Reactions of ester derivatives of carcinogenic N-(4-biphenylyl)hydroxylamine and the corresponding hydroxamic acid with purine nucleosides

The nitrenium ions 3a,b derived from hydrolysis of N-(sulfonatooxy)-N-acetyl-4-aminobiphenyl (1a) and N-(4-biphenylyl)-O-pivaloylhydroxylamine (1b) are trapped by the purine nucleosides 2'-deoxyguanosine (dG), guanosine (G), 8-methylguanosine (8-MeG), adenosine (A), inosine (I), and xanthosine (X) with varying degrees of efficiency. Those nucleosides with a basic N-7 (pK(a)(N-7-H+) greater than or equal to 2.3) react with 3a,b with an apparently diffusion-limited rate constant at 20 degrees C of ca. 2.0 x 10(9) M-1 s(-1), determined from the experimental trapping ratios k(nuc)/k(s) and known values of k(s) for the two nitrenium ions. All nucleosides with a basic N-7, including 8-MeG, generate only C-8 adducts upon reaction with 3a,b. The reactions of 8-MeG with 3a,b produce metastable adducts, tentatively identified as 16a,b, that decompose over time into the stable 7,8-dihydroguanosine derivatives 8a,b. Our data, and those of other workers, are consistent with a mechanism that involves initial attack of N-7 on the nitrogen of the nitrenium ions followed by a 1,2 migration and deprotonation (Scheme 2b) to yield the final C-8 adducts. Nucleosides with a less basic N-7 react more slowly with the nitrenium ions and also produce adducts other than C-8 adducts. Inosine generates both the C-8 adducts 6a,b and the O-6 adducts 7a,b. Adenosine reacts with 3a,b to produce the unique azabicyclo[4.1.0]hepta-2,4-dien derivatives 11a,b. Plots of log k(nuc) vs pK(a)(N-7-H+) show that the beta(nuc) for C-8 adduct formation is at least 0.7 for purine nucleosides with pk(a) less than or equal to 2.3. The purine and pyrimidine selectivity data conclusively demonstrate that the high abundance of C-8 dG adducts observed in DNA from in vivo or in vitro experiments is a consequence of the high selectivity of nitrenium ions for N-7 of dG. Other minor DNA adducts may be produced as a result of structure-dependent modification of site selectivity.