(S)-3-((S)-asparaginylamino)-4-<4'-<(3'-carbethoxypropyl)oxy>phenyl>-1-((S)-N-prolyl-(S)-isoleucyl-(S)-valine amide)-butan-2-ol | 185303-93-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (S)-3-((S)-asparaginylamino)-4-<4'-<(3'-carbethoxypropyl)oxy>phenyl>-1-((S)-N-prolyl-(S)-isoleucyl-(S)-valine amide)-butan-2-ol
• 英文别名: 4-[4-[(2S)-4-[(2S)-2-[[(2S,3S)-1-[[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-2-[[(2S)-2,4-diamino-4-oxobutanoyl]amino]-3-hydroxybutyl]phenoxy]butanoic acid
• CAS: 185303-93-9
• 化学式: C₃₄H₅₅N₇O₉
• 分子量: 705.852
• InChiKey: UIYWPMLZNAHJSC-UCKQGWMTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.86
• 重原子数：
  50.0
• 可旋转键数：
  22.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  269.5
• 氢给体数：
  8.0
• 氢受体数：
  10.0

反应信息

• 作为反应物：
  描述：

  (S)-3-((S)-asparaginylamino)-4-<4'-<(3'-carbethoxypropyl)oxy>phenyl>-1-((S)-N-prolyl-(S)-isoleucyl-(S)-valine amide)-butan-2-ol 在 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 以28%的产率得到<2(R),11'(S),8'(S)>-2-<6',9'-dioxo-8'-ethanamido-2'-oxa-7',10'-diazabicyclo<11.2.2>heptadeca-13',15',16'-trien-11-yl>-1-(N-(S)-prolyl-(S)-isoleucyl-(S)-valine amide)ethan-2-ol
  参考文献：
  名称：

  Regioselective structural and functional mimicry of peptides. Design of hydrolytically-stable cyclic peptidomimetic inhibitors of HIV-1 protease.

  摘要：

  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.

  DOI：

  10.1021/ja00146a007
• 作为产物：
  描述：

  4-[4-((S)-2-((S)-2-Amino-3-carbamoyl-propionylamino)-4-{(S)-2-[(1S,2S)-1-((S)-1-carbamoyl-2-methyl-propylcarbamoyl)-2-methyl-butylcarbamoyl]-pyrrolidin-1-yl}-3-hydroxy-butyl)-phenoxy]-butyric acid ethyl ester 在 sodium hydroxide 作用下， 以 四氢呋喃 为溶剂， 反应 0.5h， 生成 (S)-3-((S)-asparaginylamino)-4-<4'-<(3'-carbethoxypropyl)oxy>phenyl>-1-((S)-N-prolyl-(S)-isoleucyl-(S)-valine amide)-butan-2-ol
  参考文献：
  名称：

  Regioselective structural and functional mimicry of peptides. Design of hydrolytically-stable cyclic peptidomimetic inhibitors of HIV-1 protease.

  摘要：

  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.

  DOI：

  10.1021/ja00146a007

文献信息

• Structure-activity relationships for macrocyclic peptidomimetic inhibitors of HIV-1 protease
  作者：G. Abbenante、D.A. Bergman、R.I. Brinkworth、D.R. March、R.C. Reid、P.A. Hunt、I.W. James、R.J. Dancer、B. Garnham、M.L. Stoermer、D.P. Fairlie

  DOI：10.1016/0960-894x(96)00468-4

  日期：1996.11

  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.