(6S,8aR)-N-tert-butoxycarbonyl-6-amino-8a-carboxyindolizidin-5-one methyl ester | 177320-36-4

• 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: (6S,8aR)-N-tert-butoxycarbonyl-6-amino-8a-carboxyindolizidin-5-one methyl ester
• 英文别名: 6-tert-Butoxycarbonylamino-5-oxo-hexahydro-indolizine-8a-carboxylic acid methyl ester；methyl (6S,8aR)-6-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxo-1,2,3,6,7,8-hexahydroindolizine-8a-carboxylate
• CAS: 177320-36-4
• 化学式: C₁₅H₂₄N₂O₅
• 分子量: 312.366
• InChiKey: AGWLFSYFDFJTHT-ZUZCIYMTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  84.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (6S,8aR)-N-tert-butoxycarbonyl-6-amino-8a-carboxyindolizidin-5-one methyl ester 在 劳森试剂 作用下， 以 甲苯 为溶剂， 反应 6.0h， 生成 (6S,8aR)-6-N-tert-butoxycarbonylamino-8a-carboxyindolizidin-5-thione 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：

  E,Z-N-(benzyloxycarbonyl)-2(R)-3'-(N-(tert-butoxycarbonyl)amino-3'-carboethoxy-2'-propenyl)-(2-carbomethoxy)-pyrrolidine 在 palladium on activated charcoal 氢气 、 三乙胺 作用下， 以 甲醇 、 甲苯 为溶剂， 反应 48.75h， 生成 (6S,8aR)-N-tert-butoxycarbonyl-6-amino-8a-carboxyindolizidin-5-one methyl ester
  参考文献：
  名称：

  新型双环内酰胺作为XaaPro Type VI beta Turn模拟物：设计，合成和评估。

  摘要：

  描述了新型双环内酰胺作为VIβ型转弯肽模拟物的设计，对映选择性合成和结构表征。该模拟物复制了骨架的构型和该匝的中心两个残基的侧链原子的布置。从（S）-2-（2'-丙烯基）脯氨酸开始，以良好的总收率制备了Gly L-Pro模拟物内酰胺6。（1）1 H NMR光谱确定了内酰胺六元环的取代基的相对立体化学和构象特征；X射线晶体学分析证实了构象和立体化学分配。对内酰胺6的晶体结构的检查表明，中央酰胺键明显扭曲出平面度。酰胺键的扭曲归因于在两个环的交界处存在sp（2）-杂化氮原子而导致的角度应变。内酰胺6的N，N-二甲基甲am衍生物的烯醇化物与苄基溴的烷基化选择性地提供了甲am11，其为VI-turn构型的L-Phe L-Pro二肽的模拟物。高度合成的模拟肽（例如11）的有效合成途径将在肽结构功能研究中被证明非常有用。

  DOI：

  10.1021/jo960012w

文献信息

• Allosteric Modulation of the Dopamine Receptor by Conformationally Constrained Type VI β-Turn Peptidomimetics of Pro-Leu-Gly-NH₂
  作者：Ashish P. Vartak、Kevin Skoblenick、Nancy Thomas、Ram K. Mishra、Rodney L. Johnson

  DOI：10.1021/jm070895r

  日期：2007.12.27

  A peptidomimetic of Pro-Leu-Pro-NH2, 7, possessing an indolizidinone type VI beta-turn mimic was synthesized via improved high-yielding protocols for the preparation and Cbz protection of a-allylproline. Bicyclic peptidomimetic 7 and spirobicylic peptidomimetic 8 enhanced the binding of [H-3]N-propylnorapomorphine to dopamine receptors indicating that a type VI beta-turn is a possible bioactive conformation of the homochiral Pro-Leu-Pro-NH2 and Pro-Pro-Pro-NH2 analogues of Pro-Leu-Gly-NH2 at the dopamine receptor allosteric regulatory site.
• 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.
• Novel Bicyclic Lactams as XaaPro Type VI β Turn Mimics:  Design, Synthesis, and Evaluation
  作者：Kyonghee Kim、Jean-philippe Dumas、Juris P. Germanas

  DOI：10.1021/jo960012w

  日期：1996.1.1

  The design, enantioselective synthesis, and structural characterization of novel bicyclic lactams as peptide mimics of the type VI beta turn is described. The mimics duplicate the conformation of the backbone and disposition of the side-chain atoms of the central two residues of the turn. The Gly L-Pro mimic, lactam 6, was prepared in good overall yield starting from (S)-2-(2'-propenyl)proline. (1)H

  描述了新型双环内酰胺作为VIβ型转弯肽模拟物的设计，对映选择性合成和结构表征。该模拟物复制了骨架的构型和该匝的中心两个残基的侧链原子的布置。从（S）-2-（2'-丙烯基）脯氨酸开始，以良好的总收率制备了Gly L-Pro模拟物内酰胺6。（1）1 H NMR光谱确定了内酰胺六元环的取代基的相对立体化学和构象特征；X射线晶体学分析证实了构象和立体化学分配。对内酰胺6的晶体结构的检查表明，中央酰胺键明显扭曲出平面度。酰胺键的扭曲归因于在两个环的交界处存在sp（2）-杂化氮原子而导致的角度应变。内酰胺6的N，N-二甲基甲am衍生物的烯醇化物与苄基溴的烷基化选择性地提供了甲am11，其为VI-turn构型的L-Phe L-Pro二肽的模拟物。高度合成的模拟肽（例如11）的有效合成途径将在肽结构功能研究中被证明非常有用。