7-(deoxyadenosine-N⁶-yl)aristolactam I

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 英文名称: 7-(deoxyadenosine-N⁶-yl)aristolactam I
• 英文别名: 12-[[9-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-6-yl]amino]-14-methoxy-3,5-dioxa-10-azapentacyclo[9.7.1.02,6.08,19.013,18]nonadeca-1(19),2(6),7,11,13(18),14,16-heptaen-9-one
• 化学式: C₂₇H₂₂N₆O₇
• 分子量: 542.508
• InChiKey: XHHBEDPFSNICRL-IAOVAPTHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.24
• 重原子数：
  40.0
• 可旋转键数：
  4.0
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  165.34
• 氢给体数：
  4.0
• 氢受体数：
  11.0

反应信息

• 作为产物：
  描述：

  马兜铃酸 、 2'-脱氧腺苷 在 盐酸 、 锌 作用下， 以 水 、 N,N-二甲基甲酰胺 、 aq. phosphate buffer 为溶剂， 反应 16.25h， 生成 7-(deoxyadenosine-N⁶-yl)aristolactam I
  参考文献：
  名称：

  Comparison of Aristolochic acid I derived DNA adduct levels in human renal toxicity models

  摘要：

  Aristolochic acid (AA) dependent human nephropathy results either from environmental exposure to Aristolochiaceae plant subspecies or their use in traditional phytotherapy. The toxic components are structurally related nitrophenanthrene carboxylic acids, i.e. Aristolochic acid I (AAI) and II (AAII). AAI is considered to be the major cause of Aristolochic acid nephropathy, characterized by severe renal fibrosis and upper urothelial cancer. Following enzymatic activation in kidney and/or liver, AAI metabolites react with genomic DNA to form persistent DNA adducts with purines. To determine whether AAI can be activated in human renal cells to form DNA adducts, we exposed telomerase immortalized renal proximal tubular epithelial cells (RPTEC/TERT1), the human embryonic kidney (HEK293) cell line, as well as primary human kidney cells (pHKC) to AAI in vitro. We modified an isotope dilution ultra-performance liquid chromatography/tandem mass spectrometry (ID-UPLCMS/MS) based method for the quantification of dA-AAI adducts in genomic DNA. In addition, time dependent accumulation of adducts in renal cortex and bladder tissue from AAI/II treated Eker rats were used to validate the detection method. AAI-induced toxicity in human renal cells was determined by dA-AAI adduct quantification, the impact on cell viability, and NQO1 expression and activity. Our findings demonstrated adduct formation in all cell lines, although only pHKC and RPTEC/TERT1 expressed NQO1. The highest adduct formation was detected in pHKC despite low NQO1 expression, while we observed much lower.adduct levels in NQO1-negative HEK293 cells. Adduct formation and decreased cell viability correlated only weakly. Therefore, our data suggested that enzymes other than i.) NQO1 could be at least equally important for AA bioactivation in human renal proximal tubule cells, and ii.) the suggested correlation between adduct levels and viability appears to be questionable.

  DOI：

  10.1016/j.tox.2019.03.013

文献信息

• Comparison of Aristolochic acid I derived DNA adduct levels in human renal toxicity models
  作者：Heinke Bastek、Tabea Zubel、Kerstin Stemmer、Aswin Mangerich、Sascha Beneke、Daniel R. Dietrich

  DOI：10.1016/j.tox.2019.03.013

  日期：2019.5

  Aristolochic acid (AA) dependent human nephropathy results either from environmental exposure to Aristolochiaceae plant subspecies or their use in traditional phytotherapy. The toxic components are structurally related nitrophenanthrene carboxylic acids, i.e. Aristolochic acid I (AAI) and II (AAII). AAI is considered to be the major cause of Aristolochic acid nephropathy, characterized by severe renal fibrosis and upper urothelial cancer. Following enzymatic activation in kidney and/or liver, AAI metabolites react with genomic DNA to form persistent DNA adducts with purines. To determine whether AAI can be activated in human renal cells to form DNA adducts, we exposed telomerase immortalized renal proximal tubular epithelial cells (RPTEC/TERT1), the human embryonic kidney (HEK293) cell line, as well as primary human kidney cells (pHKC) to AAI in vitro. We modified an isotope dilution ultra-performance liquid chromatography/tandem mass spectrometry (ID-UPLCMS/MS) based method for the quantification of dA-AAI adducts in genomic DNA. In addition, time dependent accumulation of adducts in renal cortex and bladder tissue from AAI/II treated Eker rats were used to validate the detection method. AAI-induced toxicity in human renal cells was determined by dA-AAI adduct quantification, the impact on cell viability, and NQO1 expression and activity. Our findings demonstrated adduct formation in all cell lines, although only pHKC and RPTEC/TERT1 expressed NQO1. The highest adduct formation was detected in pHKC despite low NQO1 expression, while we observed much lower.adduct levels in NQO1-negative HEK293 cells. Adduct formation and decreased cell viability correlated only weakly. Therefore, our data suggested that enzymes other than i.) NQO1 could be at least equally important for AA bioactivation in human renal proximal tubule cells, and ii.) the suggested correlation between adduct levels and viability appears to be questionable.