(3S,6s,8as)-6-(叔丁氧基羰基氨基)-5-氧代八氢吲哚嗪-3-羧酸 | 159303-50-1

• 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
• 中文名称: (3S,6s,8as)-6-(叔丁氧基羰基氨基)-5-氧代八氢吲哚嗪-3-羧酸
• 英文名称: (3S,6S,9S)-2-oxo-3--1-azabicyclo<4.3.0>nonane-9-carboxylic acid
• 英文别名: 2-Oxo-3-(N-BOC-amino)-1-azabicyclo<4.3.0>nonane-9-carboxylic acid；(3S,6S,8aS)-6-((tert-Butoxycarbonyl)amino)-5-oxooctahydroindolizine-3-carboxylic acid；(3S,6S,8aS)-6-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxo-2,3,6,7,8,8a-hexahydro-1H-indolizine-3-carboxylic acid
• CAS: 159303-50-1
• 化学式: C₁₄H₂₂N₂O₅
• 分子量: 298.339
• InChiKey: TUKCETWDNUERKW-GUBZILKMSA-N

物化性质

• 沸点：
  516.2±39.0 °C(Predicted)
• 密度：
  1.27±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  95.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (3S,6s,8as)-6-(叔丁氧基羰基氨基)-5-氧代八氢吲哚嗪-3-羧酸 在 盐酸 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 二异丙胺 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 为溶剂， 生成
  参考文献：
  名称：

  Structure-Based Design, Synthesis, and Evaluation of Conformationally Constrained Mimetics of the Second Mitochondria-Derived Activator of Caspase That Target the X-Linked Inhibitor of Apoptosis Protein/Caspase-9 Interaction Site

  摘要：

  A successful structure-based design of conformationally constrained second mitochondria-derived activator of caspase (Smac) mimetics that target the XIAP/caspase-9 interaction site is described. The most potent Smac mimetic 12d has a K-i of 350 nM for binding to the XIAP BIR3 domain protein. 12d is found to be effective in enhancing apoptosis induced by cisplatin in PC-3 human prostate cancer cells.

  DOI：

  10.1021/jm0499108
• 作为产物：
  描述：

  (3s,6s,8as)-6-[(叔丁氧基羰基)氨基]-5-氧代八氢吲哚嗪-3-羧酸甲酯 在 lithium hydroxide 作用下， 以 1,4-二氧六环 为溶剂， 反应 1.0h， 以92%的产率得到(3S,6s,8as)-6-(叔丁氧基羰基氨基)-5-氧代八氢吲哚嗪-3-羧酸
  参考文献：
  名称：

  配对的氮杂氨基脯氨酸脯氨酸和吲哚西酮酮氨基酸残基用于肽模拟：前列腺素F2α受体变构调节剂的构想可延迟早产。

  摘要：

  利用氮杂-氨基酰基脯氨酸和吲哚izidinone残基的组合模拟肽已被用于开发前列腺素F2α受体的变构调节剂。系统研究N末端苯乙酰基部分和中央转向二肽残基的构象和侧链功能已证明调节剂活性和拓扑之间的敏感关系。在以脂多糖治疗的小鼠早产模型中对aza-Gly-Pro和aza-Phe-Pro类似物2a和2b的检查表明，它们能够显着延长平均分娩时间（> 20小时），从而为延迟早产提供了新的原型。 。

  DOI：

  10.1021/acs.jmedchem.9b00056

文献信息

• Probing Opioid Receptor Interactions with Azacycloalkane Amino Acids. Synthesis of a Potent and Selective ORL1 Antagonist
  作者：Liliane Halab、Jérôme A. J. Becker、Zsuzsanna Darula、Dirk Tourwé、Brigitte L. Kieffer、Frédéric Simonin、William D. Lubell

  DOI：10.1021/jm020078l

  日期：2002.11.1

  between conformation and biological activity of peptide ligands to the opioid receptor-like (ORL1) receptor. Three azabicyclo[x.y.0]alkane amino acids and a 5-tBuPro type VI beta-turn mimic were introduced into peptides 10-13 by solid-phase synthesis on MBHA resin. Biological examination of peptides 10-13 showed two new antagonists (10 and 12) exhibiting increased selectivity for the ORL1 receptor.

  氮杂环烷转向模拟物6-9用于研究肽配体对阿片样受体样（ORL1）受体的构象与生物学活性之间的关系。通过在MBHA树脂上进行固相合成，将三个氮杂双环[xy0]烷烃氨基酸和一个5-tBuPro VI型β转角模拟物引入到肽10-13中。肽10-13的生物学检查显示，两种新的拮抗剂（10和12）对ORL1受体的选择性增加。
• Calcitonin Gene-Related Peptide Analogues with Aza and Indolizidinone Amino Acid Residues Reveal Conformational Requirements for Antagonist Activity at the Human Calcitonin Gene-Related Peptide 1 Receptor
  作者：Damien Boeglin、Fadi F. Hamdan、Rosa E. Melendez、Jérôme Cluzeau、Andre Laperriere、Madeleine Héroux、Michel Bouvier、William D. Lubell

  DOI：10.1021/jm061343w

  日期：2007.3.1

  regions of the backbone expected to adopt turns. Finally, the conformation of the backbone and side-chain of the C-terminal residue, Phe35-Ala36-Phe37-NH2, was explored employing (2S,4R,6R,8S)-9-oxo-8-amino-4-phenyl-indolizidin-9-one amino acid (4-Ph-I9aa) as a constrained phenylalanine mimic. The structure-activity relationships exhibited by our 26 analogues illustrate conformational requirements important

  降钙素基因相关的肽拮抗剂具有治疗和预防疾病状态的潜力，例如非胰岛素依赖性糖尿病，偏头痛，疼痛和炎症。为了深入了解CGRP拮抗作用的空间需求，采用了三种策略来限制强力十肽拮抗剂[D31，P34，F35] CGRP27-37的构象。首先，进行氮杂氨基酸扫描，合成十个氮杂肽类似物并检查其生物学活性。第二，（3S，6S，9S）-2-氧代-3-氨基吲哚并丁-2-一氨基酸（I2aa）和（2S，6S，8S）-9-氧代-8-氨基吲哚并丁-9-一个氨基酸（I9aa）都被引入到骨架的预期采用转弯的区域31-32、32-33、33-34和34-35处。最后，C末端残基的主链和侧链的构象，以（2S，4R，6R，8S）-9-氧代-8-氨基-4-苯基-吲哚并丁-9-氨基酸（4-Ph-I9aa）为约束氨基酸，探索了Phe35-Ala36-Phe37-NH2苯丙氨酸模拟物。我们的26个类似物表现出的构效关系说明了对设计C
• Structural and Functional Analysis of Pantocin A: An Antibiotic from Pantoea agglomerans Discovered by Heterologous Expression of Cloned Genes
  作者：Mi Jin、Liang Liu、Sandra A. I. Wright、Steven V. Beer、Jon Clardy

  DOI：10.1002/anie.200351053

  日期：2003.6.30
• Targeting the Prostaglandin F2α Receptor for Preventing Preterm Labor with Azapeptide Tocolytics
  作者：Carine B. Bourguet、Eugénie Goupil、Danaë Tassy、Xin Hou、Eryk Thouin、Felix Polyak、Terence E. Hébert、Audrey Claing、Stéphane A. Laporte、Sylvain Chemtob、William D. Lubell

  DOI：10.1021/jm200608k

  日期：2011.9.8

  The prostaglandin-F2 alpha (PGF2 alpha) receptor (FP) was targeted to develop tocolytic agents for inhibiting preterm labor. Azabicycloalkane and azapeptide mimics 2-10 were synthesized based on the (3S,6S,9S)-indolizidin-2-one amino acid analogue PDC113.824 (1), which was shown to modulate FP by a biased allosteric mechanism, involving both G alpha q- and G alpha 12-mediated signaling pathways, and exhibited significant tocolytic activity delaying preterm labor in a mouse model (Goupil; J. Biol. Chem. 2010, 285,25624-25636), Although changes in azabicycloalkane stereochemistry and ring size caused loss of activity, replacement of the indolizidin-2-one amino acid with azaGly-Pro and azaPhe-Pro gave azapeptides 6 and 8, which reduced PGF2 alpha-induced myometrial contractions, potentiated the effect of PGF2 alpha on G alpha q-mediated ERK1/2 activation, and inhibited FP modulation of cell ruffling, a response dependent on the G alpha 12/RhoA/ROCK signaling pathway. Revealing complementarities of azabicycloalkane and azapeptide mimics, novel probes, and efficient tocolytic agents were made to study allosteric modulation of the FP receptor.
• Rigid Dipeptide Mimetics:  Efficient Synthesis of Enantiopure Indolizidinone Amino Acids
  作者：Henry-Georges Lombart、William D. Lubell

  DOI：10.1021/jo961872f

  日期：1996.1.1

  An effective means to synthesize indolizidinone amino acids has been developed and furnishes all possible stereoisomers of these conformationally rigid mimetics of peptide secondary structures. Inexpensive glutamic acid was employed as chiral educt in a Claisen condensation/reductive amination/lactam cyclization sequence that furnished stereoselectively azabicyclo[3.4.0]alkane amino acid 1. Enantiopure (3S,6S,9S)- and (3R,6R,9R)-2-oxo-3-N-(BOC)amino-1-azabicyclo[4.3.0]nonane-9-carboxylic acids ((3S,6S,9S)- and (3R,6R,9R)-1) were respectively synthesized from L- and D-N-(PhF)glutamates 2 (PhF = 9-(9-phenylfluorenyl)). Slow addition of sodium bis(trimethylsilyl)amide to 2 provided good to excellent yields of beta-keto esters 3, which were subsequently hydrolyzed and decarboxylated to give symmetric alpha,omega-bis[N-(PhF)amino]azelate delta-ketones 5. Augmentation of hydrogen pressure increased diastereoselectivity in reductive aminations with 5 and afforded 5-alkylprolines 8 and 10. Lactam formation on exposure of 10 to triethylamine and N-protection with di-tert-butyl dicarbonate gave methyl 2-oxo-3-[N-(BOC)amino]-1-azabicyclo[4.3.0]nonane-9-carboxylate (12) which on C-terminal ester hydrolysis with hydroxide ion gave enantiopure [N-(BOC)amino]indolizidinone acid 1. Alternatively, hydride addition to ketone 5a gave symmetric alpha,omega-bis[N-(PhF)amino]azelate delta-alcohol 7a, which upon mesylation, and intramolecular S(N)2 displacement by the PhF amine gave specifically cis-5-alkylproline 15 that was similarly converted to (3S,6S,9S)-1. In addition, epimerization of the C-9 stereocenter of (3S,6S,9S)-[N-(BOC)amino]-indolizidinone methyl ester 12 with NaN(SiMe(3))(2) and ester hydrolysis gave (3S,6S,9R)-indolizidinone amino acid (3S,6S,9R)-1. By providing efficient methodology for synthesizing all of the possible stereoisomers of enantiopure indolizidinone amino acid 1, our route is specifically designed to enhance the general use of these peptide mimetics in the exploration of conformation-activity relationships of various biologically active peptides.