allyl α-D-glucuronate

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: allyl α-D-glucuronate
• 英文别名: allyl (2S,3S,4S,5R,6S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-carboxylate；prop-2-enyl (2S,3S,4S,5R,6S)-3,4,5,6-tetrahydroxyoxane-2-carboxylate
• 化学式: C₉H₁₄O₇
• 分子量: 234.206
• InChiKey: HYPHSXHTCHCXAT-RLMOJYMMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.4
• 重原子数：
  16
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  116
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  D-葡萄糖醛酸 、 3-溴丙烯 在 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 allyl α-D-glucuronate 、 allyl β-D-glucuronate
  参考文献：
  名称：

  Plasma Stability-Dependent Circulation of Acyl Glucuronide Metabolites in Humans: How Circulating Metabolite Profiles of Muraglitazar and Peliglitazar Can Lead to Misleading Risk Assessment

  摘要：

  Muraglitazar 和 peliglitazar 是两种结构相似的显著不同于一个甲基组的化合物，都是双重的过氧化物增殖物活化受体-α/γ 激活剂。这两种化合物在人体内经过酰基葡萄糖醛酸化被广泛代谢，形成 1-O-β-酰基葡萄糖醛酸（AG）代谢物，作为胆汁中主要的药物相关成分，口服给药后至少占剂量的 15% 到 16%。在体内，peliglitazar AG 是主要的循环代谢物，而 muraglitazar AG 在人体内则是非常微量的循环代谢物。与人类相比，peliglitazar AG 在动物种群中以较低浓度循环。这两种化合物在 UDP-葡萄糖醛酸强化的人肝微粒体培养中具有相似的葡萄糖醛酸化速率，而在人体肝细胞中的代谢速率也相似。Muraglitazar AG 和 peligrositazar AG 经过化学合成，被发现通过氢氧化和 O-去甲基化在 NADPH 强化的人肝微粒体培养中有相似的氧化反应。相比于 muraglitazar AG，peliglitazar AG 在缓冲液、鼠或人类血浆（pH 7.4）的培养中表现出更大的稳定性。与在缓冲液中的培养相比，muraglitazar AG 或 peliglitazar AG 在血浆中的培养中产生了更多的无糖部分而不是酰基迁移产物。这些数据表明，血浆稳定性之间的差异，而不是 muraglitazar AG 或 peliglitazar AG 内在形成、直接排泄或进一步氧化的差异，导致了在人体中观察到的这两种 AG 代谢物循环的差异。这项研究表明，基于血浆中代谢物暴露进行风险评估的困难，因为反应性更强的 muraglitazar AG 不会根据美国食品和药物管理局关于安全性测试中代谢物的最新指导触发关注的阈值，而更稳定的 peliglitazar AG 则会。

  DOI：

  10.1124/dmd.110.035048

文献信息

• Syntheses and Characterization of the Acyl Glucuronide and Hydroxy Metabolites of Diclofenac
  作者：Jane R. Kenny、James L. Maggs、Xiaoli Meng、Deborah Sinnott、Stephen E. Clarke、B. Kevin Park、Andrew V. Stachulski

  DOI：10.1021/jm030891w

  日期：2004.5.1

  quantities of 2-4 are required and their syntheses and characterization are described here. Key steps were a convenient two-step preparation of aniline 5 from phenol, efficient and selective 6-iodination of amide 18, and high-yielding Ullmann couplings to generate diarylamines 11 and 21. The acyl glucuronide 4 was obtained by Mitsunobu reaction of 1 (free acid) with allyl glucuronate 23 followed by Pd(0) deprotection

  在人类中，常用的非甾体类抗炎药双氯芬酸1的代谢主要产生4'-羟基2、5-羟基3和酰基葡糖醛酸4代谢物。所有这三种代谢物都与这种广泛使用的药物相关的罕见特发性不良反应有关。因此，对于1的机械毒理学研究，需要大量的2-4，并在此描述其合成和表征。关键步骤包括从苯酚方便地分两步制备苯胺5，酰胺18进行高效且选择性的6碘化以及高产率的Ullmann偶联以生成二芳基胺11和21.酰基的葡糖醛酸苷4通过1的Mitsunobu反应获得葡萄糖醛酸23烯丙基酯，然后使用Pd（0）脱保护，使用公开程序的修改方法。我们报告了4的全部特征，并注意到该重要的代谢物已首次以纯净和大量提供。我们还报告了合成代谢产物的代谢命运：2和3在大鼠中是葡萄糖醛酸化的，但在体内和通过醌亚胺中间体的酶促合成中，只有3个形成了谷胱甘肽加合物。通过酶促合成获得先前未描述的3的谷胱甘肽加合物。如氰基硼氢化钠捕获所示，化合物4形成了亚胺连接
• Efficient synthesis of 1β-O-acyl glucuronides via selective acylation of allyl or benzyl d-glucuronate
  作者：Elizabeth R. Bowkett、John R. Harding、James L. Maggs、B. Kevin Park、Jennifer A. Perrie、Andrew V. Stachulski

  DOI：10.1016/j.tet.2007.05.050

  日期：2007.8

  Acyl glucuronides are key metabolites for many carboxylic acid-containing drugs, notably those of the non-steroidal anti-inflammatory class. In the processes of drug safety assessment and new drug development, it is essential that acyl glucuronides, if formed in vivo, should be made conveniently available for bioevaluation. We recently showed that selective acylation of allyl glucuronate is a promising method for the synthesis of these metabolites in good yield and with excellent beta-anomeric selectivity. We now give fuller details of the allyl ester method and further report that benzyl glucuronate performs at least equally well in the acylation step, offering the advantage of very mild deprotection by catalytic transfer (or conventional) hydrogenation. Depending on the compatibility of other functional groups, as discussed below, this will be the method of choice for many acyl glucuronide syntheses. The value of the method is demonstrated in particular by the synthesis of several acyl glucuronides that are known metabolites of important drugs. (C) 2007 Elsevier Ltd. All rights reserved.
• A convenient synthesis of β-acyl glucuronides
  作者：Hélène Juteau、Yves Gareau、Marc Labelle

  DOI：10.1016/s0040-4039(97)00135-4

  日期：1997.3

  beta-Acyl glucuronides are readily prepared in two steps from allyl D-glucuronate 1 in 14 to 29% overall yields. (C) 1997 Elsevier Science Ltd.
• Plasma Stability-Dependent Circulation of Acyl Glucuronide Metabolites in Humans: How Circulating Metabolite Profiles of Muraglitazar and Peliglitazar Can Lead to Misleading Risk Assessment
  作者：Donglu Zhang、Nirmala Raghavan、Lifei Wang、Yongjun Xue、Mary Obermeier、Stephanie Chen、Shiwei Tao、Hao Zhang、Peter T. Cheng、Wenying Li、Ragu Ramanathan、Zheng Yang、W. Griffith Humphreys

  DOI：10.1124/dmd.110.035048

  日期：2011.1

  Muraglitazar and peliglitazar, two structural analogs differing by a methyl group, are dual peroxisome proliferator-activated receptor-α/γ activators. Both compounds were extensively metabolized in humans through acyl glucuronidation to form 1- O -β-acyl glucuronide (AG) metabolites as the major drug-related components in bile, representing at least 15 to 16% of the dose after oral administration. Peliglitazar AG was the major circulating metabolite, whereas muraglitazar AG was a very minor circulating metabolite in humans. Peliglitazar AG circulated at lower concentrations in animal species than in humans. Both compounds had a similar glucuronidation rate in UDP-glucuronic acid-fortified human liver microsomal incubations and a similar metabolism rate in human hepatocytes. Muraglitazar AG and peliglitazar AG were chemically synthesized and found to be similarly oxidized through hydroxylation and O -demethylation in NADPH-fortified human liver microsomal incubations. Peliglitazar AG had a greater stability than muraglitazar AG in incubations in buffer, rat, or human plasma (pH 7.4). Incubations of muraglitazar AG or peliglitazar AG in plasma produced more aglycon than acyl migration products compared with incubations in the buffer. These data suggested that the difference in plasma stability, not differences in intrinsic formation, direct excretion, or further oxidation of muraglitazar AG or peliglitazar AG, contributed to the observed difference in the circulation of these AG metabolites in humans. The study demonstrated the difficulty in doing risk assessment based on metabolite exposure in plasma because the more reactive muraglitazar AG would not have triggered a threshold of concern based on the recent U.S. Food and Drug Administration guidance on Metabolites in Safety Testing, whereas the more stable peliglitazar AG would have.

  Muraglitazar 和 peliglitazar 是两种结构相似的显著不同于一个甲基组的化合物，都是双重的过氧化物增殖物活化受体-α/γ 激活剂。这两种化合物在人体内经过酰基葡萄糖醛酸化被广泛代谢，形成 1-O-β-酰基葡萄糖醛酸（AG）代谢物，作为胆汁中主要的药物相关成分，口服给药后至少占剂量的 15% 到 16%。在体内，peliglitazar AG 是主要的循环代谢物，而 muraglitazar AG 在人体内则是非常微量的循环代谢物。与人类相比，peliglitazar AG 在动物种群中以较低浓度循环。这两种化合物在 UDP-葡萄糖醛酸强化的人肝微粒体培养中具有相似的葡萄糖醛酸化速率，而在人体肝细胞中的代谢速率也相似。Muraglitazar AG 和 peligrositazar AG 经过化学合成，被发现通过氢氧化和 O-去甲基化在 NADPH 强化的人肝微粒体培养中有相似的氧化反应。相比于 muraglitazar AG，peliglitazar AG 在缓冲液、鼠或人类血浆（pH 7.4）的培养中表现出更大的稳定性。与在缓冲液中的培养相比，muraglitazar AG 或 peliglitazar AG 在血浆中的培养中产生了更多的无糖部分而不是酰基迁移产物。这些数据表明，血浆稳定性之间的差异，而不是 muraglitazar AG 或 peliglitazar AG 内在形成、直接排泄或进一步氧化的差异，导致了在人体中观察到的这两种 AG 代谢物循环的差异。这项研究表明，基于血浆中代谢物暴露进行风险评估的困难，因为反应性更强的 muraglitazar AG 不会根据美国食品和药物管理局关于安全性测试中代谢物的最新指导触发关注的阈值，而更稳定的 peliglitazar AG 则会。