β-glucuronide of α-dihydroartemisinin

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: β-glucuronide of α-dihydroartemisinin
• 英文别名: α-dihydroartemisinin β-glucuronide；1-(dihydroartemisinin-12α-yl)-β-D-glucopyranuronic acid；dihydroartemisinin glucuronide；(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-[[(1R,4S,5R,8S,9R,10R,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.04,13.08,13]hexadecan-10-yl]oxy]oxane-2-carboxylic acid
• 化学式: C₂₁H₃₂O₁₁
• 分子量: 460.478
• InChiKey: ZPXMEOGHWWIMAF-UTDJYNOXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  32
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.95
• 拓扑面积：
  153
• 氢给体数：
  4
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  β-glucuronide of α-dihydroartemisinin 在 Escherichia coli β-glucuronidase IX-A 作用下， 反应 2.0h， 生成 双氢青蒿素
  参考文献：
  名称：

  Development and validation of a liquid chromatography and ion spray tandem mass spectrometry method for the quantification of artesunate, artemether and their major metabolites dihydroartemisinin and dihydroartemisinin-glucuronide in sheep plasma

  摘要：

  最近，在大鼠和绵羊身上发现了青蒿琥酯和蒿甲醚具有良好的杀筋膜活性。因此，本研究开发了一种液相色谱-串联质谱（LC-MS/MS）方法，用于定量检测绵羊血浆中的青蒿琥酯、蒿甲醚及其代谢产物双氢青蒿素和双氢青蒿素-葡萄糖醛酸苷。样品处理采用甲醇沉淀蛋白法。使用 Atlantis C18 分析柱和甲酸铵-乙腈流动相梯度系统进行反相高效液相色谱分析。采用选择反应监测（SRM）和电喷雾离子化正离子模式（跃迁 m/z 267.4 → 163.0），对分析物进行 MS/MS 检测。双氢青蒿素、双氢青蒿素-葡萄糖醛酸和青蒿琥酯的分析范围为 10-1000 纳克/毫升，蒿甲醚为 90-3000 纳克/毫升，定量下限分别为 10 和 90 纳克/毫升。日间和日内的准确度和精密度偏差均小于 10%。在调查的校准范围内，所有分析物的相对回收率一致（60-80%）。所有分析物在自动进样器中至少稳定 30 小时（6 °C），并经过三次冻融循环。验证结果表明，LC-MS/MS方法精确、准确、选择性好，可用于绵羊血浆中青蒿素类药物的检测。该方法成功地应用于肌肉注射绵羊血浆中青蒿琥酯及其代谢物的药代动力学参数的测定。Copyright © 2011 John Wiley & Sons, Ltd. All Rights Reserved.

  DOI：

  10.1002/jms.1883
• 作为产物：
  描述：

  dihydroartemisinin 在 氢氧化钾 、 溶剂黄146 、 silver carbonate 作用下， 以 甲醇 、 苯 为溶剂， 反应 98.5h， 生成 β-glucuronide of α-dihydroartemisinin
  参考文献：
  名称：

  蒿乙醚羟基化代谢物葡糖苷酸的合成、表征和抗疟活性。

  摘要：

  在保留其内过氧化物部分的大鼠肝微粒体中，β-蒿甲醚 (1) 的羟基化代谢物 (log P 2.6-2.7) 显示出与母体药物蒿甲醚相当的体外抗疟活性 (log P = 3.89)。寻找更适合静脉内使用的青蒿素类似物 (7) 导致合成了蒿乙醚 I 相羟基化代谢物的葡糖苷酸结合物，发现其具有良好的水溶性，但仍保持适度的亲脂性（log P = 0.6-1.8 ）。虽然在葡萄糖醛酸苷、I 相代谢物和母体化合物的 log P 值之间观察到很强的相关性，但发现 9 β-羟基蒿甲醚葡萄糖醛酸苷 (26) 是最活跃和极性最强的 (log P = 0.61)的葡萄糖醛酸。而体外抗疟活性为 26 (IC50 = 89.

  DOI：

  10.1021/jm00011a011

文献信息

• Synthesis, Characterization, and Antimalarial Activity of the Glucuronides of the Hydroxylated Metabolites of Arteether
  作者：Kumar Ramu、John K. Baker

  DOI：10.1021/jm00011a011

  日期：1995.5

  The hydroxylated metabolites (log P 2.6-2.7) of beta-arteether (1) in rat liver microsomes that retain their endoperoxide moiety showed comparable in vitro antimalarial activity to that of the parent drug arteether (log P = 3.89). The search for analogs of artemisinin (7) more suitable for intravenous use led to the synthesis of the glucuronide conjugates of the phase I hydroxylated metabolites of arteether

  在保留其内过氧化物部分的大鼠肝微粒体中，β-蒿甲醚 (1) 的羟基化代谢物 (log P 2.6-2.7) 显示出与母体药物蒿甲醚相当的体外抗疟活性 (log P = 3.89)。寻找更适合静脉内使用的青蒿素类似物 (7) 导致合成了蒿乙醚 I 相羟基化代谢物的葡糖苷酸结合物，发现其具有良好的水溶性，但仍保持适度的亲脂性（log P = 0.6-1.8 ）。虽然在葡萄糖醛酸苷、I 相代谢物和母体化合物的 log P 值之间观察到很强的相关性，但发现 9 β-羟基蒿甲醚葡萄糖醛酸苷 (26) 是最活跃和极性最强的 (log P = 0.61)的葡萄糖醛酸。而体外抗疟活性为 26 (IC50 = 89.
• Efficient Preparations of the β-Glucuronides of Dihydroartemisinin and Structural Confirmation of the Human Glucuronide Metabolite
  作者：Paul M. O'Neill、Feodor Scheinmann、Andrew V. Stachulski、James L. Maggs、B. Kevin Park

  DOI：10.1021/jm001061a

  日期：2001.4.1

  New and greatly improved preparations of the 12 alpha ,1 ' beta- (5) and 12 beta ,1 ' beta- (6) glucuronides of dihydroartemisinin (DHA, 2) are reported using anomeric hydroxy and imidate glucuronate intermediates. Comparison of the synthetic and natural materials shows that the human metabolite of DHA is the 12 alpha -epimer 5.
• Development and validation of a liquid chromatography and ion spray tandem mass spectrometry method for the quantification of artesunate, artemether and their major metabolites dihydroartemisinin and dihydroartemisinin-glucuronide in sheep plasma
  作者：Urs Duthaler、Jennifer Keiser、Jörg Huwyler

  DOI：10.1002/jms.1883

  日期：2011.2

  Recently, promising fasciocidal activities of artesunate and artemether were described in rats and sheep. Therefore, a liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed to quantify artesunate, artemether and their metabolites dihydroartemisinin and dihydroartemisinin-glucuronide in sheep plasma. Protein precipitation with methanol was used for sample workup. Reversed-phase high-performance liquid chromatography (HPLC) was performed using an Atlantis C18 analytical column with a mobile phase gradient system of ammonium formate and acetonitrile. The analytes were detected by MS/MS using selected reaction monitoring (SRM) with electrospray ionisation in the positive mode (transition m/z 267.4 → 163.0). The analytical range for dihydroartemisinin, dihydroartemisinin-glucuronide and artesunate was 10–1000 ng/ml and for artemether 90–3000 ng/ml with a lower limit of quantification of 10 and 90 ng/ml, respectively. Inter- and intra-day accuracy and precision deviations were < 10%. Consistent relative recoveries (60–80%) were observed over the investigated calibration range for all analytes. All analytes were stable in the autosampler for at least 30 h (6 °C) and after three freeze and thaw cycles. The validation results demonstrated that the LC–MS/MS method is precise, accurate and selective and can be used for the determination of the artemisinins in sheep plasma. The method was applied successfully to determine the pharmacokinetic parameters of artesunate and its metabolites in plasma of intramuscularly treated sheep. Copyright © 2011 John Wiley & Sons, Ltd.

  最近，在大鼠和绵羊身上发现了青蒿琥酯和蒿甲醚具有良好的杀筋膜活性。因此，本研究开发了一种液相色谱-串联质谱（LC-MS/MS）方法，用于定量检测绵羊血浆中的青蒿琥酯、蒿甲醚及其代谢产物双氢青蒿素和双氢青蒿素-葡萄糖醛酸苷。样品处理采用甲醇沉淀蛋白法。使用 Atlantis C18 分析柱和甲酸铵-乙腈流动相梯度系统进行反相高效液相色谱分析。采用选择反应监测（SRM）和电喷雾离子化正离子模式（跃迁 m/z 267.4 → 163.0），对分析物进行 MS/MS 检测。双氢青蒿素、双氢青蒿素-葡萄糖醛酸和青蒿琥酯的分析范围为 10-1000 纳克/毫升，蒿甲醚为 90-3000 纳克/毫升，定量下限分别为 10 和 90 纳克/毫升。日间和日内的准确度和精密度偏差均小于 10%。在调查的校准范围内，所有分析物的相对回收率一致（60-80%）。所有分析物在自动进样器中至少稳定 30 小时（6 °C），并经过三次冻融循环。验证结果表明，LC-MS/MS方法精确、准确、选择性好，可用于绵羊血浆中青蒿素类药物的检测。该方法成功地应用于肌肉注射绵羊血浆中青蒿琥酯及其代谢物的药代动力学参数的测定。Copyright © 2011 John Wiley & Sons, Ltd. All Rights Reserved.