(S)-2-[2-(2-{(S)-2-[(S)-2-((S)-2-Amino-propionyloxymethoxycarbonylamino)-3-(1H-indol-3-yl)-propionylamino]-propionylamino}-acetylamino)-acetylamino]-succinic acid 4-benzyl ester | 187977-15-7

• 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: (S)-2-[2-(2-{(S)-2-[(S)-2-((S)-2-Amino-propionyloxymethoxycarbonylamino)-3-(1H-indol-3-yl)-propionylamino]-propionylamino}-acetylamino)-acetylamino]-succinic acid 4-benzyl ester
• 英文别名: (2S)-2-[[2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-aminopropanoyl]oxymethoxycarbonylamino]-3-(1H-indol-3-yl)propanoyl]amino]propanoyl]amino]acetyl]amino]acetyl]amino]-4-oxo-4-phenylmethoxybutanoic acid
• CAS: 187977-15-7
• 化学式: C₃₄H₄₁N₇O₁₂
• 分子量: 739.739
• InChiKey: LTFBFNIXHRTOJK-HKDRDPIHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2
• 重原子数：
  53
• 可旋转键数：
  22
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  286
• 氢给体数：
  8
• 氢受体数：
  13

反应信息

• 作为反应物：
  描述：

  (S)-2-[2-(2-{(S)-2-[(S)-2-((S)-2-Amino-propionyloxymethoxycarbonylamino)-3-(1H-indol-3-yl)-propionylamino]-propionylamino}-acetylamino)-acetylamino]-succinic acid 4-benzyl ester 在 N-甲基吗啉 、 4-二甲氨基吡啶 、 双(2-氧代-3-恶唑烷基)次磷酰氯 作用下， 以 二氯甲烷 为溶剂， 反应 72.0h， 以20%的产率得到[(6S,9S,18S,21S)-6-(1H-Indol-3-ylmethyl)-9,21-dimethyl-4,7,10,13,16,19,22-heptaoxo-1,3-dioxa-5,8,11,14,17,20-hexaaza-cyclodocos-18-yl]-acetic acid benzyl ester
  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：

  (2S)-3-(1H-indol-3-yl)-2-[[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]oxymethoxycarbonylamino]propanoic acid 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 58.0h， 生成 (S)-2-[2-(2-{(S)-2-[(S)-2-((S)-2-Amino-propionyloxymethoxycarbonylamino)-3-(1H-indol-3-yl)-propionylamino]-propionylamino}-acetylamino)-acetylamino]-succinic acid 4-benzyl ester
  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

• 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.