(-)-2-(S)-[N-(2-tert-butoxycarbonylaminopropionylamino)acetylamino]acetic acid | 115035-47-7

• 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: (-)-2-(S)-[N-(2-tert-butoxycarbonylaminopropionylamino)acetylamino]acetic acid
• 英文别名: N-Boc-(S)-alanine-glycine-glycine；Boc-Ala-Gly-Gly-OH；2-[[2-[[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]acetyl]amino]acetic acid
• CAS: 115035-47-7
• 化学式: C₁₂H₂₁N₃O₆
• 分子量: 303.315
• InChiKey: RIBHQSRGHUDSSF-ZETCQYMHSA-N

物化性质

• 熔点：
  76-77 °C(Solv: hexane (110-54-3); ethyl ether (60-29-7))
• 沸点：
  632.5±50.0 °C(Predicted)
• 密度：
  1.233±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.4
• 重原子数：
  21
• 可旋转键数：
  8
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  134
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (-)-2-(S)-[N-(2-tert-butoxycarbonylaminopropionylamino)acetylamino]acetic acid 在 N-甲基吗啉 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 29.0h， 生成
  参考文献：
  名称：

  Synthesis of a Novel Esterase-Sensitive Cyclic Prodrug of a Hexapeptide Using an (Acyloxy)alkoxy Promoiety

  摘要：

  Synthetic methodology for preparing novel esterase-sensitive cyclic prodrugs of peptides with increased protease stability and cell membrane permeability compared to linear peptides is described. Cyclic prodrug 1 of the hexapeptide H-Trp-Ala-Gly-Gly-Asp-Ala-OH linked by the N-terminal amino group to the C-terminal carboxyl group via an (acyloxy)alkoxy promoiety was synthesized. A convergent synthetic approach involving Boc[[(alaninyloxy)methyl]carbonyl]-N-tryptophan (2) and H-Ala-Gly-Gly-Asp(OBzl)-OTce (3) was used. The key fragment 2 has the promoiety inserted between the Ala and the Trp residues. Fragment 3 was synthesized by a solution-phase approach using standard Boc-amino acid chemistry. These fragments were coupled to produce the protected linear hexapeptide, which after deprotection was cyclized using standard high-dilution techniques to yield cyclic prodrug 1. In pH 7.4 buffer (HBSS) at 37 degrees C, cyclic prodrug 1 was shown to degrade quantitatively to the hexapeptide (t(1/2) = 206 +/- 11 min). The rate of hydrolysis of cyclic prodrug 1 was significantly faster in human blood (t(1/2) = 132 +/- 4 min) than in HBSS. Paraoxon, a known inhibitor of esterases, slowed this hydrolysis of cyclic prodrug 1 to a value (t(1/2) = 198 +/- 9 min) comparable to the chemical stability. In human blood, cyclic prodrug 1 was shown to be 25-fold more stable than the linear hexapeptide.

  DOI：

  10.1021/jo961696a
• 作为产物：
  描述：

  叔丁氧羰基-丙氨酰-甘氨酸 在 palladium on activated charcoal N-甲基吗啉 、 氢气 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 50.0h， 生成 (-)-2-(S)-[N-(2-tert-butoxycarbonylaminopropionylamino)acetylamino]acetic acid
  参考文献：
  名称：

  Synthesis of a Novel Esterase-Sensitive Cyclic Prodrug of a Hexapeptide Using an (Acyloxy)alkoxy Promoiety

  摘要：

  Synthetic methodology for preparing novel esterase-sensitive cyclic prodrugs of peptides with increased protease stability and cell membrane permeability compared to linear peptides is described. Cyclic prodrug 1 of the hexapeptide H-Trp-Ala-Gly-Gly-Asp-Ala-OH linked by the N-terminal amino group to the C-terminal carboxyl group via an (acyloxy)alkoxy promoiety was synthesized. A convergent synthetic approach involving Boc[[(alaninyloxy)methyl]carbonyl]-N-tryptophan (2) and H-Ala-Gly-Gly-Asp(OBzl)-OTce (3) was used. The key fragment 2 has the promoiety inserted between the Ala and the Trp residues. Fragment 3 was synthesized by a solution-phase approach using standard Boc-amino acid chemistry. These fragments were coupled to produce the protected linear hexapeptide, which after deprotection was cyclized using standard high-dilution techniques to yield cyclic prodrug 1. In pH 7.4 buffer (HBSS) at 37 degrees C, cyclic prodrug 1 was shown to degrade quantitatively to the hexapeptide (t(1/2) = 206 +/- 11 min). The rate of hydrolysis of cyclic prodrug 1 was significantly faster in human blood (t(1/2) = 132 +/- 4 min) than in HBSS. Paraoxon, a known inhibitor of esterases, slowed this hydrolysis of cyclic prodrug 1 to a value (t(1/2) = 198 +/- 9 min) comparable to the chemical stability. In human blood, cyclic prodrug 1 was shown to be 25-fold more stable than the linear hexapeptide.

  DOI：

  10.1021/jo961696a

文献信息

• Photoinduced Decarboxylative Radical Addition Reactions for Late Stage Functionalization of Peptide Substrates
  作者：Patricia Fernandez‐Rodriguez、Fabien Legros、Thomas Maier、Angelika Weber、María Méndez、Volker Derdau、Gerhard Hessler、Michael Kurz、Ana Villar‐Garea、Sven Ruf

  DOI：10.1002/ejoc.202001178

  日期：2021.2.5

  In our contribution we showcase an application of photochemistry for Late Stage Functionalization (LSF) of amino acids and small peptides in an industrial medicinal chemistry environment. The radical intermediates generated under photochemical conditions from the C‐terminal carboxylates undergo rapid 1,4‐conjugate additions to a variety of Michael acceptors. The studied methodology is applicable to

  在我们的贡献中，我们展示了在工业药物化学环境中光化学在氨基酸和小肽的后期功能化（LSF）中的应用。在光化学条件下，由C末端羧酸盐生成的自由基中间体会快速与各种Michael受体进行1,4-共轭加成。研究的方法学适用于已建立的药物和药物前体的功能化。
• Synthesis of optically active oxazoles from phosphorylated 2H-azirines and N-protected amino acids or peptides
  作者：Francisco Palacios、Ana Marı́a Ochoa de Retana、José Ignacio Gil、José Marı́a Alonso

  DOI：10.1016/s0957-4166(02)00686-9

  日期：2002.11

  triphenylphosphine and hexachloroethane in the presence of triethylamine leads to the formation of racemic and optically active phosphorylated oxazoles containing N-protected amino acid residues 8 and 10. Deprotection of these oxazoles gives aminoalkyl oxazoles 11 and 12. 2H-Azirines 1 and 6 also react with N-protected peptides 13 and give functionalized ketamides 14 and 15, ring closure of which leads to the formation

  光学活性的磷酸化的恶唑的简单合成8，10，11，和12含有2个氨基酸残基ħ -azirine-氧化膦1或-phosphonates 6进行说明。衍生自氧化膦1和膦酸酯6的2个H-叠氮基与N保护的氨基酸2的开环反应，得到官能化的磷酸化酮酰胺3和7。酮酰胺3和7的环化在三乙胺存在下与三苯膦和六氯乙烷反应会导致形成外消旋和旋光的磷酸化恶唑，其中含有N保护的氨基酸残基8和10。这些恶唑的脱保护得到氨基烷基恶唑11和12。2 H-嗪1和6也与N-保护的肽13反应并生成官能化的酮酰胺14和15，其闭环导致形成含有肽残基16和17的磷酸化恶唑。
• Cyclic prodrugs of peptides and peptide nucleic acids having improved
  申请人：The University of Kansas

  公开号：US05672584A1

  公开（公告）日：1997-09-30

  Provided are cyclic prodrugs of biologically active peptides and peptide nucleic acids exhibiting improved cell membrane permeability and enzymatic stability, containing 3-(2'-hydroxy-4',6'-dimethyl phenyl)-3,3-dimethyl propionic acid and its deriveatives and acyloxyalkoxy linkers. Also provided are pharmaceutical compositions containing effective amounts of these cyclic prodrugs in combination with pharmaceutically acceptable carriers, excipients, or diluents.

  提供了具有改善细胞膜渗透性和酶稳定性的生物活性肽和肽核酸的环状前药，包含3-（2'-羟基-4'，6'-二甲基苯基）-3,3-二甲基丙酸及其衍生物和酰氧基烷氧基连接剂。还提供了含有这些环状前药的有效量的制药组合物，其中包含药用可接受载体，辅料或稀释剂。
• Synthesis of a Novel Esterase-Sensitive Cyclic Prodrug System for Peptides That Utilizes a “Trimethyl Lock”-Facilitated Lactonization Reaction
  作者：Binghe Wang、Sanjeev Gangwar、Giovanni M. Pauletti、Teruna J. Siahaan、Ronald T. Borchardt

  DOI：10.1021/jo961778z

  日期：1997.3.1

  This paper describes a unique strategy for preparing cyclic prodrugs of peptides that have increased metabolic stability and increased cell membrane permeability when compared to the linear peptides. By taking advantage of a unique ''trimethyl lock''-facilitated lactonization system, an esterase-sensitive cyclic prodrug of a model hexapeptide H-Trp-Ala-Gly-Gly-Asp-Ala-OH was synthesized by linking the N-terminal amino group to the C-terminal carboxyl group. The key intermediate for both approaches was compound 9 with Boc-Ala attached to the phenol hydroxyl group of the ''trimethyl lock'' linker through an ester bond, which can then be incorporated into the peptide using a normal coupling reagent for peptide synthesis. The synthesis of the linear peptides was accomplished using both solution-phase and solid-phase approaches with the solution-phase approach having the advantage of using the key intermediate 9 most efficiently. Cyclization using standard high-dilution techniques provided cyclic prodrug 13. In 90% human plasma, prodrug 13 released the original peptide, as designed, through an apparent esterase-catalyzed hydrolysis of the phenol ester bond.