N-(2'-deoxyguanosine-8-yl)-4,4'-methylenedianiline

• 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: N-(2'-deoxyguanosine-8-yl)-4,4'-methylenedianiline
• 英文别名: 2-amino-8-[4-[(4-aminophenyl)methyl]anilino]-9-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1H-purin-6-one
• 化学式: C₂₃H₂₅N₇O₄
• 分子量: 463.496
• InChiKey: BNYKZOUBJADLNU-RCCFBDPRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  34
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  173
• 氢给体数：
  6
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  N-乙酰基-4,4'-二氨基二苯基甲烷 在 palladium on activated charcoal carboxyesterase ⁽¹¹⁵⁰⁾ 、 nuclease P₁ 、 一水合肼 、 三乙胺 、 间氯过氧苯甲酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 5.5h， 生成 N-(2'-deoxyguanosine-8-yl)-4,4'-methylenedianiline
  参考文献：
  名称：

  Synthesis and Quantification of DNA Adducts of 4,4‘-Methylenedianiline

  摘要：

  4,4'-Methylenedianiline (MDA) is used as a hardener in the manufacture of plastics and polyurethanes. MDA has been classified as a carcinogen in animals and is a suspected human carcinogen. Assuming that MDA would yield similar DNA adducts to other arylamines, we synthesized the following C-8 guanine adducts: N'-acetyl-N-(deoxyguanosin-8-yl)-MDA, N-(deoxyguanosin-8-yl)-MDA, N-(deoxyguanosin-8-yl)-4MA, and their corresponding 3'-monophosphate derivatives. We developed methods to identify these adducts of MDA in liver DNA using P-32-postlabeling, HPLC, and GC-MS techniques. Liver DNA was obtained from rats treated with radiolabeled MDA (1.11 and 116.5 mu mol/kg body weight). The total radioactivity bound to the DNA corresponded to 0.06 and 2.7 adducts per 10(7) nucleotides [covalent binding index (CBI=(mu mol of adduct per mol of nucleotide)/(mmol of compound per kg body weight)) of 1.05 and 2.3]. This DNA-binding potency is in the range of weakly genotoxic compounds. The liver DNA was analyzed for the presence of the synthesized adducts by the following methods: (I) HPLC analysis of nucleotides and purines after enzymatic and acid hydrolysis, and (II) P-32-postlabeling after enzymatic hydrolysis. The major adducts found in vivo did not correspond to the synthesized standards. Further work was carried out to determine the structure of the unidentified adducts. It was possible to release MDA and MDA-d(4) from DNA of rats dosed with MDA and/or MDA-d(4) and from the synthesized adducts using strong base hydrolysis. Liver of two female Wistar rats given 500 mu mol/kg MDA . 2HCl was hydrolyzed in 0.1 M NaOH overnight at 110 degrees C. GC-MS analysis of the heptafluorobutyric anhydride derivatized dichloromethane extracts detected 428+/-40 fmol of MDA/mg of DNA. In the control animals no MDA was found. The experiment was repeated with livers from animals dosed 500 mu mol/kg MDA-d(4) . 2HCl. In these rats 488+/-19 fmol MDA-d(4) was found to be bound at liver DNA. Taking into account a 68% yield of the method, the CBI found in these cases was 0.82 and 1.0, respectively.

  DOI：

  10.1021/tx950194+

文献信息

• Synthesis and Quantification of DNA Adducts of 4,4‘-Methylenedianiline
  作者：Dietrich Schütze、Peter Sagelsdorff、Ovnair Sepai、Gabriele Sabbioni

  DOI：10.1021/tx950194+

  日期：1996.1.1

  4,4'-Methylenedianiline (MDA) is used as a hardener in the manufacture of plastics and polyurethanes. MDA has been classified as a carcinogen in animals and is a suspected human carcinogen. Assuming that MDA would yield similar DNA adducts to other arylamines, we synthesized the following C-8 guanine adducts: N'-acetyl-N-(deoxyguanosin-8-yl)-MDA, N-(deoxyguanosin-8-yl)-MDA, N-(deoxyguanosin-8-yl)-4MA, and their corresponding 3'-monophosphate derivatives. We developed methods to identify these adducts of MDA in liver DNA using P-32-postlabeling, HPLC, and GC-MS techniques. Liver DNA was obtained from rats treated with radiolabeled MDA (1.11 and 116.5 mu mol/kg body weight). The total radioactivity bound to the DNA corresponded to 0.06 and 2.7 adducts per 10(7) nucleotides [covalent binding index (CBI=(mu mol of adduct per mol of nucleotide)/(mmol of compound per kg body weight)) of 1.05 and 2.3]. This DNA-binding potency is in the range of weakly genotoxic compounds. The liver DNA was analyzed for the presence of the synthesized adducts by the following methods: (I) HPLC analysis of nucleotides and purines after enzymatic and acid hydrolysis, and (II) P-32-postlabeling after enzymatic hydrolysis. The major adducts found in vivo did not correspond to the synthesized standards. Further work was carried out to determine the structure of the unidentified adducts. It was possible to release MDA and MDA-d(4) from DNA of rats dosed with MDA and/or MDA-d(4) and from the synthesized adducts using strong base hydrolysis. Liver of two female Wistar rats given 500 mu mol/kg MDA . 2HCl was hydrolyzed in 0.1 M NaOH overnight at 110 degrees C. GC-MS analysis of the heptafluorobutyric anhydride derivatized dichloromethane extracts detected 428+/-40 fmol of MDA/mg of DNA. In the control animals no MDA was found. The experiment was repeated with livers from animals dosed 500 mu mol/kg MDA-d(4) . 2HCl. In these rats 488+/-19 fmol MDA-d(4) was found to be bound at liver DNA. Taking into account a 68% yield of the method, the CBI found in these cases was 0.82 and 1.0, respectively.