(6R,8aR)-6-Amino-5-oxo-hexahydro-indolizine-8a-carboxylic acid methyl ester | 1054633-63-4

• 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: (6R,8aR)-6-Amino-5-oxo-hexahydro-indolizine-8a-carboxylic acid methyl ester
• 英文别名: methyl (6R,8aR)-6-amino-5-oxo-1,2,3,6,7,8-hexahydroindolizine-8a-carboxylate
• CAS: 1054633-63-4
• 化学式: C₁₀H₁₆N₂O₃
• 分子量: 212.249
• InChiKey: IFYAGMMQQDOTSW-GMSGAONNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.4
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  72.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (6R,8aR)-6-Amino-5-oxo-hexahydro-indolizine-8a-carboxylic acid methyl ester 在 盐酸 、 4 A molecular sieve 、 三乙胺 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 4.0h， 生成 (6S,8aR)-6-Amino-6-naphthalen-2-ylmethyl-5-oxo-hexahydro-indolizine-8a-carboxylic acid methyl ester
  参考文献：
  名称：

  Structure−Activity Studies of Ground- and Transition-State Analogue Inhibitors of Cyclophilin

  摘要：

  Peptidyl-prolyl isomerases (PPIases) are ubiquitous cellular enzymes that play roles in cellular signaling and protein folding. In addition, these proteins are the receptors for the widely used immunosuppressants cyclosporin A and FK506. We report the first structure-activity studies of de novo designed inhibitors of cyclophilin, the cellular target of cyclosporin A. Our mechanism-based inhibitors were modeled on the ground- and transition-state structures of proline-containing peptides, the natural substrates of the enzyme. Both ground-state analogues I and transition-state analogues 2 were prepared as single enantiomers from L-proline following a "self-reproduction of chirality" procedure. The binding affinities of the analogues for the active site of cyclophilin were measured by a fluorescence perturbation assay. While the transition-state analogues 2 did not display significant avidity for the active site (K-d = 77 muM for 2b), several ground-state analogues bound to the enzyme with low micromolar affinity (K-d = 1.5 muM for 1e). These results proclaim that properly designed small molecular weight molecules can form strong complexes with cyclophilin and may find use as probes in cell biology and as therapeutic agents.

  DOI：

  10.1021/jm010009r
• 作为产物：
  描述：

  (6R,8aR)-N-(tert-butoxycarbonyl)-6-amino-8a-carboxyindolizidin-5-one methyl ester 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成 (6R,8aR)-6-Amino-5-oxo-hexahydro-indolizine-8a-carboxylic acid methyl ester
  参考文献：
  名称：

  Structure−Activity Studies of Ground- and Transition-State Analogue Inhibitors of Cyclophilin

  摘要：

  Peptidyl-prolyl isomerases (PPIases) are ubiquitous cellular enzymes that play roles in cellular signaling and protein folding. In addition, these proteins are the receptors for the widely used immunosuppressants cyclosporin A and FK506. We report the first structure-activity studies of de novo designed inhibitors of cyclophilin, the cellular target of cyclosporin A. Our mechanism-based inhibitors were modeled on the ground- and transition-state structures of proline-containing peptides, the natural substrates of the enzyme. Both ground-state analogues I and transition-state analogues 2 were prepared as single enantiomers from L-proline following a "self-reproduction of chirality" procedure. The binding affinities of the analogues for the active site of cyclophilin were measured by a fluorescence perturbation assay. While the transition-state analogues 2 did not display significant avidity for the active site (K-d = 77 muM for 2b), several ground-state analogues bound to the enzyme with low micromolar affinity (K-d = 1.5 muM for 1e). These results proclaim that properly designed small molecular weight molecules can form strong complexes with cyclophilin and may find use as probes in cell biology and as therapeutic agents.

  DOI：

  10.1021/jm010009r

文献信息

• Structure−Activity Studies of Ground- and Transition-State Analogue Inhibitors of Cyclophilin
  作者：Harry C. Wang、Kyonghee Kim、Ray Bakhtiar、Juris P. Germanas

  DOI：10.1021/jm010009r

  日期：2001.8.1

  Peptidyl-prolyl isomerases (PPIases) are ubiquitous cellular enzymes that play roles in cellular signaling and protein folding. In addition, these proteins are the receptors for the widely used immunosuppressants cyclosporin A and FK506. We report the first structure-activity studies of de novo designed inhibitors of cyclophilin, the cellular target of cyclosporin A. Our mechanism-based inhibitors were modeled on the ground- and transition-state structures of proline-containing peptides, the natural substrates of the enzyme. Both ground-state analogues I and transition-state analogues 2 were prepared as single enantiomers from L-proline following a "self-reproduction of chirality" procedure. The binding affinities of the analogues for the active site of cyclophilin were measured by a fluorescence perturbation assay. While the transition-state analogues 2 did not display significant avidity for the active site (K-d = 77 muM for 2b), several ground-state analogues bound to the enzyme with low micromolar affinity (K-d = 1.5 muM for 1e). These results proclaim that properly designed small molecular weight molecules can form strong complexes with cyclophilin and may find use as probes in cell biology and as therapeutic agents.