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

A) n -胺化核酸的反应性s1) 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3个产物i；n -氨基与咪唑C8(2)位之间桥接形成的三环体系产物，ii；i、iii的咪唑开环产物；希夫碱积。这些结果表明，n -氨基可以形成新的环体系。2) 7-氨基腺嘌呤或1-氨基苯并咪唑与四乙酸铅（LTA）反应得到两个n -氨基偶联形成的二聚体（N-N=N-N）。第四类化合物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反应生成9-乙基-8-氮杂鸟嘌呤和1-甲基-2-氮杂苯并咪唑衍生物。这些反应可用于合成具有双活性的8-氮杂嘌呤。3)作为4NQO的N7鸟嘌呤加合物模型，挑战了1-甲基-3-苯基氨基苯并咪唑的合成，并取得了成功。利用该模型化合物，阐明了N7加合物的化学特性。B)脱氧鸟苷C8位自由基甲基化致癌甲基肼被代谢后与细胞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的C8位发生反应。由于8-甲基鸟嘌呤在DNA中的生物学意义尚不清楚，本次我们对其进行了研究。首先制备了含有8-甲基脱氧鸟苷（8-MedG）的寡核苷酸。利用该低聚物进行引物延伸反应，并测定其误掺入活性。结果表明，8-MedG虽然频率很低，但能与G和A配对。我们得出结论，在dG的c8位置的修饰是诱变和致癌的。

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.