(E)-N-((S)-3-(3,5-difluorophenyl)-1-(((6S,8aS,14aS,20S,21S,23aS)-6,21-dimethyl-5,8,14,19,23-pentaoxooctadecahydro-1H,5H,14H,19H-pyrido[2,1-i]dipyrrolo[2,1-c:2',1'-l][1]oxa[4,7,10,13]tetraazacyclohexadecin-20-yl)amino)-1-oxopropan-2-yl)hept-2-enamide | 1542206-57-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: (E)-N-((S)-3-(3,5-difluorophenyl)-1-(((6S,8aS,14aS,20S,21S,23aS)-6,21-dimethyl-5,8,14,19,23-pentaoxooctadecahydro-1H,5H,14H,19H-pyrido[2,1-i]dipyrrolo[2,1-c:2',1'-l][1]oxa[4,7,10,13]tetraazacyclohexadecin-20-yl)amino)-1-oxopropan-2-yl)hept-2-enamide
• 英文别名: (E)-N-[(2S)-3-(3,5-difluorophenyl)-1-[[(3S,9S,10S,13S,19S,22S)-10,19-dimethyl-2,8,12,18,21-pentaoxo-11-oxa-1,7,17,20-tetrazatetracyclo[20.4.0.03,7.013,17]hexacosan-9-yl]amino]-1-oxopropan-2-yl]hept-2-enamide
• CAS: 1542206-57-4
• 化学式: C₃₉H₅₂F₂N₆O₈
• 分子量: 770.874
• InChiKey: ONWAIXMTMWCLOZ-ZHZUKTBISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  55
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  175
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  (S)-2-{1-[(S)-2-((S)-1-Carboxy-ethylcarbamoyl)-piperidin-1-yl]-methanoyl}-pyrrolidin-1-carboxylic acid tert-butylester 在 盐酸 、 palladium 10% on activated carbon 、 氢气 、 碳酸氢钠 、 溶剂黄146 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 三氟乙酸 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 锌 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 22.0h， 生成 (E)-N-((S)-3-(3,5-difluorophenyl)-1-(((6S,8aS,14aS,20S,21S,23aS)-6,21-dimethyl-5,8,14,19,23-pentaoxooctadecahydro-1H,5H,14H,19H-pyrido[2,1-i]dipyrrolo[2,1-c:2',1'-l][1]oxa[4,7,10,13]tetraazacyclohexadecin-20-yl)amino)-1-oxopropan-2-yl)hept-2-enamide
  参考文献：
  名称：

  Restriction of the Conformational Dynamics of the Cyclic Acyldepsipeptide Antibiotics Improves Their Antibacterial Activity

  摘要：

  The cyclic acyldepsipeptide (ADEP) antibiotics are a new class of antibacterial agents that kill bacteria via a mechanism that is distinct from all clinically used drugs. These molecules bind and dysregulate the activity of the ClpP peptidase. The potential of these antibiotics as antibacterial drugs has been enhanced by the elimination of pharmacological liabilities through medicinal chemistry efforts. Here, we demonstrate that the ADEP conformation observed in the ADEP-ClpP crystal structure is fortified by transannular hydrogen bonding and can be further stabilized by judicious replacement of constituent amino acids within the peptidolactone core structure with more conformationally constrained counterparts. Evidence supporting constraint of the molecule into the bioactive conformer was obtained by measurements of deuterium-exchange kinetics of hydrogens that were proposed to be engaged in transannular hydrogen bonds. We show that the rigidified ADEP analogs bind and activate ClpP at lower concentrations in vitro. Remarkably, these compounds have up to 1200-fold enhanced antibacterial activity when compared to those with the peptidolactone core structure common to two ADEP natural products. This study compellingly demonstrates how rational modulation of conformational dynamics may be used to improve the bioactivities of natural products.

  DOI：

  10.1021/ja410385c

文献信息

• Substituted urea depsipeptide analogs as activators of the CLPP endopeptidase
  申请人：St. Jude Children's Research Hospital

  公开号：US10457707B2

  公开（公告）日：2019-10-29

  In one aspect, the invention relates to substituted urea depsipeptide analogs, derivatives thereof, and related compounds, which are useful as activators the ClpP endopeptidease; synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating infectious disease using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  在一个方面，本发明涉及取代的脲去肽类似物、其衍生物和相关化合物，它们可用作 ClpP 内肽酶的激活剂；制造这些化合物的合成方法；包含这些化合物的药物组合物；以及使用这些化合物和组合物治疗传染性疾病的方法。本摘要旨在作为在特定技术领域进行检索的扫描工具，并非对本发明的限制。
• Substituted urea depsipeptide analogs as activators of the ClpP endopeptidase
  申请人：ST. JUDE CHILDREN'S RESEARCH HOSPITAL

  公开号：US10676510B2

  公开（公告）日：2020-06-09

  In one aspect, the invention relates to substituted urea depsipeptide analogs, derivatives thereof, and related compounds, which are useful as activators the C1pP endopeptidease; synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating infectious disease using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  在一个方面，本发明涉及取代的脲去肽类似物、其衍生物和相关化合物，它们可用作 C1pP 内肽酶的激活剂；制造这些化合物的合成方法；包含这些化合物的药物组合物；以及使用这些化合物和组合物治疗传染病的方法。本摘要旨在作为在特定技术领域进行检索的扫描工具，并非对本发明的限制。
• US9879050B2
  申请人：——

  公开号：US9879050B2

  公开（公告）日：2018-01-30