Amination of nucleic acid bases-A basic study on the reaction mechanism of aminating carcinogens

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Arylnitrenium ion, a reactive intermediate of genotoxic arylhydroxylamine, is considered to modify cellular DNA. However, its reaction mechanism is not clear. This study was carried out in order to obtain a basic knowledge of amination reaction of nucleic acid bases. Hydroxylamine-O-sulfonic acid (HAOS) and 2, 4-dinitrophenoxyamine (DNPA) were used as models of activated genotoxic arylhydroxylamines.1) Aminations of guanosine (GUO) and deoxyguanosine (dG) with HAOS or DNPA gave various products depending on the reaction condition. Amination of Guo with DNPA in DMF gave 7-amino-Guo, which was readily converted to 8, 5'-O-cyclo-Guo and 8-hydroxy-Guo. dG gave only deglycosylated 7-amino-guanine under the same reaction condition. Amination of Guo and dG with HAOS at above pH 9 gave the corresponding 1-amino derivatives, whereas those in acidic media at pH 2-4 gave 8-amino-Guo and 7-amino-G as the main products, respectively. The mechanism of 8-amino-Guo formation became apparent; 7-NH_2-Guo 7-NH_2-8-NHOH-Guo 8-NHON-Guo 8-NH_2-Guo. 2) Although positional isomers of ring-nitrogen methylated guanines and hydroxylated guanines are known, ring-nitrogen aminated guanines have not been reported. Then, we challenged to the synthesis of all N-aminoguanine isomers. Using dG and O^6-methylguanine (as substrates) and DNPA and HAOS (as reagents), we succeeded in the syntheses of 1-amino-, 3-amino-, 7-amino-, and 9-aminoguanines. Further, diaminoguanines, 1, 7-diamino- and 3, 7- diaminoguanines, were also synthesized.