2-(4-(2,5-dihydroxyphenyl)butanoyl)-5,8-dihydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid | 1326317-26-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: 2-(4-(2,5-dihydroxyphenyl)butanoyl)-5,8-dihydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
• 英文别名: 2-[4-(2,5-dihydroxyphenyl)butanoyl]-5,8-dihydroxy-3,4-dihydro-1H-isoquinoline-3-carboxylic acid
• CAS: 1326317-26-3
• 化学式: C₂₀H₂₁NO₇
• 分子量: 387.389
• InChiKey: PLEDFGWDTQHQGM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  139
• 氢给体数：
  5
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-(4-(2,5-dihydroxyphenyl)butanoyl)-5,8-dihydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 在 三甲基铵三氧化硫共聚物 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 、 水 为溶剂， 反应 5.0h， 生成 sodium 2-(4-(2,5-di-O-sulfonatophenyl)butanoyl)-5,8-di-O-sulfonato-1,2,3,4-tetrahydroisoquinoline-3-carboxylate
  参考文献：
  名称：

  Designing Nonsaccharide, Allosteric Activators of Antithrombin for Accelerated Inhibition of Factor Xa

  摘要：

  Antithrombin is a key regulator of coagulation and prime target of heparins, clinically used anticoagulants. Heparins induce a two-step conformational activation of antithrombin, a process that has remained challenging to target with molecules devoid of the antithrombin-binding pentasaccharide DEFGH. Computational screening of a focused library led to the design of two tetra-sulfated N-arylacyl tetrahydroisoquinoline variants as potential nonsaccharide activators of antithrombin. A high yielding synthetic scheme based on Horner-Wadsworth-Emmons or Pictet-Spengler reactions was developed to facilitate the functionalization of the tetrahydoisoquinoline ring, which upon further amidation, deprotection, and sulfation gave the targeted nonsaccharide activators. Spectrofluorometric measurement of affinity displayed antithrombin binding affinities in the low to high micromolar range at pH 6.0, I 0.05, 25 degrees C. Measurement of second-order rate constants of antithrombin inhibition of factor Xa in the presence and absence of the designed activators showed antithrombin activation in the range of 8-80-fold in the pH 6.0 buffer. This work puts forward 20c, a novel tetra-sulfated N-arylacyl tetrahydroisoquinoline-based molecule, that activates AT only 3.8-fold less than that achieved with DEFGH, suggesting a strong possibility of rationally designing sulfated organic molecules as clinically relevant AT activators.

  DOI：

  10.1021/jm2008387
• 作为产物：
  描述：

  methyl 2,5-dimethoxyphenylalanine 在 4-二甲氨基吡啶 、 三溴化硼 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 5.42h， 生成 2-(4-(2,5-dihydroxyphenyl)butanoyl)-5,8-dihydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
  参考文献：
  名称：

  Designing Nonsaccharide, Allosteric Activators of Antithrombin for Accelerated Inhibition of Factor Xa

  摘要：

  Antithrombin is a key regulator of coagulation and prime target of heparins, clinically used anticoagulants. Heparins induce a two-step conformational activation of antithrombin, a process that has remained challenging to target with molecules devoid of the antithrombin-binding pentasaccharide DEFGH. Computational screening of a focused library led to the design of two tetra-sulfated N-arylacyl tetrahydroisoquinoline variants as potential nonsaccharide activators of antithrombin. A high yielding synthetic scheme based on Horner-Wadsworth-Emmons or Pictet-Spengler reactions was developed to facilitate the functionalization of the tetrahydoisoquinoline ring, which upon further amidation, deprotection, and sulfation gave the targeted nonsaccharide activators. Spectrofluorometric measurement of affinity displayed antithrombin binding affinities in the low to high micromolar range at pH 6.0, I 0.05, 25 degrees C. Measurement of second-order rate constants of antithrombin inhibition of factor Xa in the presence and absence of the designed activators showed antithrombin activation in the range of 8-80-fold in the pH 6.0 buffer. This work puts forward 20c, a novel tetra-sulfated N-arylacyl tetrahydroisoquinoline-based molecule, that activates AT only 3.8-fold less than that achieved with DEFGH, suggesting a strong possibility of rationally designing sulfated organic molecules as clinically relevant AT activators.

  DOI：

  10.1021/jm2008387