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Reactions of Ester Derivatives of Carcinogenic N-(4-Biphenylyl)hydroxylamine and the Corresponding Hydroxamic Acid with Purine Nucleosides
journal contribution
posted on 1997-08-20, 00:00 authored by Sonya A. Kennedy, Michael Novak, Brent A. KolbThe 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
(pKa(N7−H+) ≥
2.3) react with 3a,b with an apparently
diffusion-limited rate constant at 20 °C of ca. 2.0 × 109
M-1 s-1, determined
from the experimental trapping ratios
knuc/ks and
known values of ks 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
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 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
knuc vs
pKa(N7−H+) show
that the βnuc for
C-8 adduct formation is at least 0.7 for purine nucleosides with
pKa ≤ 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.