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Amination of the imidazole moiety of guanine and the properties of the N-aminated imidazoles. Molecular mechanisms of induction of DNA damage.

鸟嘌呤咪唑部分的胺化和 N-胺化咪唑的性质。

基本信息

批准号：
07672280
负责人：
KOHDA Kohfuku
金额：
$ 0.58万
依托单位：
Nagoya City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

A) Reactivity of N-aminated nucleic acids1) Reaction of 9-aminoadenine, 7-aminoadenine, 1-aminobenzimidazole derivatives or 1-amino-3-methylbenzimidazole derivatives with acetylacetone gave three products, i ; the three ring-system product that was formed by the bridge formation between the N-amino group and the imidazole C8 (2) position, ii ; imidazole ring-opened product of i, and iii ; Schiff base product. These results suggested that the N-amino group is available for formation of new ring system.2) Reaction of 7-aminoadenine or 1-aminobenzimidazole with lead tetraacetate (LTA) gave dimer (N-N=N-N) which was formed by the coupling of the two N-amino groups. On the other hand, quarternary compounds, 7-amino-9-ethylguanine and 1-amino-3-methylbenzimidazole derivatives afforded 9-ethyl-8-azaguanine and 1-methyl-2-azabenzimidazole derivatives, respectively, by the reaction with LTA.These reactions can be applicable for the syntheses of biactive 8-azapurines.3) As a model of the N7 guanine adduct of 4NQO,the synthesis of 1-methyl-3-phenylaminobenzimidazole was challenged and we succeeded. Using this model compound, the chemical characteristic of N7 adduct will be elucidated.B) Radical methylation at the C8 position of deoxyguanosineCarcinogenic methylhydrazine reacts with cellular DNA after it was metabolized. One of the active species is methyl radical and it is known that methyl radical reacts at the C8 position of guanine moiety. Since the biological significance of 8-methylguanine in DNA was not known, we investigated about it in this time. First we prepared an oligonucleotide that contains 8-methyldeoxyguanosine (8-MedG). The primer extenstion reaction using this oligomer was carried out and the misincorporation activity was measured. Results showed that 8-MedG makes pair with G and A although the frequency is so low. We concluded that the modification at the C8-position of dG is mutagenic and carcinogenic.

A）N-胺化核酸的反应性1）9-氨基腺嘌呤、7-氨基腺嘌呤、1-氨基苯并咪唑衍生物或1-氨基-3-甲基苯并咪唑衍生物与乙酰丙酮反应得到三种产物，i.通过N-氨基和咪唑C8（2）位之间的桥形成形成的三环系统产物，ii. i的咪唑开环产物，和iii.席夫碱产物。2）7-氨基腺嘌呤或1-氨基苯并咪唑分别与四乙酸铅（LTA）反应，两个N-氨基偶联生成二聚体（N-N=N-N）。另一方面，四元化合物7-氨基-9-乙基鸟嘌呤和1-氨基-3-甲基苯并咪唑衍生物分别与LTA反应得到9-乙基-8-氮鸟嘌呤和1-甲基-2-氮苯并咪唑衍生物，这些反应可用于合成具有生物活性的8-氮杂嘌呤。1-甲基-3-苯基氨基苯并咪唑的合成受到挑战，我们成功了。B）脱氧鸟苷C8位的自由基甲基化致癌的甲基肼代谢后与细胞DNA发生反应。其中一种活性物质是甲基自由基，已知甲基自由基在鸟嘌呤部分的C8位反应。由于8-甲基鸟嘌呤在DNA中的生物学意义尚不清楚，我们对此进行了研究。首先，我们制备了含有8-甲基脱氧鸟苷（8-MedG）的寡核苷酸。使用该寡聚物进行引物延伸反应，测定错误掺入活性。结果表明，8-MedG与G和A配对，尽管频率很低。我们的结论是，在C8位的dG的修饰是致突变性和致癌性。