propofol-glucuronide

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: propofol-glucuronide
• 英文别名: propofol O-glucuronide；(2S,3S,4S,5R)-6-[2,6-di(propan-2-yl)phenoxy]-3,4,5-trihydroxyoxane-2-carboxylic acid
• 化学式: C₁₈H₂₆O₇
• 分子量: 354.4
• InChiKey: JZSJIASBMOIIKI-ODEDACCXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  116
• 氢给体数：
  4
• 氢受体数：
  7

ADMET

代谢

(2S,3S,4S,5R)-6-[2,6-二(丙-2-基)苯氧基]-3,4,5-三羟基氧杂环己烷-2-羧酸是丙泊酚的人类已知代谢物。

(2S,3S,4S,5R)-6-[2,6-Di(propan-2-yl)phenoxy]-3,4,5-trihydroxyoxane-2-carboxylic acid is a known human metabolite of propofol.

来源:NORMAN Suspect List Exchange

反应信息

• 作为产物：
  描述：

  丙泊酚 、 UDP-glucuronic acid 在 human UDP-glucuronosyltransferase 1A₉ 、 magnesium chloride 、 alamethicin 、 糖质酸-1,4-内酯 作用下， 生成 propofol-glucuronide
  参考文献：
  名称：

  Accurate Prediction of Glucuronidation of Structurally Diverse Phenolics by Human UGT1A9 Using Combined Experimental and In Silico Approaches

  摘要：

  通过实验使用145种酚类化合物，并通过3D-QSAR方法分析，确定了人UGT1A9的催化选择性。UGT1A9是一种重要的膜结合酶，催化外源性物质的葡糖醛酸化反应。通过动力学分析确定了UGT1A9的催化效率。使用CoMFA和CoMSIA技术分析了定量结构活性关系。通过将葡糖醛酸化位点及其相邻的芳香环重叠，实现了底物结构的最大立体重叠。对于具有多个活性葡糖醛酸化位点的底物，每个位点被视为单独的底物。3D-QSAR分析产生了统计上可靠的模型，具有良好的预测能力（CoMFA：q2=0.548，r2=0.949，r pred 2=0.775；CoMSIA：q2=0.579，r2=0.876，r pred 2=0.700）。通过轮廓系数图阐明了底物中负责选择性差异的结构特征。将轮廓系数图叠加在UGT1A9的同源模型的催化口袋中，能够高度自信地识别UGT1A9的催化口袋。CoMFA/CoMSIA模型可以预测底物的选择性和UGT1A9的体外清除率。我们的发现还提供了理解UGT1A9功能和底物选择性的可能分子基础。

  DOI：

  10.1007/s11095-012-0666-z

文献信息

• Identification of Human UGT2B7 as the Major Isoform Involved in the<i>O</i>-Glucuronidation of Chloramphenicol
  作者：Mei Chen、Barbara LeDuc、Stephen Kerr、David Howe、David A. Williams

  DOI：10.1124/dmd.109.029900

  日期：2010.3

  Chloramphenicol (CP), a broad spectrum antibiotic, is eliminated in humans by glucuronidation. The primary UGT enzymes responsible for CP O -glucuronidation remain unidentified. We have previously identified the 3- O -CP (major) and 1- O -CP (minor) glucuronides by β-glucuronidase hydrolysis, liquid chromatography-tandem mass spectrometry, and 1D/2D H NMR. Reaction phenotyping for the glucuronidation of CP with 12 expressed human liver UGT isoforms has identified UGT2B7 as having the highest activity for 3- O - and 1- O -CP glucuronidation with minor contributions from UGT1A6 and UGT1A9. The kinetics of CP 3- O -glucuronidation by pooled human liver microsomes (HLMs) exhibited biphasic Michaelis-Menten kinetics with the apparent high-affinity K m1 and low-affinity K m2 values of 46.0 and 1027 μM, whereas expressed UGT2B7 exhibited Michaelis-Menten kinetics with the apparent K m value of 109.1 μM. The formation of 1- O -CP glucuronide by pooled HLM and expressed UGT2B7 exhibited substrate inhibition kinetics with apparent K m values of 408.2 and 115.0 μM, respectively. Azidothymidine (AZT) and hyodeoxycholic acid (substrates of UGT2B7) inhibited 3- O - and 1- O -CP glucuronidation in pooled HLMs. In 10 donor HLM preparations, both CP 3- O - and CP 1- O -glucuronidation showed a significant correlation with AZT glucuronidation (UGT2B7) ( r s = 0.85 and r s = 0.83, respectively) at 30 μM CP, whereas no significant correlation was observed between CP 3- O -glucuronidation and serotonin glucuronidation (UGT1A6) or propofol glucuronidation (UGT1A9) at this CP concentration. These results suggest that UGT2B7 is the primary human hepatic UDP-glucuronosyltransferase isoform catalyzing 3- O - and 1- O -CP glucuronidation with minor contributions from UGT1A6 and UGT1A9.

  氯霉素(CP)是一种广谱抗生素,在人体内通过葡糖醛酸化途径被清除。负责CP O-葡糖醛酸化的主要UGT酶仍然未被识别。我们之前通过β-葡糖醛酸苷酶水解、液相色谱-串联质谱和1D/2D 1H NMR鉴定了3-O-CP(主要)和1-O-CP(次要)葡糖醛酸苷。对12种表达的人肝UGT同工酶的CP葡糖醛酸化反应表型进行鉴定,发现UGT2B7对3-O-和1-O-CP葡糖醛酸化活性最高,UGT1A6和UGT1A9有较小贡献。人肝微粒体(HLMs)中CP 3-O-葡糖醛酸化动力学呈双相米氏动力学,高亲和力Km1值和低亲和力Km2值分别为46.0μM和1027μM,而表达的UGT2B7呈现单相米氏动力学,Km值为109.1μM。人肝微粒体和表达的UGT2B7的1-O-CP葡糖醛酸苷形成呈现底物抑制动力学,Km值分别为408.2μM和115.0μM。叠氮胸苷(AZT)和猪胆酸(UGT2B7的底物)抑制了人肝微粒体中的3-O-和1-O-CP葡糖醛酸化。在10个供体的人肝微粒体中,30μM CP时,CP 3-O-和CP 1-O-葡糖醛酸化与AZT葡糖醛酸化(UGT2B7)显著相关(rs=0.85和rs=0.83),而CP 3-O-葡糖醛酸化与5-羟色胺葡糖醛酸化(UGT1A6)或丙泊酚葡糖醛酸化(UGT1A9)在此CP浓度下无显著相关性。这些结果表明,UGT2B7是催化3-O-和1-O-CP葡糖醛酸化的主要人肝UDP-葡糖醛酸基转移酶同工酶,UGT1A6和UGT1A9有较小贡献。
• Validated assay for the evaluation of multiple glucuronidation activities in human liver microsomes via liquid chromatography-tandem mass spectrometry
  作者：Rong Shi、Yuanyuan Yang、Jie Zhong、Tianming Wang、Yueming Ma

  DOI：10.1039/c4ra10687c

  日期：——

  A faster and more accurate LC-MS/MS method was established for the activity determination of multiple UGT isoforms in HLMs.

  在人类肝微粒体中，建立了一种更快、更准确的LC-MS/MS方法，用于确定多种UGT同工酶的活性。
• Yang, Jing; Zhang, Beibei; Qin, Zi Fei, International Journal of Clinical and Experimental Medicine, 2019, vol. 12, # 5, p. 4960 - 4971
  作者：Yang, Jing、Zhang, Beibei、Qin, Zi Fei、Zhang, Xiao Jian

  DOI：——

  日期：——