cis-4-benzyloxycarbonyl-3-(4'-tert-butyldiphenylsilyloxybenzyl)-1-(4'-methoxyphenyl)-2-azetidionone

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酰胺类
• 英文名称: cis-4-benzyloxycarbonyl-3-(4'-tert-butyldiphenylsilyloxybenzyl)-1-(4'-methoxyphenyl)-2-azetidionone
• 英文别名: benzyl (2S,3S)-3-[[4-[tert-butyl(diphenyl)silyl]oxyphenyl]methyl]-1-(4-methoxyphenyl)-4-oxoazetidine-2-carboxylate
• 化学式: C₄₁H₄₁NO₅Si
• 分子量: 655.866
• InChiKey: KNCHTIGKTPGQFB-UWXQCODUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.95
• 重原子数：
  48
• 可旋转键数：
  13
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  65.1
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  cis-4-benzyloxycarbonyl-3-(4'-tert-butyldiphenylsilyloxybenzyl)-1-(4'-methoxyphenyl)-2-azetidionone 在 ammonium cerium(IV) nitrate 作用下， 以 水 、 乙腈 为溶剂， 反应 0.5h， 以70%的产率得到cis-4-benzyloxycarbonyl-3-(4'-tert-butyldiphenylsilyloxybenzyl)-2-azetidinone
  参考文献：
  名称：

  Efficient and highly stereoselective synthesis of a β-Lactam inhibitor of the serine protease prostate-specific antigen

  摘要：

  An efficient synthesis of a beta-lactam precursor of the serine protease, prostate-specific antigen inhibitor 1 has been accomplished. The synthesis relies on two completely stercoselective reactions that allow the introduction of the stereocenters at C-3 and C-4 of the azetidinone ring in a predictable manner. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(02)00017-2
• 作为产物：
  描述：

  3-(4-乙酰氧基苯基)丙酸 在 4-二甲氨基吡啶 咪唑 、 chromium(VI) oxide 、 草酰氯 、 硫酸 、 三乙胺 、 N,N'-二环己基碳二亚胺 、 锌 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 丙酮 、 甲苯 为溶剂， 反应 118.5h， 生成 cis-4-benzyloxycarbonyl-3-(4'-tert-butyldiphenylsilyloxybenzyl)-1-(4'-methoxyphenyl)-2-azetidionone
  参考文献：
  名称：

  Design, Synthesis, and Proposed Active Site Binding Analysis of Monocyclic 2-Azetidinone Inhibitors of Prostate Specific Antigen

  摘要：

  A homology derived molecular model of prostate specific antigen (PSA) was created and refined. The active site region was investigated for specific interacting functionality and a binding model postulated for the novel 2-azetidinone acyl enzyme inhibitor 1 (IC50 = 8.98 +/- 0.90 muM) which was used as a lead compound in this study. A single low energy conformation structure II (Figure 2) was adopted as most likely to represent binding after minimization and dynamics calculations. Systematic analysis of the binding importance of all three side chains appended to the 2-azetidinone was conducted by the synthesis of several analogues. A proposed salt bridge to Lys-145 with 4 (IC50 = 5.84 +/- 0.92 muM) gave improved inhibition, but generally the binding of the N-1 side chain in a specific secondary aromatic binding site did not tolerate much structural alteration. A hydrophobic interaction of the C-4 side chain afforded inhibitor 6 (IC50 = 1.43 +/- 0.19 muM), and polar functionality could also be added in a proposed interaction with Gln-166 in 5 (IC50 = 1.34 +/- 0.05 muM). Reversal of the C-4 ester connectivity furnished inhibitors 7 (IC50 = 1 59 +/- 0 15 muM), 11 (IC50 = 3.08 +/- 0.41 muM), and 13 (IC50 = 2.19 +/- 0.36 muM) which were perceived to bind to PSA by a rotation of 180 degrees relative to the C-4 ester of normal connectivity. Incorporation of hydroxyl functionality into the C-3 side chain provided 16 (IC50 = 348 +/- 50 nM) with the greatest increase in PSA inhibition by a single modification. Multiple copy simultaneous search (MCSS) analysis of the PSA active site further supported our model and suggested that 18 would bind strongly. Asymmetric synthesis yielded 18 (IC50 = 226 +/- 10 nM) as the most potent inhibitor of PSA reported to date. It is concluded that our design approach has been successful in developing PSA inhibitors and could also be applied to the inhibition of other enzymes, especially in the absence of crystallographic information.

  DOI：

  10.1021/jm000145g

文献信息

• Design and synthesis of novel monocyclic β-lactam inhibitors of prostate specific antigen
  作者：Robert M. Adlington、Jack E. Baldwin、Beining Chen、Stephen L. Cooper、William McCoull、Gareth J. Pritchard、Trevor J. Howe、Gerald W. Becker、Robert B. Hermann、Ann M. McNulty、Blake L. Neubauer

  DOI：10.1016/s0960-894x(97)00285-0

  日期：1997.7

  A novel series of monocyclic B-lactam analogues was designed using a homology derived model of prostate specific antigen (PSA) and by application of a multiple copy simultaneous search technique. Syntheses were conducted by assembly of the B-lactam core via a Staudinger reaction with elaboration at the 1, 3 and 4 positions to probe active site binding. Inhibition against PSA was evaluated. (C) 1997 Elsevier Science Ltd.
• Design, Synthesis, and Proposed Active Site Binding Analysis of Monocyclic 2-Azetidinone Inhibitors of Prostate Specific Antigen
  作者：Robert M. Adlington、Jack E. Baldwin、Gerald W. Becker、Beining Chen、Leifeng Cheng、Stephen L. Cooper、Robert B. Hermann、Trevor J. Howe、William McCoull、Ann M. McNulty、Blake L. Neubauer、Gareth J. Pritchard

  DOI：10.1021/jm000145g

  日期：2001.5.1

  A homology derived molecular model of prostate specific antigen (PSA) was created and refined. The active site region was investigated for specific interacting functionality and a binding model postulated for the novel 2-azetidinone acyl enzyme inhibitor 1 (IC50 = 8.98 +/- 0.90 muM) which was used as a lead compound in this study. A single low energy conformation structure II (Figure 2) was adopted as most likely to represent binding after minimization and dynamics calculations. Systematic analysis of the binding importance of all three side chains appended to the 2-azetidinone was conducted by the synthesis of several analogues. A proposed salt bridge to Lys-145 with 4 (IC50 = 5.84 +/- 0.92 muM) gave improved inhibition, but generally the binding of the N-1 side chain in a specific secondary aromatic binding site did not tolerate much structural alteration. A hydrophobic interaction of the C-4 side chain afforded inhibitor 6 (IC50 = 1.43 +/- 0.19 muM), and polar functionality could also be added in a proposed interaction with Gln-166 in 5 (IC50 = 1.34 +/- 0.05 muM). Reversal of the C-4 ester connectivity furnished inhibitors 7 (IC50 = 1 59 +/- 0 15 muM), 11 (IC50 = 3.08 +/- 0.41 muM), and 13 (IC50 = 2.19 +/- 0.36 muM) which were perceived to bind to PSA by a rotation of 180 degrees relative to the C-4 ester of normal connectivity. Incorporation of hydroxyl functionality into the C-3 side chain provided 16 (IC50 = 348 +/- 50 nM) with the greatest increase in PSA inhibition by a single modification. Multiple copy simultaneous search (MCSS) analysis of the PSA active site further supported our model and suggested that 18 would bind strongly. Asymmetric synthesis yielded 18 (IC50 = 226 +/- 10 nM) as the most potent inhibitor of PSA reported to date. It is concluded that our design approach has been successful in developing PSA inhibitors and could also be applied to the inhibition of other enzymes, especially in the absence of crystallographic information.
• Efficient and highly stereoselective synthesis of a β-Lactam inhibitor of the serine protease prostate-specific antigen
  作者：R Annunziata

  DOI：10.1016/s0968-0896(02)00017-2

  日期：2002.6

  An efficient synthesis of a beta-lactam precursor of the serine protease, prostate-specific antigen inhibitor 1 has been accomplished. The synthesis relies on two completely stercoselective reactions that allow the introduction of the stereocenters at C-3 and C-4 of the azetidinone ring in a predictable manner. (C) 2002 Elsevier Science Ltd. All rights reserved.