Reactions of Ester Derivatives of Carcinogenic <i>N</i>-(4-Biphenylyl)hydroxylamine and the Corresponding Hydroxamic Acid with Purine Nucleosides

The nitrenium ions <b>3a</b>,<b>b</b> derived from hydrolysis of <i>N</i>-(sulfonatooxy)-<i>N</i>-acetyl-4-aminobiphenyl (<b>1a</b>) and <i>N</i>-(4-biphenylyl)-<i>O</i>-pivaloylhydroxylamine (<b>1b</b>) 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<i>K</i><sub>a</sub>(N<sup>7</sup>−H<sup>+</sup>) ≥ 2.3) react with <b>3a</b>,<b>b</b> with an apparently diffusion-limited rate constant at 20 °C of ca. 2.0 × 10<sup>9</sup> M<sup>-1</sup> s<sup>-1</sup>, determined from the experimental trapping ratios <i>k</i><sub>nuc</sub>/<i>k</i><sub>s</sub> and known values of <i>k</i><sub>s</sub> for the two nitrenium ions. All nucleosides with a basic N-7, including 8-MeG, generate only C-8 adducts upon reaction with <b>3a</b>,<b>b</b>. The reactions of 8-MeG with <b>3a</b>,<b>b</b> produce metastable adducts, tentatively identified as <b>16a,b</b>, that decompose over time into the stable 7,8-dihydroguanosine derivatives <b>8a</b>,<b>b</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 b) 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 <b>6a</b>,<b>b</b> and the O-6 adducts <b>7a</b>,<b>b</b>. Adenosine reacts with <b>3a</b>,<b>b</b> to produce the unique azabicyclo[4.1.0]hepta-2,4-diene derivatives <b>11a</b>,<b>b</b>. Plots of log <i>k</i><sub>nuc</sub> vs p<i>K</i><sub>a</sub>(N<sup>7</sup>−H<sup>+</sup>) show that the β<sub>nuc</sub> for C-8 adduct formation is at least 0.7 for purine nucleosides with p<i>K</i><sub>a</sub> ≤ 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.