3-[2-(N-Boc-L-alanyloxy)-4,6-dimethylphenyl]-3,3-dimethylpropionic acid | 187978-51-4

• 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: 3-[2-(N-Boc-L-alanyloxy)-4,6-dimethylphenyl]-3,3-dimethylpropionic acid
• 英文别名: 3-[2,4-dimethyl-6-[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]oxyphenyl]-3-methylbutanoic acid
• CAS: 187978-51-4
• 化学式: C₂₁H₃₁NO₆
• 分子量: 393.48
• InChiKey: HNJZLYRKYSTHAA-AWEZNQCLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  28
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  102
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-[2-(N-Boc-L-alanyloxy)-4,6-dimethylphenyl]-3,3-dimethylpropionic acid 在 palladium on activated charcoal N-甲基吗啉 、 ethandithiol 、 氢气 、 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 乙醇 、 二氯甲烷 、 溶剂黄146 、 N,N-二甲基甲酰胺 为溶剂， 反应 114.0h， 生成 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]acetic 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：

  N-叔丁氧羰基-L-丙氨酸 4-硝基苯酯 在 4-二甲氨基吡啶 、 potassium permanganate 、 水 、 溶剂黄146 、 pyridinium chlorochromate 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 丙酮 为溶剂， 反应 33.0h， 生成 3-[2-(N-Boc-L-alanyloxy)-4,6-dimethylphenyl]-3,3-dimethylpropionic 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

文献信息

• Drug Delivery Systems Based on Trimethyl Lock Lactonization:  Poly(ethylene glycol) Prodrugs of Amino-Containing Compounds
  作者：Richard B. Greenwald、Yun H. Choe、Charles D. Conover、Kwok Shum、Dechun Wu、Maksim Royzen

  DOI：10.1021/jm990498j

  日期：2000.2.1

  ranges of drug concentration in plasma. In vivo screening of PEG prodrugs was done using a M109 syngeneic solid mouse tumor model. One of the PEG-daunorubicin prodrugs, with a half-life of 2 h, was evaluated in an in vivo solid tumor panel and found to be more efficacious against ovarian tumors (SKOV3) than equivalent amounts of daunorubicin.

  基于三甲基锁内酯化反应，已经开发了一种合成含氨基化合物的聚乙二醇（PEG）前药的新方法。这些PEG修饰的双前体药物是水溶性的，通过选择性修饰修饰剂或引发剂，可以随意调节血浆半衰期，以产生宽范围的数值。实现了酯，碳酸酯和氨基甲酸酯官能团的简便合成，并将其与间隔基或芳香族骨架中的空间位阻或多或少地结合在一起，以实现血浆中药物浓度的可预测范围。使用M109同系实体小鼠肿瘤模型对PEG前药进行体内筛选。一种PEG-柔红霉素前药，半衰期为2小时，
• Coumarin Derivatives as Protease-Sensitive Prodrugs
  作者：Karin Achilles

  DOI：10.1002/1521-4184(200106)334:6<209::aid-ardp209>3.0.co;2-y

  日期：2001.6

  To overcome the lack of selectivity of anticancer drugs toward malignant cells, the development of prodrugs, which could be activated selectively by tumour-specific proteases is the goal of these studies. In this work tripartate prodrugs have been evaluated consisting of a carrier unit and a spacer group, which allows for intramolecular cyclisation while releasing the third component, the compound attached to the carboxylic acid moiety of the spacer group. As carrier units amino acids or peptides have been used, which are required for recognition by the protease. As the spacer unit the "trimethyl-lock"-spacer has been applied; as a model leaving group p-anisidine was attached to the carboxylic acid moiety. It was intended to test the compounds for their releasing rate of p-anisidine. Two of the evaluated compounds, 9b and 9h, were degraded with half-lives of 46 min at room temperature. However, the poor solubility in aqueous solutions proved the major disadvantage of the TML-based prodrugs.
• 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.