2S-(12-{2-[benzenesulfonyl-(3-methylbutyl)amino]-1S-hydroxyethyl}-6,10-dioxo-2-oxa-7,11-diazabicyclo[12.2.2]octadeca-1(17),14(18),15-trien-8S-yl)acetamide

• 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: 2S-(12-{2-[benzenesulfonyl-(3-methylbutyl)amino]-1S-hydroxyethyl}-6,10-dioxo-2-oxa-7,11-diazabicyclo[12.2.2]octadeca-1(17),14(18),15-trien-8S-yl)acetamide
• 英文别名: 2-[(8S,11S)-11-{(1R)-1-Hydroxy-2-[isopentyl(phenylsulfonyl)amino]ethyl}-6,9-dioxo-2-oxa-7,10-diazabicyclo[11.2.2]heptadeca-1(15),13,16-trien-8-YL]acetamide；2-[(8S,11S)-11-[(1R)-2-[benzenesulfonyl(3-methylbutyl)amino]-1-hydroxyethyl]-6,9-dioxo-2-oxa-7,10-diazabicyclo[11.2.2]heptadeca-1(15),13,16-trien-8-yl]acetamide
• 化学式: C₂₉H₄₀N₄O₇S
• 分子量: 588.725
• InChiKey: HOUHLOFMBSYNBO-KKUQBAQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  41
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  177
• 氢给体数：
  4
• 氢受体数：
  8

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 2S-(12-{2-[benzenesulfonyl-(3-methylbutyl)amino]-1S-hydroxyethyl}-6,10-dioxo-2-oxa-7,11-diazabicyclo[12.2.2]octadeca-1(17),14(18),15-trien-8S-yl)acetamide
  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

• Countering Cooperative Effects in Protease Inhibitors Using Constrained β-Strand-Mimicking Templates in Focused Combinatorial Libraries
  作者：Robert C. Reid、Leonard K. Pattenden、Joel D. A. Tyndall、Jennifer L. Martin、Terry Walsh、David P. Fairlie

  DOI：10.1021/jm030337m

  日期：2004.3.1

  unpredictably in response to subtle structural changes within a ligand. We have investigated the possibility of dampening the induced fit by using a constrained template as a replacement for adjoining segments of a ligand. The template preorganizes the ligand structure, thereby organizing the local enzyme environment. To test this approach, we used templates consisting of constrained cyclic tripeptides, formed

  酶抑制剂从头设计的主要问题是诱导配合的不可预测性，配体和酶的形状响应于配体中的细微结构变化而协同且不可预测地变化。我们已经研究了通过使用受约束的模板作为配体的相邻片段的替代物来衰减诱导拟合的可能性。模板预组织配体结构，从而组织局部酶环境。为了测试这种方法，我们使用了由受约束的环状三肽组成的模板，这些模板是通过侧链与主链连接而形成的，作为N-或C端三个相邻氨基酸残基的蛋白酶结合的扩展β链构象的结构模拟物底物易裂键的两面。通过结合羟乙胺过渡态等位基因的非肽类附件的集中组合变化，将大环模板衍生为30种结构多样的分子。文库中的大多数化合物都是测试蛋白酶（HIV-1蛋白酶）的有效抑制剂。比较五个包含N末端大环的蛋白酶抑制剂复合物和三个包含C末端大环的蛋白酶抑制剂复合物的晶体结构，可以确定大环固定了其周围的酶环境，从而允许无环抑制剂组分的独立变化而仅受到局部干扰蛋白酶。这样，可以精确地预测大环模板两侧