(3aS,6R,7R,7aS)-4-bromo-6,7-di-tert-butyldimethylsiloxy-2,2-dimethyl-3a,6,7,7a-tetrahydro-1,3-benzodioxole | 173381-14-1

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (3aS,6R,7R,7aS)-4-bromo-6,7-di-tert-butyldimethylsiloxy-2,2-dimethyl-3a,6,7,7a-tetrahydro-1,3-benzodioxole
• 英文别名: (3R,4S,5R,6S)-1-bromo-3,4-di(tert-butyldimethylsilyloxy)-5,6-isopropylidenedioxycyclohex-1-ene；[(3aR,4S,5R,7aS)-7-bromo-4-[tert-butyl(dimethyl)silyl]oxy-2,2-dimethyl-3a,4,5,7a-tetrahydro-1,3-benzodioxol-5-yl]oxy-tert-butyl-dimethylsilane
• CAS: 173381-14-1
• 化学式: C₂₁H₄₁BrO₄Si₂
• 分子量: 493.629
• InChiKey: DCGMTPHNTUBKKV-BRSBDYLESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.58
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.9
• 拓扑面积：
  36.9
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (3aS,6R,7R,7aS)-4-bromo-6,7-di-tert-butyldimethylsiloxy-2,2-dimethyl-3a,6,7,7a-tetrahydro-1,3-benzodioxole 在 盐酸 、 四丁基氟化铵 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 乙醇 、 水 为溶剂， 反应 56.0h， 生成 ethyl (3R,4S,5R,6R)-3,4,5,6-tetrahydroxycyclohex-1-ene-1-carboxylate
  参考文献：
  名称：

  Mycobacterium tuberculosis Shikimate Kinase Inhibitors: Design and Simulation Studies of the Catalytic Turnover

  摘要：

  Shikimate kinase (SK) is an essential enzyme in several pathogenic bacteria and does not have any counterpart in human cells, thus making it an attractive target for the development of new antibiotics. The key interactions of the substrate and product binding and the enzyme movements that are essential for catalytic turnover of the Mycobacterium tuberculosis shikimate kinase enzyme (Mt-SK) have been investigated by structural and computational studies. Based on these studies several substrate analogs were designed and assayed. The crystal structure of Mt-SK in complex with ADP and one of the most potent inhibitors has been solved at 2.15 angstrom. These studies reveal that the fixation of the diaxial conformation of the C4 and C5 hydroxyl groups recognized by the enzyme or the replacement of the C3 hydroxyl group in the natural substrate by an amino group is a promising strategy for inhibition because it causes a dramatic reduction of the flexibility of the LID and shikimic acid binding domains. Molecular dynamics simulation studies showed that the product is expelled from the active site by three arginines (Arg117, Arg136, and Arg58). This finding represents a previously unknown key role of these conserved residues. These studies highlight the key role of the shikimic acid binding domain in the catalysis and provide guidance for future inhibitor designs.

  DOI：

  10.1021/ja405853p
• 作为产物：
  描述：

  叔丁基二甲硅基三氟甲磺酸酯 、 [3aS-(3aα,4α,5α,7aα)]-7-溴-3a,4,5,7a-四氢-2,2-二甲基-1,3-苯并二茂-4,5-二醇 在 咪唑 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.5h， 以71%的产率得到(3aS,6R,7R,7aS)-4-bromo-6,7-di-tert-butyldimethylsiloxy-2,2-dimethyl-3a,6,7,7a-tetrahydro-1,3-benzodioxole
  参考文献：
  名称：

  Blacker, A. John; Booth, R. John; Davies, Gareth M., Journal of the Chemical Society. Perkin transactions I, 1995, # 22, p. 2861 - 2870

  摘要：

  DOI：

文献信息

• Blacker, A. John; Booth, R. John; Davies, Gareth M., Journal of the Chemical Society. Perkin transactions I, 1995, # 22, p. 2861 - 2870
  作者：Blacker, A. John、Booth, R. John、Davies, Gareth M.、Sutherland, James K.

  DOI：——

  日期：——
• Mycobacterium tuberculosis Shikimate Kinase Inhibitors: Design and Simulation Studies of the Catalytic Turnover
  作者：Beatriz Blanco、Verónica Prado、Emilio Lence、José M. Otero、Carmela Garcia-Doval、Mark J. van Raaij、Antonio L. Llamas-Saiz、Heather Lamb、Alastair R. Hawkins、Concepción González-Bello

  DOI：10.1021/ja405853p

  日期：2013.8.21

  Shikimate kinase (SK) is an essential enzyme in several pathogenic bacteria and does not have any counterpart in human cells, thus making it an attractive target for the development of new antibiotics. The key interactions of the substrate and product binding and the enzyme movements that are essential for catalytic turnover of the Mycobacterium tuberculosis shikimate kinase enzyme (Mt-SK) have been investigated by structural and computational studies. Based on these studies several substrate analogs were designed and assayed. The crystal structure of Mt-SK in complex with ADP and one of the most potent inhibitors has been solved at 2.15 angstrom. These studies reveal that the fixation of the diaxial conformation of the C4 and C5 hydroxyl groups recognized by the enzyme or the replacement of the C3 hydroxyl group in the natural substrate by an amino group is a promising strategy for inhibition because it causes a dramatic reduction of the flexibility of the LID and shikimic acid binding domains. Molecular dynamics simulation studies showed that the product is expelled from the active site by three arginines (Arg117, Arg136, and Arg58). This finding represents a previously unknown key role of these conserved residues. These studies highlight the key role of the shikimic acid binding domain in the catalysis and provide guidance for future inhibitor designs.