OXIDATION OF ACETYLATED GUANOSINE BY 3,3-DISUBSTITUTED 1,2-DIOXETANESTHROUGH NUCLEOPHILIC-ATTACK ON THE PEROXIDE BOND - MODEL STUDIES ON THE OXIDATIVE DNA-DAMAGE BY REACTIVE PEROXIDES
W. Adam et A. Treiber, OXIDATION OF ACETYLATED GUANOSINE BY 3,3-DISUBSTITUTED 1,2-DIOXETANESTHROUGH NUCLEOPHILIC-ATTACK ON THE PEROXIDE BOND - MODEL STUDIES ON THE OXIDATIVE DNA-DAMAGE BY REACTIVE PEROXIDES, Journal of the American Chemical Society, 117(10), 1995, pp. 2686-2693
The reaction of the disubstituted 3-(methoxymethyl)-3-phenyl-1,2-dioxe
tane (1a) with the acetylated guanine nucleoside (2) in methanol affor
ds 8-methoxyguanosine 5 as oxidation product, as well as guanine (6) a
nd 1-methoxyribose 7 by deglycosylation (total yield ca. 30%). The dio
xetane-derived reduction product constitutes the 1,2-diol 40, while th
e major dioxetane-derived product (85%) is omega-methoxyacetophenone (
3a). A Grob-type fragmentation is made responsible for the exclusive f
ormation of the dioxetane cleavage products in the reactions with the
acetylated nucleosides 8-10 derived from adenine, cytosine, and thymin
e. Rather than redox chemistry, this guanosine oxidation, unprecedente
d for peroxides, is proposed to involve nucleophilic attack by the N-7
atom of the nucleosides on the peroxide bond of the dioxetane la elec
trophile to generate a zwitterionic intermediate. S(N)2 attack by meth
anol at the C-8 position of the guanine moiety in the zwitterionic int
ermediate leads to the 8-methoxyguanosine 5 and the diol 4a. Alternati
vely, heterolytic cleavage of the glycosidic bond affords the methoxyl
ated ribose 7 (after methanol trapping) and the N-7-alkoxylated guanin
e. The latter, after protonation, subsequently undergoes Grob fragment
ation into guanine (6) and the dioxetane decomposition products omega-
methoxyacetophenone (3a) and formaldehyde. We propose that the present
novel oxidation of guanosine is general for electrophilic peroxides a
nd may constitute a prominent route of oxidative DNA damage. In contra
st, the corresponding 3-(bromethyl)-3-phenyl- 1,2-dioxetane (1b) gave
with the guanosine 2 an intractable, complex product mixture, for whic
h presumably the bromo substituent is responsible on account of compet
itive alkylation chemistry. However, with the 2'-deoxythymidine 10, a
novel acid-catalyzed ring-opening of the bromo-substituted dioxetane I
b to its beta-methoxy hydroperoxide 11b is observed, a reaction which
does not take place for the methoxy-substituted dioxetane 1a. This unu
sual process for simple dioxetanes is rationalized in terms of stabili
zation of the intermediary benzylic cation by the adjacent beta-bromo
substituent through neighboring group participation.