Reaction of N-hydroxylamine and N-acetoxy derivatives of 2-amino-3-methylimidazolo[4,5-f]quinoline with DNA. Synthesis and identification of N-(deoxyguanosin-8-yl)-IQ.

The N-hydroxylamine of the carcinogen 2-amino-3-methylimidazolo[4,5-f]quinoline (IQ) covalently bound to calf thymus DNA at pH 7, and the binding was 11% higher under acidic conditions (pH 5). The extent of N-hydroxy-IQ binding to single-stranded polynucleotides at neutral pH was in the following order: polyguanylic acid much greater than polyadenylic acid greater than polycytidylic acid = polyuridylic acid. The binding of the carcinogen to DNA, polyguanylic acid and polyadenylic acid at neutral pH was enhanced 6-, 4- and 2-fold respectively by the presumed in situ formation of N-acetoxy-IQ from N-hydroxy-IQ and acetic anhydride. N-(Deoxyguanosin-8-yl)-IQ was synthesized by reaction at pH 7 of N-acetoxy-IQ (formed in situ with N-hydroxy-IQ and acetic anhydride) with deoxyguanosine and the structure characterized by NMR, mass spectral and UV absorption spectral analyses. Reverse phase HPLC of enzymatically hydrolyzed DNA which had been reacted with N-hydroxy-IQ in vitro showed a major adduct which was chromatographically identical to synthetic N-(deoxyguanosin-8-yl)-IQ. In addition, N-acetoxy-IQ, generated chemically by acetic anhydride or enzymatically with mammalian acetyltransferase, formed one major adduct with DNA which was chromatographically identical to the synthetic N-(deoxyguanosin-8-yl)-IQ. The results indicate that N-hydroxy-IQ and N-acetoxy-IQ react with DNA forming primarily the N-(deoxyguanosin-8-yl)-IQ adduct.