编码的概念来创建DNA编码的动态库（DEDL）。但是，当前所有的DEDL都仅限于片段识别，并且在选择后需要一个具有挑战性的片段链接过程。我们报告了一种锚定的DEDL方法，该方法可以从大规模DEDL中识别出完整的配体结构。这种方法还能够将无偏文库转换为针对特定蛋白质类别的集中文库。我们通过选择针对五种蛋白质的DEDLs证明了这种方法，并为所有靶标确定了新型抑制剂。值得注意的是 从针对重要的抗癌药物靶标bromodomain 4（BRD4）的选择中鉴定出了几种选择性的BD1 / BD2抑制剂。这项工作可以为抑制剂发现提供广泛适用的方法。
• A Practical Large-Scale Synthesis of Cyclic RGD Pentapeptides Suitable for Further Functionalization through ‘Click' Chemistry
  作者：Andreas Kirschning、Jiří Paleček、Gerald Dräger

  DOI：10.1055/s-0030-1258396

  日期：2011.2

  A multigram batch of the cyclo[Arg-Gly-Asp-d-Phe-Lys] and its N-ε-azido derivative was accomplished via solution-phase synthesis using an epimerization-free fragment condensation. The C-terminus of d-Phe was protected as its tert-butyl ester. Fmoc (Arg, Gly, Asp, d-Phe) and Boc (Lys) groups were used to protect all N-α-termini. The Ts and NO2 groups, respectively were chosen to protect the guanidine

  阿多克一批的环[精氨酸-甘氨酸- Asp-的d -Phe赖氨酸]及其Ñ -ε叠氮基衍生物，使用无差向异构化，片段缩合经由溶液相合成来完成。d- Phe的C末端被保护为叔丁基酯。Fmoc（Arg，Gly，Asp，d -Phe）和Boc（Lys）基团用于保护所有N -α-末端。分别选择Ts和NO 2基团来保护胍基。大环化步骤（在d -Phe和l之间-Lys）在TBTU / HOBt或DPPA缩合条件下进行。最后，通过重氮转移反应将赖氨酸残基的ε-氨基选择性地转化为叠氮基。 RGD肽-溶液相合成-氨基酸-环化-重氮化合物