(R)-benzyl 5-oxo-4-(3-oxopropyl)oxazolidine-3-carboxylate

• 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: (R)-benzyl 5-oxo-4-(3-oxopropyl)oxazolidine-3-carboxylate
• 英文别名: (4R)-4-(2-Formylethyl)-3-[(phenylmethoxy)carbonyl]oxazolidin-5-one；benzyl (4R)-5-oxo-4-(3-oxopropyl)-1,3-oxazolidine-3-carboxylate
• 化学式: C₁₄H₁₅NO₅
• 分子量: 277.277
• InChiKey: TZGYDRVYROGOLO-GFCCVEGCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  20
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  72.9
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  L-半胱氨酸甲酯盐酸盐 、 (R)-benzyl 5-oxo-4-(3-oxopropyl)oxazolidine-3-carboxylate 在 吡啶 、 potassium carbonate 作用下， 以 甲醇 为溶剂， 反应 91.0h， 以25%的产率得到(2R,5S,8R)-1-aza-8-benzyloxycarbonylamino-9-oxo-4-thiabicyclo[3.4.0]nonane-2-carboxylic acid methyl ester
  参考文献：
  名称：

  Constrained Peptidomimetics Reveal Detailed Geometric Requirements of Covalent Prolyl Oligopeptidase Inhibitors

  摘要：

  Prolyl oligopeptidases cleave peptides on the carboxy side of internal proline residues and their inhibition has potential in the treatment of human brain disorders. Using our docking program FITTED, we have designed a series of constrained covalent inhibitors, built from a series of bicyclic scaffolds, to study the optimal shape required for these small molecules. These structures bear nitrile functional groups that we predicted to covalently bind to the catalytic serine of the enzyme. Synthesis and biological assays using human brain-derived astrocytic cells and endothelial cells and human fibroblasts revealed that these compounds act as selective inhibitors of prolyl oligopeptidase activity compared to prolyl-dipeptidyl-aminopeptidase activity, are able to penetrate the cells and inhibit intracellular activities in intact living cells. This integrated computational and experimental study shed light oil the binding mode of inhibitors in the enzyme active site and will guide the design of future drug-like molecules.

  DOI：

  10.1021/jm901013a
• 作为产物：
  描述：

  (R)-3-(benzyloxycarbonyl)-5-oxo-4-oxazolidinepropionyl chloride 在 lithium tri-t-butoxyaluminum hydride 作用下， 以 四氢呋喃 为溶剂， 生成 (R)-benzyl 5-oxo-4-(3-oxopropyl)oxazolidine-3-carboxylate
  参考文献：
  名称：

  Constrained Peptidomimetics Reveal Detailed Geometric Requirements of Covalent Prolyl Oligopeptidase Inhibitors

  摘要：

  Prolyl oligopeptidases cleave peptides on the carboxy side of internal proline residues and their inhibition has potential in the treatment of human brain disorders. Using our docking program FITTED, we have designed a series of constrained covalent inhibitors, built from a series of bicyclic scaffolds, to study the optimal shape required for these small molecules. These structures bear nitrile functional groups that we predicted to covalently bind to the catalytic serine of the enzyme. Synthesis and biological assays using human brain-derived astrocytic cells and endothelial cells and human fibroblasts revealed that these compounds act as selective inhibitors of prolyl oligopeptidase activity compared to prolyl-dipeptidyl-aminopeptidase activity, are able to penetrate the cells and inhibit intracellular activities in intact living cells. This integrated computational and experimental study shed light oil the binding mode of inhibitors in the enzyme active site and will guide the design of future drug-like molecules.

  DOI：

  10.1021/jm901013a

文献信息

• Bicyclic thiazolidine lactam peptidomimetics of the dopamine receptor modulating peptide Pro-Leu-Gly-NH2
  作者：Nalin L. Subasinghe、Roger J. Bontems、Edward McIntee、Ram K. Mishra、Rodney L. Johnson

  DOI：10.1021/jm00068a013

  日期：1993.8

  achieve a beta-turn conformation. Peptidomimetics 3 and 4 were found to enhance the binding of the dopamine receptor agonist ADTN to the dopamine receptor, while 5 was found to be inactive. Like PLG the dose-response curves for 3 and 4 were bell-shaped in nature with the maximum effect occurring at a concentration of 1 microM. Both 3 and 4 were more effective than PLG in enhancing the binding of ADTN to

  已经合成了双环噻唑烷内酰胺内拟肽3-5，作为多巴胺受体调节肽Pro-Leu-Gly-NH2（PLG）的潜在类似物。拟肽3和4被设计为将四个扭转角中的两个psi 2和phi 3约束为一个β-转角，使其接近于II型β-转角，而5被设计为一种化合物，可以无法实现β转弯构象。发现拟肽3和4增强多巴胺受体激动剂ADTN与多巴胺受体的结合，而发现5是无活性的。像PLG一样，3和4的剂量反应曲线实际上是钟形的，在浓度为1 microM时产生最大作用。3和4在增强ADTN与多巴胺受体的结合方面均比PLG更有效。5 5-双环噻唑烷内酰胺肽模拟物3将ADTN的结合提高了近200％，而6,5-双环噻唑烷内酰胺肽模拟物4将ADTN的结合提高了约75％。这些结果提供了进一步的证据，支持了PLG的生物活性构象是II型β转角的假说。
• NOVEL THIAZOLIDINE DERIVATIVES
  申请人：SANTEN PHARMACEUTICAL CO., LTD.

  公开号：EP1103560A1

  公开（公告）日：2001-05-30

  An object of the present invention is to provide novel thiazolidine derivatives which are useful as drugs. The thiazolidine derivatives according to the present invention are compounds represented by the following general formula [I] and salts thereof, wherein R1 is alkyl, hydroxy, alkoxy, alkoxyalkyl, phenyl, phenylalkyl, phenylalkoxy, phenoxy, phenoxyalkyl, amino, alkylamino or a nonaromatic heterocycle; R2 is H or alkyl; R3 is H, alkyl or phenyl; R4 is H or alkyl; R5 is alkyl, halogenoalkyl, hydroxy, alkoxy, phenyl, phenylalkoxy, phenoxy, carboxyl, alkoxycarbonyl, phenylalkoxycarbonyl or an aromatic heterocycle; A1 is alkylene; and A2 is alkylene.

  本发明的目的是提供可用作药物的新型噻唑烷衍生物。根据本发明的噻唑烷衍生物是由以下通式[I]代表的化合物及其盐类、 其中 R1 是烷基、羟基、烷氧基、烷氧基烷基、苯基、苯基烷基、苯基烷氧基、苯氧基、苯氧基烷基、氨基、烷基氨基或非芳香杂环；R2 是 H 或烷基；R3 是 H、烷基或苯基；R4 是 H 或烷基；R5 是烷基、卤代烷基、羟基、烷氧基、苯基、苯基烷氧基、苯氧基、羧基、烷氧基羰基、苯基烷氧基羰基或芳香杂环；A1 是亚烷基；A2 是亚烷基。
• US6410576B1
  申请人：——

  公开号：US6410576B1

  公开（公告）日：2002-06-25