O⁶-[4-hydroxy-4-(3-pyridyl)butyl]guanine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: O⁶-[4-hydroxy-4-(3-pyridyl)butyl]guanine
• 英文别名: O⁶-[1-hydroxy-1-(3-pyridyl)but-4-yl]guanine；4-[(2-amino-7H-purin-6-yl)oxy]-1-pyridin-3-ylbutan-1-ol
• 化学式: C₁₄H₁₆N₆O₂
• 分子量: 300.32
• InChiKey: YFCJGMCAMDVNHQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  22
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  123
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  O⁶-[1-oxo-1-(3-pyridyl)but-4-yl]-2'deoxyguanosine 在 sodium tetrahydroborate 作用下， 以 盐酸 、 甲醇 、 acetate buffer 为溶剂， 反应 3.5h， 生成 O⁶-[4-hydroxy-4-(3-pyridyl)butyl]guanine
  参考文献：
  名称：

  Identification of Adducts Produced by the Reaction of 4-(Acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanol with Deoxyguanosine and DNA

  摘要：

  4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is a metabolite of the tobacco specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). NNAL is present in the blood and urine of people exposed to tobacco products and has carcinogenic activity in rodents similar to that of NNK. DNA adducts specific to NNAL have not been previously identified. Metabolic activation of NNAL by a-methyl hydroxylation, a pathway known to occur in rodent and human microsomes, would produce pyridylhydroxybutylating agents that could react with DNA. We investigated this possibility in the present study by allowing 4-(acetoxymethylnitrosamino)1-(3-pyridyl)-1-butanone (NNALCH(2)OAc) to react with dGuo and DNA. Products were identified by HPLC with UV detection, liquid chromatography/electrospray ionization-mass spectrometry (LC/ESI-MS) and LC/ESI-tandem mass spectrometry (LC/ESI-MS/MS). In the dGuo reactions, selected ion monitoring for m/z 417, corresponding to pyridylhydroxybutylated dGuo, showed several peaks. One adduct was identified as 7-[1-hydroxy-1-(3-pyridyl)but-4-yl]dGuo (21) by neutral thermal hydrolysis, which converted it to 7-[1-hydroxy-1-(3-pyridyl)but-4-yl]Gua (22) and 4-hydroxy-1-(3-pyridyl)-1-butanol (16). Adduct 22 was identified by comparison of its LC/ESI-MS and LC/ESI-MS/MS properties to those of standard 22. Two other adducts, O-6-[1-hydroxy-1-(3-pyridyl)but-4-yl]dGuo (17) and N-2-[1-hydroxy-1-(3-pyridyl)but-4-yl]dGuo (19), were identified by comparison of their LC/ESI-MS and LC/ESI-MS/MS properties to those of standard 17 and 19. Further evidence for the identity of 17 and 19 was obtained by mild acid hydrolysis, which converted them to the corresponding Gua bases 18 and 20, identified by comparison to synthetic standards. Neutral thermal hydrolysis of DNA that had been reacted with NNALCH2OAc produced 22, identified by comparison to a standard. Adducts 17 and 19 were identified in enzyme hydrolysates of this DNA by comparison to standards. Thus, DNA that had been allowed to react with NNALCH(2)OAc contained adducts 17, 19, and 21. The results of this study provide markers for investigating the role of specific NNAL-DNA adducts in carcinogenesis by NNAL and NNK.

  DOI：

  10.1021/tx0256376

文献信息

• The Pyridyloxobutyl DNA Adduct, <i>O⁶</i><i>-</i>[4-Oxo-4-(3-pyridyl)butyl]guanine, Is Detected in Tissues from 4-(Methylnitrosamino)- 1-(3-pyridyl)-1-butanone-treated A/J Mice
  作者：Nicole M. Thomson、Patrick M. Kenney、Lisa A. Peterson

  DOI：10.1021/tx025585k

  日期：2003.1.1

  4-hydroxy-1-(3-pyridyl)-1-butanone (HPB). One of the HPB-releasing adducts,O6-[4-oxo-4-(3-pyridyl)butyl]guanine (O6-pobG), has been detected in DNA reacted in vitro with the model pyridyloxobutylating agent, 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKOAc). To determine whether this adduct was formed in vivo, A/J mice were treated with 10 mumol of [5-3H]NNK and sacrificed 24 h postinjection. The

  烟草特有的亚硝胺4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）是一种有效的肺致癌物。这种不对称的亚硝胺可以被代谢活化为肺DNA甲基化和吡啶基氧代丁基化中间体。甲基DNA加合物具有良好的特征。吡啶基氧代丁基加合物在DNA水解条件下不稳定，并分解释放出4-羟基-1-（3-吡啶基）-1-丁酮（HPB）。已在体外与模型吡啶基氧代丁基化剂4-（乙酰氧基甲基亚硝基氨基）反应的DNA中检测到一种可释放HPB的加合物O6- [4-氧代-4-（3-吡啶基）丁基]鸟嘌呤（O6-pobG）。 -1-（3-吡啶基）-1-丁酮（NNKOAc）。为了确定这种加合物是否在体内形成，将A / J小鼠用10μmol的[5-3H] NNK处理并在注射后24小时处死。在这些动物的肝脏中检测到了诱变的O6-pobG，但未检测到肺DNA。由于4-（甲基亚硝基氨基）-1-（3-吡啶基）-1-丁醇（NNAL）是NNK的主
• Identification of Adducts Produced by the Reaction of 4-(Acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanol with Deoxyguanosine and DNA
  作者：Pramod Upadhyaya、Shana J. Sturla、Natalia Tretyakova、Rebecca Ziegel、Peter W. Villalta、Mingyao Wang、Stephen S. Hecht

  DOI：10.1021/tx0256376

  日期：2003.2.1

  4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is a metabolite of the tobacco specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). NNAL is present in the blood and urine of people exposed to tobacco products and has carcinogenic activity in rodents similar to that of NNK. DNA adducts specific to NNAL have not been previously identified. Metabolic activation of NNAL by a-methyl hydroxylation, a pathway known to occur in rodent and human microsomes, would produce pyridylhydroxybutylating agents that could react with DNA. We investigated this possibility in the present study by allowing 4-(acetoxymethylnitrosamino)1-(3-pyridyl)-1-butanone (NNALCH(2)OAc) to react with dGuo and DNA. Products were identified by HPLC with UV detection, liquid chromatography/electrospray ionization-mass spectrometry (LC/ESI-MS) and LC/ESI-tandem mass spectrometry (LC/ESI-MS/MS). In the dGuo reactions, selected ion monitoring for m/z 417, corresponding to pyridylhydroxybutylated dGuo, showed several peaks. One adduct was identified as 7-[1-hydroxy-1-(3-pyridyl)but-4-yl]dGuo (21) by neutral thermal hydrolysis, which converted it to 7-[1-hydroxy-1-(3-pyridyl)but-4-yl]Gua (22) and 4-hydroxy-1-(3-pyridyl)-1-butanol (16). Adduct 22 was identified by comparison of its LC/ESI-MS and LC/ESI-MS/MS properties to those of standard 22. Two other adducts, O-6-[1-hydroxy-1-(3-pyridyl)but-4-yl]dGuo (17) and N-2-[1-hydroxy-1-(3-pyridyl)but-4-yl]dGuo (19), were identified by comparison of their LC/ESI-MS and LC/ESI-MS/MS properties to those of standard 17 and 19. Further evidence for the identity of 17 and 19 was obtained by mild acid hydrolysis, which converted them to the corresponding Gua bases 18 and 20, identified by comparison to synthetic standards. Neutral thermal hydrolysis of DNA that had been reacted with NNALCH2OAc produced 22, identified by comparison to a standard. Adducts 17 and 19 were identified in enzyme hydrolysates of this DNA by comparison to standards. Thus, DNA that had been allowed to react with NNALCH(2)OAc contained adducts 17, 19, and 21. The results of this study provide markers for investigating the role of specific NNAL-DNA adducts in carcinogenesis by NNAL and NNK.