cis-3-benzyl-1-(4'-nitrobenzenesulfonyl)-4-phenylcarbonyloxymethyl-2-azetidinone

• 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-3-benzyl-1-(4'-nitrobenzenesulfonyl)-4-phenylcarbonyloxymethyl-2-azetidinone
• 英文别名: Benzoic acid 3-benzyl-1-(4-nitro-benzenesulfonyl)-4-oxo-azetidin-2-ylmethyl ester；[(2S,3S)-3-benzyl-1-(4-nitrophenyl)sulfonyl-4-oxoazetidin-2-yl]methyl benzoate
• 化学式: C₂₄H₂₀N₂O₇S
• 分子量: 480.498
• InChiKey: WPEODRYHIIBRHR-FCHUYYIVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  34
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  135
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  3-苯丙酰氯 在 4-二甲氨基吡啶 sodium tetrahydroborate 、 ammonium cerium(IV) nitrate 、 sodium hexamethyldisilazane 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 甲苯 、 乙腈 为溶剂， 反应 70.42h， 生成 cis-3-benzyl-1-(4'-nitrobenzenesulfonyl)-4-phenylcarbonyloxymethyl-2-azetidinone
  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

• An Investigation of the N-Arylsulfonylation of 2-Azetidinones
  作者：Robert M. Adlington、Jack E. Baldwin、William MC Coull、Gareth J. Pritchard、Christopher J. Schofield、Nicholas J. Westwood

  DOI：10.1080/00397919708007305

  日期：1997.11

  N-Arylsulfonylation of 2-azetidinones can lead to the diastereoselective formation of oligomerization products. However, a simple increase of arylsulfonyl chloride concentration minimized oligomerization and allowed preparation of 1-arylsulfonyl-2-azetidinones in good yield.