(S)-7-hydroxywarfarin

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 高异黄酮
• 英文名称: (S)-7-hydroxywarfarin
• 英文别名: 2,7-dihydroxy-3-[(1S)-3-oxo-1-phenylbutyl]chromen-4-one
• 化学式: C₁₉H₁₆O₅
• 分子量: 324.333
• InChiKey: BQSUFDMOXLLKQK-HNNXBMFYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  83.8
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  rac-7-hydroxywarfarin 在 chirobiotic V chiral liquid chromatography column 作用下， 以 乙醇 为溶剂， 以1 mg的产率得到(R)-7-hydroxywarfarin
  参考文献：
  名称：

  Analysis of R- and S-Hydroxywarfarin Glucuronidation Catalyzed by Human Liver Microsomes and Recombinant UDP-Glucuronosyltransferases

  摘要：

  Coumadin ( R -, S -warfarin) is a challenging drug to accurately dose, both initially and for maintenance, because of its narrow therapeutic range and wide interpatient variability and is typically administered as a racemic (Rac) mixture, which complicates the biotransformation pathways. The goal of the current work was to identify the human UDP-glucuronosyltransferases (UGTs) involved in the glucuronidation of the separated R - and S -enantiomers of 6-, 7-, and 8-hydroxywarfarin and the possible interactions between these enantiomers. The kinetic and inhibition constants for human recombinant 1A family UGTs toward these separated enantiomers have been assessed using high-performance liquid chromatography (HPLC)-UV-visible analysis, and product confirmations have been made using HPLC-mass spectrometry/mass spectrometry. We found that separated R - and S -enantiomers of 6-, 7-, and 8-hydroxywarfarin demonstrate significantly different glucuronidation kinetics and can be mutually inhibitory. In some cases significant substrate inhibition was observed, as shown by K m, V max, and K i, comparisons. In particular, UGT1A1 and extrahepatic UGT1A10 have significantly higher capacities than other isoforms for S -7-hydroxywarfarin and R -7-hydroxywarfarin glucuronidation, respectively. Activity data generated using a set of well characterized human liver microsomes supported the recombinant enzyme data, suggesting an important (although not exclusive) role for UGT1A1 in glucuronidation of the main warfarin metabolites, including Rac-6- and 7-hydroxywarfarin and their R - and S -enantiomers in the liver. This is the first demonstration that the R - and S -enantiomers of hydroxywarfarins are glucuronidated, with significantly different enzymatic affinity and capacity, and supports the importance of UGT1A1 as the major hepatic isoform involved.

  DOI：

  10.1124/jpet.111.184721