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 (p K a (N 7 −H + ) ≥ 2.3) react with 3a, b with an apparently diffusion-limited rate constant at 20 °C of ca. 2.0 × 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-diene derivatives 11a, b . Plots of log k nuc vs p K a (N 7 −H + ) show that the β nuc for C-8 adduct formation is at least 0.7 for purine nucleosides with p K a ≤ 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.