Sa. Kennedy et al., REACTIONS OF ESTER DERIVATIVES OF CARCINOGENIC N-(4-BIPHENYLYL)HYDROXYLAMINE AND THE CORRESPONDING HYDROXAMIC ACID WITH PURINE NUCLEOSIDES, Journal of the American Chemical Society, 119(33), 1997, pp. 7654-7664
The nitrenium ions 3a,b derived from hydrolysis of N-(sulfonatooxy)-N-
acetyl-4-aminobiphenyl (1a) and N-(4-biphenylyl)-O-pivaloylhydroxylami
ne (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 nucleosid
es 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 de
grees 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 nitr
enium ions. All nucleosides with a basic N-7, including 8-MeG, generat
e only C-8 adducts upon reaction with 3a,b. The reactions of 8-MeG wit
h 3a,b produce metastable adducts, tentatively identified as 16a,b, th
at decompose over time into the stable 7,8-dihydroguanosine derivative
s 8a,b. Our data, and those of other workers, are consistent with a me
chanism that involves initial attack of N-7 on the nitrogen of the nit
renium 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 reac
t more slowly with the nitrenium ions and also produce adducts other t
han 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 azab
icyclo[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 l
east 0.7 for purine nucleosides with pk(a) less than or equal to 2.3.
The purine and pyrimidine selectivity data conclusively demonstrate th
at the high abundance of C-8 dG adducts observed in DNA from in vivo o
r in vitro experiments is a consequence of the high selectivity of nit
renium ions for N-7 of dG. Other minor DNA adducts may be produced as
a result of structure-dependent modification of site selectivity.