Fmoc-Dab-OAll | 688316-86-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: Fmoc-Dab-OAll
• 英文别名: Allyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-aminobutanoate；prop-2-enyl (2S)-4-amino-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoate
• CAS: 688316-86-1
• 化学式: C₂₂H₂₄N₂O₄
• 分子量: 380.444
• InChiKey: ZQEMRNSUMRUNLN-FQEVSTJZSA-N

物化性质

• 沸点：
  587.1±50.0 °C(Predicted)
• 密度：
  1.202±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  28
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  90.6
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  四氢吡咯 、 N-乙基乙二胺 、 聚合甲醛 、 FMOC-L-3,4-二氟苯丙氨酸 、 Fmoc-Dab-OAll 、 生成 4-Amino-2-[(S)-2-{3-[1-(2,6-dichloro-benzyl)-3-pyrrolidin-1-ylmethyl-1H-indol-6-yl]-ureido}-3-(3,4-difluoro-phenyl)-propionylamino]-N-(2-ethylamino-ethyl)-butyramide
  参考文献：
  名称：

  High-affinity thrombin receptor (PAR-1) ligands: a new generation of indole-based peptide mimetic antagonists with a basic amine at the C-terminus

  摘要：

  A new generation of indole-based peptide mimetics, bearing a basic amine at the C-terminus, was developed by the agency of two complementary, multistep, trityl resin-based approaches. Thus, we obtained several high-affinity thrombin receptor (PAR-1) ligands, such as 32 and 34. Compounds 32 and 34 were found to bind to PAR-1 with excellent affinity IC50 = 25 and 35 nM, respectively) and to effectively block platelet aggregation induced by SFLLRN-NH2 (TRAP-6) and alpha-thrombin. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(03)00325-1
• 作为产物：
  描述：

  NAlpha-芴甲氧羰基-Nγ-羰-L-2,4-氨基丁酸 在 甲基三辛基氯化铵 、 碳酸氢钠 、 三氟乙酸 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 2.0h， 生成 Fmoc-Dab-OAll
  参考文献：
  名称：

  总和半合成具有2 Thr或10 Thr修饰的多粘菌素类似物，以破解结构与活性之间的关系并提高抗菌活性

  摘要：

  本文中，我们报道了一系列具有2-Thr和10-Thr修饰的多粘菌素类似物的全部和半合成，以揭示结构-活性关系（SAR），此前尚未充分阐明。我们采用了两种全合成策略，分别促进了2-Thr或10-Thr的多样化替代。此外，使用半合成方法来实现2-Thr的选择性酯化或2-Thr和10-Thr的双重酯化。根据体外抗菌测定的结果，SAR分析表明，用带有疏水性侧链的氨基酸取代2- / 10-Thr可以维持抗铜绿假单胞菌的活性但对其他经过测试的革兰氏阴性细菌有不同的影响。2- / 10-Thr上的氨基乙酰基酯化具有优异的抗菌活性，化合物76对不同菌株的活性高2-8倍，对HK-2细胞系的毒性也较低。这项工作探讨了多粘菌素2- / 10-Thr的SAR，并为开发新型多粘菌素衍生物提供了有希望的策略。

  DOI：

  10.1021/acs.jmedchem.0c02217

文献信息

• A new strategy for total solid-phase synthesis of polymyxins
  作者：Wei-Liang Xu、A-Long Cui、Xin-Xin Hu、Xue-Fu You、Zhuo-Rong Li、Ji-Shen Zheng

  DOI：10.1016/j.tetlet.2015.06.056

  日期：2015.8

  serious Gram-negative bacteria due to their highly efficient antibacterial activity and nephrotoxicity. Many research groups have been performed on designing polymyxin analogues by chemical synthesis in order to decrease the nephrotoxicity and increase the antibacterial activity simultaneously. In this study, we developed a new strategy for total solid phase synthesis of polymyxins and their analogues. This

  多粘菌素B和E由于其高效的抗菌活性和肾毒性，被用作严重革兰氏阴性细菌感染的“最后一道疗法”。为了通过化学合成来设计多粘菌素类似物，以减少肾毒性并同时增加抗菌活性，已经进行了许多研究。在这项研究中，我们为多粘菌素及其类似物的全固相合成开发了一种新策略。该方法是通过首先将Dab9的胺侧链锚固在树脂上，最后在树脂上环化来实现的。与最常用的多粘菌素化学合成方法（涉及固相肽合成然后液相环化）相比，此处报道的方法更加方便，高效。所以，
• Polymyxins with Potent Antibacterial Activity against Colistin-Resistant Pathogens: Fine-Tuning Hydrophobicity with Unnatural Amino Acids
  作者：Johan Storm Jørgensen、Elnaz Harifi Mood、Anne Sofie Holst Knap、Simone Eidnes Nielsen、Peter E. Nielsen、Dorota Żabicka、Carina Matias、Ilona Domraceva、Fredrik Björkling、Henrik Franzyk

  DOI：10.1021/acs.jmedchem.3c01908

  日期：2024.1.25

  discernible correlation with their antimicrobial activity. This trend was particularly pronounced for colistin-resistant pathogens. The most active compounds demonstrated competitive activity against a panel of Gram-negative pathogens, while exhibiting low in vitro cytotoxicity. Importantly, most of these hits also retained (or even had increased) potency against colistin-susceptible strains. These findings

  鉴于人类病原体中抗菌素耐药性的普遍性增加，迫切需要针对多重耐药 （MDR） 细菌的抗生素。特别是，对用于治疗严重革兰阴性 MDR 感染的最后手段抗生素粘菌素迅速出现的耐药性至关重要。在这里，探索了一系列含有非天然氨基酸的多粘菌素，一些类似物对大肠杆菌、肺炎克雷伯菌、鲍曼不动杆菌和铜绿假单胞菌表现出优异的抗菌活性。该系列化合物的疏水性（通过在反相分析 HPLC 中的保留性测量）与其抗菌活性表现出明显的相关性。这种趋势对于粘菌素耐药病原体尤为明显。最活跃的化合物对一组革兰氏阴性病原体表现出竞争活性，同时表现出低体外细胞毒性。重要的是，这些命中中的大多数还保留（甚至增加了）对粘菌素敏感菌株的效力。这些发现推断，微调疏水性可能使设计出具有良好活性特征的多粘菌素类似物。
• Synthesis and Bioactivity Investigation of the Individual Components of Cyclic Lipopeptide Antibiotics
  作者：A-Long Cui、Xin-Xin Hu、Yan Gao、Jie Jin、Hong Yi、Xiu-Kun Wang、Tong-Ying Nie、Yang Chen、Qi-Yang He、Hui-Fang Guo、Jian-Dong Jiang、Xue-Fu You、Zhuo-Rong Li

  DOI：10.1021/acs.jmedchem.7b01367

  日期：2018.3.8

  In this paper, 26 natural polymyxin components and a new derivative S-2 were synthesized, and their differences in efficacy and toxicity have been investigated. Almost all of the synthesized components showed strong activity against both susceptible and resistant strains of E. coli, K. pneumoniae, P. aeruginosa, and A. baumannii. The toxicities were obviously different between the components. Only some of the components were tested for toxicity in vivo. Compounds E-2, E-2-Val, A(2), M-2, D-2, and S-2 showed obviously lower renal cytotoxicity and acute toxicity than polymyxins B and E. The in vivo nephrotoxicity of E-2, M-2, and S-2 was similar to that of polymyxin E. Compound S-2, with four positive charges, was especially interesting as it possessed both increased efficacy and decreased toxicity. The SAR and toxicity studies indicated that further structural modification could concentrate on polymyxin S. The results also indicated that S-2 could be a new drug candidate.
• Total and Semisyntheses of Polymyxin Analogues with 2-Thr or 10-Thr Modifications to Decipher the Structure–Activity Relationship and Improve the Antibacterial Activity
  作者：Jian Li、Dongliang Guan、Feifei Chen、Weiwei Shi、Lefu Lan、Wei Huang

  DOI：10.1021/acs.jmedchem.0c02217

  日期：2021.5.13

  total and semisyntheses of a series of polymyxin analogues with 2-Thr and 10-Thr modifications to reveal the structure–activity relationship (SAR), which has not been fully elucidated previously. We employed two total-synthetic strategies to facilitate the diversified replacements on 2-Thr or 10-Thr, respectively. Moreover, semisynthetic approaches were utilized to achieve selective esterification

  本文中，我们报道了一系列具有2-Thr和10-Thr修饰的多粘菌素类似物的全部和半合成，以揭示结构-活性关系（SAR），此前尚未充分阐明。我们采用了两种全合成策略，分别促进了2-Thr或10-Thr的多样化替代。此外，使用半合成方法来实现2-Thr的选择性酯化或2-Thr和10-Thr的双重酯化。根据体外抗菌测定的结果，SAR分析表明，用带有疏水性侧链的氨基酸取代2- / 10-Thr可以维持抗铜绿假单胞菌的活性但对其他经过测试的革兰氏阴性细菌有不同的影响。2- / 10-Thr上的氨基乙酰基酯化具有优异的抗菌活性，化合物76对不同菌株的活性高2-8倍，对HK-2细胞系的毒性也较低。这项工作探讨了多粘菌素2- / 10-Thr的SAR，并为开发新型多粘菌素衍生物提供了有希望的策略。
• High-affinity thrombin receptor (PAR-1) ligands: a new generation of indole-based peptide mimetic antagonists with a basic amine at the C-terminus
  作者：Han-Cheng Zhang、Kimberly B. White、David F. McComsey、Michael F. Addo、Patricia Andrade-Gordon、Claudia K. Derian、Donna Oksenberg、Bruce E. Maryanoff

  DOI：10.1016/s0960-894x(03)00325-1

  日期：2003.7

  A new generation of indole-based peptide mimetics, bearing a basic amine at the C-terminus, was developed by the agency of two complementary, multistep, trityl resin-based approaches. Thus, we obtained several high-affinity thrombin receptor (PAR-1) ligands, such as 32 and 34. Compounds 32 and 34 were found to bind to PAR-1 with excellent affinity IC50 = 25 and 35 nM, respectively) and to effectively block platelet aggregation induced by SFLLRN-NH2 (TRAP-6) and alpha-thrombin. (C) 2003 Elsevier Science Ltd. All rights reserved.