Fmoc-L-octahydroindole-2-carboxylic acid

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: Fmoc-L-octahydroindole-2-carboxylic acid
• 英文别名: (2S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-2,3,3a,4,5,6,7,7a-octahydroindole-2-carboxylic acid
• 化学式: C₂₄H₂₅NO₄
• 分子量: 391.467
• InChiKey: JBZXLQHJZHITMW-KGSCVUAUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  66.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  Fmoc-L-octahydroindole-2-carboxylic acid 在 1-羟基苯并三唑 、 N,N-二异丙基乙胺 、 N,N'-二异丙基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 生成
  参考文献：
  名称：

  Detection of Active Granzyme A in NK92 Cells with Fluorescent Activity-Based Probe

  摘要：

  Cytotoxic T-lymphocytes (CTLs) and natural killer cells (NKs) kill compromised cells to defend against tumor and viral infections. Both effector cell types use multiple strategies to induce target cell death including Fas/CD95 activation and the release of perforin and a group of lymphocyte granule serine proteases called granzymes. Granzymes have relatively broad and overlapping substrate specificities and may hydrolyze a wide range of peptidic epitopes; it is therefore challenging to identify their natural and synthetic substrates and to distinguish their localization and functions. Here, we present a specific and potent substrate, an inhibitor, and an activity-based probe of Granzyme A (GrA) that can be used to follow functional GrA in cells.

  DOI：

  10.1021/acs.jmedchem.9b02042

文献信息

• Unnatural amino acids increase sensitivity and provide for the design of highly selective caspase substrates
  作者：M Poreba、P Kasperkiewicz、S J Snipas、D Fasci、G S Salvesen、M Drag

  DOI：10.1038/cdd.2014.64

  日期：2014.9

  proteases - the human caspases. The power of this library for caspase discrimination extends far beyond traditional PS-SCL approach, as in addition to 19 natural amino acids we also used 110 diverse unnatural amino acids that can more extensively explore the chemical space represented by caspase-active sites. Using this approach we identified and employed peptide-based substrates that provided excellent

  传统的组合肽基底物库方法通常利用天然氨基酸，限制了该工具在为具有相似底物特异性特征的蛋白酶生成选择性底物方面的用途。为了解决这个限制，我们合成了一个具有 Ac-P4-P3-P2-Asp-ACC 通式的混合组合底物库 (HyCoSuL)，在一个密切相关的蛋白酶家族 - 人类半胱天冬酶上测试了该方法。这个库用于 caspase 区分的能力远远超出了传统的 PS-SCL 方法，因为除了 19 种天然氨基酸之外，我们还使用了 110 种不同的非天然氨基酸，可以更广泛地探索由 caspase 活性位点表示的化学空间。
• Structural and mechanistic insights into the inhibition of amyloid-β aggregation by Aβ39-42 fragment derived synthetic peptides
  作者：Akshay Kapadia、Krishna K. Sharma、Indresh Kumar Maurya、Varinder Singh、Madhu Khullar、Rahul Jain

  DOI：10.1016/j.ejmech.2020.113126

  日期：2021.2

  permeability and offered proteolytic stability to the synthetic peptides. Several peptides exhibited promising protection against Aβ aggregation-mediated-neurotoxicity in PC-12 cells at doses ranged between 10 μM and 0.1 μM, further confirmed by the thioflavin-T fluorescence assay. CD study illustrate that these peptides restrict the β-sheet formation, and the non-appearance of Aβ42 fibrillar structures in

  淀粉样-β（Aβ）聚集的抑制是治疗阿尔茨海默氏病（AD）的有前途的方法。合成了基于亲本Aβ肽的Aβ39-42 C末端片段的38个四肽。使用非天然氨基酸的顺序替换/修饰赋予了支架多样性，增强的活性，增强的血脑屏障通透性并为合成肽提供了蛋白水解稳定性。硫黄素-T荧光测定进一步证实了几种肽在PC-12细胞中对Aβ聚集介导的神经毒性具有有希望的保护作用，剂量范围为10μM至0.1μM。CD研究表明，这些肽限制了β-折叠的形成以及Aβ42的不出现电镜中的原纤维结构证实了对Aβ42聚集的抑制。HRMS和ANS荧光光谱分析提供了更多的机理见解。两种选择的前导肽5和16表现出增强的血脑渗透性以及对血清和蛋白水解酶的稳定性。通过计算研究了在Aβ的单体和原纤维单元上的配体-Aβ相互作用的结构见解。前导肽的潜在抑制潜力和短序列为AD的肽衍生疗法的发展提供了新途径。
• Potent α4β1 Peptide Antagonists as Potential Anti-Inflammatory Agents
  作者：David Y. Jackson、Clifford Quan、Dean R. Artis、Thomas Rawson、Brent Blackburn、Martin Struble、Geraldine Fitzgerald、Kathryn Chan、Sheldon Mullins、J. P. Burnier、Wayne J. Fairbrother、Kevin Clark、Maureen Berisini、Henry Chui、Mark Renz、Susan Jones、Sherman Fong

  DOI：10.1021/jm970175s

  日期：1997.10.1

  migration, adhesion, and subsequent extravasation of leukocytes into inflamed tissues contribute to the pathogenesis of a variety of inflammatory diseases including asthma, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. The integrin adhesion receptor alpha 4 beta 1 expressed on leukocytes binds to the extracellular matrix protein fibronectin and to the cytokine inducible vascular

  白细胞向发炎组织的迁移，粘附和随后的外渗促成多种炎性疾病的发病机理，包括哮喘，类风湿性关节炎，炎性肠病和多发性硬化症。在白细胞上表达的整联蛋白粘附受体α4 beta 1在发炎部位与细胞外基质蛋白纤连蛋白和细胞因子诱导的血管细胞粘附分子-1（VCAM-1）结合。α4 beta 1与VCAM-1的结合可引发白细胞与血管内皮的牢固粘附，然后渗入组织。针对alpha 4 beta 1或VCAM-1产生的单克隆抗体可以在多种动物模型中缓解这种炎症反应。最近，含有基于纤连蛋白连接节段1（CS-1）的共有LDV序列的肽和含有RCD基序的环状肽已显示出有望通过阻断α4 beta 1与VCAM-的相互作用来调节白细胞迁移和炎症。 1。在这里，我们描述了新颖，高效的环状肽，它们在亚纳摩尔浓度下竞争性抑制α4β1与VCAM-1和纤连蛋白的结合。代表性类似物的结构通过NMR光谱法确定，并用于促进肽前导的优化。本文
• Introduction of Pro and Its Analogues in the Conserved P1 Position of Trypsin Inhibitor SFTI-1 Retains Its Inhibitory Activity
  作者：Anna Legowska、Dawid Debowski、Rafal Lukajtis、Emilia Sztabkowska、Aneta Mizeria、Krzysztof Brzozowski、Magdalena Wysocka、Adam Lesner、Krzysztof Rolka

  DOI：10.2174/092986611797201002

  日期：2011.11.1

  A number of monocyclic SFTI-1 analogues modified in the conserved inhibitor P1 position by Pro, its L-hydroxyproline (Hyp) derivative as well as mimetics with different ring size were synthesized by the solid-phase method. Replacement of Ser6 by Pro, Hyp, and a four-member ring, L-azetidine-2-carboxylic acid (Aze), retained trypsin or chymotrypsin inhibitory activity. The determined association equilibrium constants of these analogues with a cognate enzyme were about two orders of magnitude lower than those obtained for ones with conserved Ser6. In all analogues, with the exception of one, [Phe5,Aze6]SFTI-1, the P1-P1 reactive site remained intact. The results provide first evidence that the conserved Ser in the P1 position of Bowman-Birk inhibitors can be successfully replaced by an amino acid with a secondary amine group.

  通过固相法合成了许多单环SFTI-1类似物，在保守的抑制剂P1位上分别用脯氨酸、其L-羟脯氨酸（Hyp）衍生物以及具有不同环大小的模拟物进行了修饰。用脯氨酸、Hyp和四元环L-氮杂环丁烷-2-羧酸（Aze）取代Ser6保留了胰蛋白酶或糜蛋白酶的抑制活性。这些类似物与同源酶的确定的结合平衡常数比保守的Ser6的常数低两个数量级。在所有类似物中，除了一种[Phe5,Aze6]SFTI-1外，P1-P1反应位点保持不变。这些结果首次证明，鲍曼-比尔克抑制剂P1位上保守的Ser可以成功地被具有仲胺基团的氨基酸取代。
• Urea moiety as amide bond mimetic in peptide-like inhibitors of VEGF-A165/NRP-1 complex
  作者：Anna K. Puszko、Piotr Sosnowski、Karolina Pułka-Ziach、Olivier Hermine、Gérard Hopfgartner、Yves Lepelletier、Aleksandra Misicka

  DOI：10.1016/j.bmcl.2019.07.016

  日期：2019.9

  NRP-1 is an important co-receptor of vascular endothelial growth factor receptor-2 (VEGFR-2). Many reports suggested that NRP-1 might also serve as a separate receptor for VEGF-A(165) causing stimulation of tumour growth and metastasis. Therefore, compounds interfering with VEGF-A(165)/NRP-1 complex triggered interest in the design of new molecules, including peptides, as anti-angiogenic and anti-tumour drugs. Here, we report the synthesis, affinity and stability evaluation of the urea-peptide hybrids, based on general Lys(hArg)-AA(2)-AA(3)-Arg sequence, where hArg residue was substituted by Arg urea unit. Such substitution does not substantially affected affinity of compounds for NRP-1 but significantly increased their proteolytic stability in plasma.