Boc-Asp(OBzl)-OTce | 187977-10-2

• 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: Boc-Asp(OBzl)-OTce
• 英文别名: 4-O-benzyl 1-O-(2,2,2-trichloroethyl) (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanedioate
• CAS: 187977-10-2
• 化学式: C₁₈H₂₂Cl₃NO₆
• 分子量: 454.735
• InChiKey: AZFMVAODZMXVCH-ZDUSSCGKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  28
• 可旋转键数：
  11
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  90.9
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  Boc-Asp(OBzl)-OTce 在 N-甲基吗啉 、 ethandithiol 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三氟乙酸 、 锌 、 苯酚 作用下， 以 二氯甲烷 、 溶剂黄146 为溶剂， 反应 116.75h， 生成 (2S)-2-[[2-[[2-[[(2S)-2-[[(2S)-2-[[3-[2-[(2S)-2-aminopropanoyl]oxy-4,6-dimethylphenyl]-3-methylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]propanoyl]amino]acetyl]amino]acetyl]amino]-4-oxo-4-phenylmethoxybutanoic acid
  参考文献：
  名称：

  Synthesis of a Novel Esterase-Sensitive Cyclic Prodrug System for Peptides That Utilizes a “Trimethyl Lock”-Facilitated Lactonization Reaction

  摘要：

  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.

  DOI：

  10.1021/jo961778z
• 作为产物：
  描述：

  2,2,2-三氯乙醇 、 Boc-L-天冬氨酸 4-苄酯 在 4-二甲氨基吡啶 、 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， 以83%的产率得到Boc-Asp(OBzl)-OTce
  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

• 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.
• Synthesis of a Novel Esterase-Sensitive Cyclic Prodrug of a Hexapeptide Using an (Acyloxy)alkoxy Promoiety
  作者：Sanjeev Gangwar、Giovanni M. Pauletti、Teruna J. Siahaan、Valentino J. Stella、Ronald T. Borchardt

  DOI：10.1021/jo961696a

  日期：1997.3.1

  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.