(2S,3R)-3-phenyl-pyrrolidine-1,2-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester | 281655-32-1

• 物质功能分类: 生物化工 - 生化试剂 - 氨基酸
• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: (2S,3R)-3-phenyl-pyrrolidine-1,2-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester
• 英文别名: Fmoc-(2S,3R)-3-phenylpyrrolidine-2-carboxylic acid；(2S,3R)-1-(9H-fluoren-9-ylmethoxycarbonyl)-3-phenylpyrrolidine-2-carboxylic acid
• CAS: 281655-32-1
• 化学式: C₂₆H₂₃NO₄
• 分子量: 413.473
• InChiKey: XZINBBVSLWSWBO-KOSHJBKYSA-N

物化性质

• 沸点：
  626.3±55.0 °C(Predicted)
• 密度：
  1.299±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  66.8
• 氢给体数：
  1
• 氢受体数：
  4

安全信息

• 危险等级：
  IRRITANT

反应信息

• 作为反应物：
  描述：

  5-甲基异恶唑-3-甲酸 、 (2S,3R)-3-phenyl-pyrrolidine-1,2-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester 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 、 N,N-二甲基甲酰胺 为溶剂， 反应 17.0h， 生成 ethyl (E,4S)-4-[[(2S,3R)-1-[(2S)-3-methyl-2-[(5-methyl-1,2-oxazole-3-carbonyl)amino]butanoyl]-3-phenylpyrrolidine-2-carbonyl]amino]-5-[(3S)-2-oxopyrrolidin-3-yl]pent-2-enoate
  参考文献：
  名称：

  Peptidomimetic ethyl propenoate covalent inhibitors of the enterovirus 71 3C protease: a P2–P4 study

  摘要：

  Enterovirus 71 (EV71) is a highly infectious pathogen primarily responsible for Hand, Foot, and Mouth Disease, particularly among children. Currently, no approved antiviral drug has been developed against this disease. The EV71 3C protease is deemed an attractive drug target due to its crucial role in viral polyprotein processing. Rupintrivir, a peptide-based inhibitor originally developed to target the human rhinovirus 3C protease, was found to inhibit the EV71 3C protease. In this communication, we report the inhibitory activities of 30 Rupintrivir analogs against the EV71 3C protease. The most potent inhibitor, containing a P2 ring-constrained phenylalanine analog (compound 9), was found to be two-fold more potent than Rupintrivir (IC50 value 3.4 +/- 0.4 versus 7.3 +/- 0.8 mu M). Our findings suggest that employing geometrically constrained residues in peptide-based protease inhibitors can potentially enhance their inhibitory activities.

  DOI：

  10.3109/14756366.2015.1018245
• 作为产物：
  描述：

  氯甲酸-9-芴基甲酯 、 3-苯基-L-脯氨酸 在 碳酸氢钠 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 18.08h， 以78%的产率得到(2S,3R)-3-phenyl-pyrrolidine-1,2-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester
  参考文献：
  名称：

  Exploiting differences in caspase-2 and -3 S2 subsites for selectivity: Structure-based design, solid-phase synthesis and in vitro activity of novel substrate-based caspase-2 inhibitors

  摘要：

  Several caspases have been implicated in the pathogenesis of Huntington's disease (HD); however, existing caspase inhibitors lack the selectivity required to investigate the specific involvement of individual caspases in the neuronal cell death associated with HD. In order to explore the potential role played by caspase-2, the potent but non-selective canonical Ac-VDVAD-CHO caspase-2 inhibitor 1 was rationally modified at the P-2 residue in an attempt to decrease its activity against caspase-3. With the aid of structural information on the caspase-2, and -3 active sites and molecular modeling, a 3-(S)-substituted-L-proline along with four additional scaffold variants were selected as P-2 elements for their predicted ability to clash sterically with a residue of the caspase-3 S-2 pocket. These elements were then incorporated by solid-phase synthesis into pentapeptide aldehydes 33a-v. Proline-based compound 33h bearing a bulky 3-(S)-substituent displayed advantageous characteristics in biochemical and cellular assays with 20- to 60-fold increased selectivity for caspase-2 and similar to 200-fold decreased caspase-3 potency compared to the reference inhibitor 1. Further optimization of this prototype compound may lead to the discovery of valuable pharmacological tools for the study of caspase-2 mediated cell death, particularly as it relates to HD. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.08.020

文献信息

• Optimization of linear and cyclic peptide inhibitors of KEAP1-NRF2 protein-protein interaction
  作者：Stefania Colarusso、Daniele De Simone、Tommaso Frattarelli、Matteo Andreini、Mauro Cerretani、Antonino Missineo、Daniele Moretti、Sara Tambone、Georg Kempf、Martin Augustin、Stefan Steinbacher、Ignacio Munoz-Sanjuan、Larry Park、Vincenzo Summa、Licia Tomei、Alberto Bresciani、Celia Dominguez、Leticia Toledo-Sherman、Elisabetta Bianchi

  DOI：10.1016/j.bmc.2020.115738

  日期：2020.11

  Inhibition of KEAP1-NRF2 protein-protein interaction is considered a promising strategy to selectively and effectively activate NRF2, a transcription factor which is involved in several pathologies such as Huntington’s disease (HD). A library of linear peptides based on the NRF2-binding motifs was generated on the nonapeptide lead Ac-LDEETGEFL-NH2 spanning residues 76–84 of the Neh2 domain of NRF2

  抑制KEAP1-NRF2蛋白质-蛋白质相互作用被认为是有选择地和有效地激活NRF2的一种有前途的策略，NRF2是一种转录因子，涉及多种病理学，例如亨廷顿舞蹈病（HD）。在非肽铅Ac-LDEETGEFL-NH 2上生成了基于NRF2结合基序的线性肽库跨越NRF2 Neh2域的76-84位残基，目的是用非酸性氨基酸取代E78，E79和E82。基于结构的设计还旨在更深入地了解T80副口袋的功能和可及性。研究了使用不同种类的环肽以及与细胞穿透肽结合的提高细胞通透性的方法。这一见识将指导大环化合物，肽模拟物以及最重要的是中性小脑穿透分子的未来设计，以评估NRF2激活剂是否可用于HD。
• Accelerated Identification of Cell Active KRAS Inhibitory Macrocyclic Peptides using Mixture Libraries and Automated Ligand Identification System (ALIS) Technology
  作者：Michael Garrigou、Bérengère Sauvagnat、Ruchia Duggal、Nicole Boo、Pooja Gopal、Jennifer M. Johnston、Anthony Partridge、Tomi Sawyer、Kaustav Biswas、Nicolas Boyer

  DOI：10.1021/acs.jmedchem.2c00154

  日期：2022.7.14
• Exploiting differences in caspase-2 and -3 S2 subsites for selectivity: Structure-based design, solid-phase synthesis and in vitro activity of novel substrate-based caspase-2 inhibitors
  作者：Michel C. Maillard、Frederick A. Brookfield、Stephen M. Courtney、Florence M. Eustache、Mark J. Gemkow、Rebecca K. Handel、Laura C. Johnson、Peter D. Johnson、Mark A. Kerry、Florian Krieger、Mirco Meniconi、Ignacio Muñoz-Sanjuán、Jordan J. Palfrey、Hyunsun Park、Sabine Schaertl、Malcolm G. Taylor、Derek Weddell、Celia Dominguez

  DOI：10.1016/j.bmc.2011.08.020

  日期：2011.10

  Several caspases have been implicated in the pathogenesis of Huntington's disease (HD); however, existing caspase inhibitors lack the selectivity required to investigate the specific involvement of individual caspases in the neuronal cell death associated with HD. In order to explore the potential role played by caspase-2, the potent but non-selective canonical Ac-VDVAD-CHO caspase-2 inhibitor 1 was rationally modified at the P-2 residue in an attempt to decrease its activity against caspase-3. With the aid of structural information on the caspase-2, and -3 active sites and molecular modeling, a 3-(S)-substituted-L-proline along with four additional scaffold variants were selected as P-2 elements for their predicted ability to clash sterically with a residue of the caspase-3 S-2 pocket. These elements were then incorporated by solid-phase synthesis into pentapeptide aldehydes 33a-v. Proline-based compound 33h bearing a bulky 3-(S)-substituent displayed advantageous characteristics in biochemical and cellular assays with 20- to 60-fold increased selectivity for caspase-2 and similar to 200-fold decreased caspase-3 potency compared to the reference inhibitor 1. Further optimization of this prototype compound may lead to the discovery of valuable pharmacological tools for the study of caspase-2 mediated cell death, particularly as it relates to HD. (C) 2011 Elsevier Ltd. All rights reserved.
• Peptidomimetic ethyl propenoate covalent inhibitors of the enterovirus 71 3C protease: a P2–P4 study
  作者：Melgious J. Y. Ang、Qiu Ying Lau、Fui Mee Ng、Siew Wen Then、Anders Poulsen、Yuen Kuen Cheong、Zi Xian Ngoh、Yong Wah Tan、Jianhe Peng、Thomas H. Keller、Jeffrey Hill、Justin J. H. Chu、C. S. Brian Chia

  DOI：10.3109/14756366.2015.1018245

  日期：2016.3.3

  Enterovirus 71 (EV71) is a highly infectious pathogen primarily responsible for Hand, Foot, and Mouth Disease, particularly among children. Currently, no approved antiviral drug has been developed against this disease. The EV71 3C protease is deemed an attractive drug target due to its crucial role in viral polyprotein processing. Rupintrivir, a peptide-based inhibitor originally developed to target the human rhinovirus 3C protease, was found to inhibit the EV71 3C protease. In this communication, we report the inhibitory activities of 30 Rupintrivir analogs against the EV71 3C protease. The most potent inhibitor, containing a P2 ring-constrained phenylalanine analog (compound 9), was found to be two-fold more potent than Rupintrivir (IC50 value 3.4 +/- 0.4 versus 7.3 +/- 0.8 mu M). Our findings suggest that employing geometrically constrained residues in peptide-based protease inhibitors can potentially enhance their inhibitory activities.