4-O-benzyl 1-O-(2,2,2-trichloroethyl) (2S)-2-[[2-[[2-[[(2S)-2-[[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino]propanoyl]amino]acetyl]amino]acetyl]amino]butanedioate | 187978-55-8

• 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: 4-O-benzyl 1-O-(2,2,2-trichloroethyl) (2S)-2-[[2-[[2-[[(2S)-2-[[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino]propanoyl]amino]acetyl]amino]acetyl]amino]butanedioate
• CAS: 187978-55-8
• 化学式: C₃₁H₃₅Cl₃N₆O₈
• 分子量: 726.013
• InChiKey: XNEZVWBIQVDEER-OEOAZWSVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  48
• 可旋转键数：
  18
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  211
• 氢给体数：
  6
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  4-O-benzyl 1-O-(2,2,2-trichloroethyl) (2S)-2-[[2-[[2-[[(2S)-2-[[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino]propanoyl]amino]acetyl]amino]acetyl]amino]butanedioate 在 N-甲基吗啉 、 ethandithiol 、 双(2-氧代-3-恶唑烷基)次磷酰氯 、 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 、 N,N-二甲基甲酰胺 为溶剂， 反应 92.0h， 生成 benzyl 2-[(4S,7S,16S,19S)-19-(1H-indol-3-ylmethyl)-4,16,23,23,25,27-hexamethyl-3,6,9,12,15,18,21-heptaoxo-2-oxa-5,8,11,14,17,20-hexazabicyclo[22.4.0]octacosa-1(28),24,26-trien-7-yl]acetate
  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：

  Boc-L-天冬氨酸 4-苄酯 在 N-甲基吗啉 、 4-二甲氨基吡啶 、 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 作用下， 以 二氯甲烷 为溶剂， 反应 82.75h， 生成 4-O-benzyl 1-O-(2,2,2-trichloroethyl) (2S)-2-[[2-[[2-[[(2S)-2-[[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino]propanoyl]amino]acetyl]amino]acetyl]amino]butanedioate
  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

文献信息

• 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.