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

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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.