2′-(glutathion-S-yl)-deschloro-diclofenac | 1526988-59-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 2′-(glutathion-S-yl)-deschloro-diclofenac
• 英文别名: 2'-(Glutathion-S-yl)-deschloro-diclofenac；(2S)-2-amino-5-[[(2R)-1-(carboxymethylamino)-3-[2-[2-(carboxymethyl)anilino]-3-chlorophenyl]sulfanyl-1-oxopropan-2-yl]amino]-5-oxopentanoic acid
• CAS: 1526988-59-9
• 化学式: C₂₄H₂₇ClN₄O₈S
• 分子量: 567.019
• InChiKey: WVIHJYXEEMZIDD-RDJZCZTQSA-N

物化性质

• 沸点：
  904.6±65.0 °C(Predicted)
• 密度：
  1.52±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.68
• 重原子数：
  38.0
• 可旋转键数：
  15.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  208.15
• 氢给体数：
  7.0
• 氢受体数：
  8.0

反应信息

• 作为产物：
  描述：

  谷胱甘肽 、 双氯芬酸 在 glucose-6-phosphate dehydrogenase 、 glucose-6-phosphate 、 cytochrome P₄₅₀ 2C₉ co-expressed with human P₄₅₀ oxidoreductase and cytochrome b5 、 human glutathione-S-transferase P₁-1 作用下， 以 aq. phosphate buffer 、 二甲基亚砜 为溶剂， 反应 1.0h， 生成 2′-(glutathion-S-yl)-deschloro-diclofenac
  参考文献：
  名称：

  One-electron oxidation of diclofenac by human cytochrome P450s as a potential bioactivation mechanism for formation of 2′-(glutathion-S-yl)-deschloro-diclofenac

  摘要：

  Reactive metabolites have been suggested to play a role in the idiosyncratic hepatotoxicity observed with diclofenac (DF). By structural identification of the GSH conjugates formed after P450-catalyzed bioactivation of DF, it was shown that three types of reactive intermediates were formed: p-benzoquinone imines,o-imine methide and arene-oxide. Recently, detection of 2'-(glutathion-S-yl)-deschloro-diclofenac (DDF-SG), resulting from chlorine substitution, suggested the existence of a fourth type of P450-dependent reactive intermediate whose inactivation by GSH is completely dependent on presence of glutathione S-transferase. In this study, fourteen recombinant cytochrome P450s and three fiavin-containing monooxygenases were tested for their ability to produce oxidative DF metabolites and their corresponding GSH conjugates. Concerning the hydroxymetabolites and their GSH conjugates, results were consistent with previous studies. Unexpectedly, all tested recombinant P450s were able to form DDF-SG to almost similar extent. DDF-SG formation was found to be partially independent of NADPH and even occurred by heat-inactivated P450. However, product formation was fully dependent on both GSH and glutathione-S-transferase P1-1. DDF-SG formation was also observed in reactions with horseradish peroxidase in absence of hydrogen peroxide. Because DDF-SG was not formed by free iron, it appears that DF can be bioactivated by iron in hemeproteins. This was confirmed by DDF-SG formation by other hemeproteins such as hemoglobin. As a mechanism, we propose that DF is subject to heme-dependent one-electron oxidation. The resulting nitrogen radical cation, which might activate the chlorines of DF, then undergoes a GST-catalyzed nucleophilic aromatic substitution reaction in which the chlorine atom of the DF moiety is replaced by GSH. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

  DOI：

  10.1016/j.cbi.2013.11.001