(S)-1-[(R)-2-((8S,11S)-8-Carbamoylmethyl-6,9-dioxo-2-oxa-7,10-diaza-bicyclo[11.2.2]heptadeca-1(16),13(17),14-trien-11-yl)-2-hydroxy-ethyl]-piperidine-2-carboxylic acid tert-butylamide

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 英文名称: (S)-1-[(R)-2-((8S,11S)-8-Carbamoylmethyl-6,9-dioxo-2-oxa-7,10-diaza-bicyclo[11.2.2]heptadeca-1(16),13(17),14-trien-11-yl)-2-hydroxy-ethyl]-piperidine-2-carboxylic acid tert-butylamide
• 英文别名: 1-[2-(8-Carbamoylmethyl-6,9-dioxo-2-oxa-7,10-diaza-bicyclo[11.2.2]heptadeca-1(16),13(17),14-trien-11-YL)-2-hydroxy-ethyl]-piperidine-2-carboxylic acid tert-butylamide；(2S)-1-[(2R)-2-[(8S,11S)-8-(2-amino-2-oxoethyl)-6,9-dioxo-2-oxa-7,10-diazabicyclo[11.2.2]heptadeca-1(15),13,16-trien-11-yl]-2-hydroxyethyl]-N-tert-butylpiperidine-2-carboxamide
• 化学式: C₂₈H₄₃N₅O₆
• 分子量: 545.679
• InChiKey: GHEDXAXQQMZPLE-CWBXHPNXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  39
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  163
• 氢给体数：
  5
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  ethyl 4-<4'-<<2-<(tert-butoxycarbonyl)amino>-2-carboxy>ethyl>phenoxy>butanoate 在 N-甲基吡咯烷酮 、 盐酸 、 sodium hydroxide 、 sodium tetrahydroborate 、 氢溴酸 、 氯甲酸乙酯 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 生成 (S)-1-[(R)-2-((8S,11S)-8-Carbamoylmethyl-6,9-dioxo-2-oxa-7,10-diaza-bicyclo[11.2.2]heptadeca-1(16),13(17),14-trien-11-yl)-2-hydroxy-ethyl]-piperidine-2-carboxylic acid tert-butylamide
  参考文献：
  名称：

  Structure-activity relationships for macrocyclic peptidomimetic inhibitors of HIV-1 protease

  摘要：

  A rational approach to developing inhibitors of proteolytic enzymes is the systematic modification of their peptide substrates to proteolytically stable, low molecular weight, nonpeptidic inhibitors. Replacing the scissile amide bond with a noncleavable transition state isostere usually gives potent protease inhibitors, but the remaining hydrolysable amide bonds render the inhibitors unstable to peptidases generally. Attempts to replace them with retention of inhibitor potency has proved difficult(1,2) due to the unpredictable cooperative influences of such variations on the conformations of both neighbouring inhibitor groups and enzyme residues. We recently described a method(3) for regioselectively fixing the conformation of inhibitor components and now show effects on activity of varying both the 'free' and 'fixed' components.

  DOI：

  10.1016/0960-894x(96)00468-4

文献信息

• Regioselective structural and functional mimicry of peptides. Design of hydrolytically-stable cyclic peptidomimetic inhibitors of HIV-1 protease.
  作者：G. Abbenante、D. R. March、D. A. Bergman、P. A. Hunt、B. Garnham、R. J. Dancer、J. L. Martin、D. P. Fairlie

  DOI：10.1021/ja00146a007

  日期：1995.10

  Hydrolytically-stable cyclic mimetics of the tripeptides Leu-Asn-Phe and Phe-Ile-Val were designed and incorporated into peptidic inhibitors, Ac-Leu-Asn-Phe}-CHOHCH2-Pro-Ile-Val-NH2 and Ac-Leu-Val-Phe-CHOHCH2-Phe-Ile-Val}-NH2, of HIV-1 protease. Structural mimicry has been established through molecular modeling and X-ray crystallographic studies of inhibitors bound to HIV-1 protease. Cyclic and acyclic inhibitors had similar conformations that were superimposable and formed similar interactions with the enzyme. Functional mimicry was demonstrated by comparable inhibition of the protease by acyclic and cyclic molecules. Further substitution of the residual acyclic Pro-Ile-Val or Leu-Val-Phe inhibitor components, with Pip-NHtBu or Boc-Phe, respectively, gave hydrolytically stable, water-soluble, lipophilic inhibitors of similar potency. The use of cycles to fix the conformations of amino acid sequences in peptides allows regioselective structural mimicry leading to functional mimicry and also permits localized structure-activity optimization in inhibitors of HIV-1 protease. This approach might be usefully applied to inhibitors of other proteins.