Oxidation of acetylated guanosine by 3,3-disubstituted 1,2-dioxetanes through nucleophilic attack on the peroxide bond: Model studies on the oxidative DNA damage by reactive peroxides

Article abstract of DOI:10.1021/ja00115a002

The reaction of the disubstituted 3-(methoxymethyl)-3-phenyl-1,2-dioxetane (1a) with the acetylated guanine nucleoside (2) in methanol affords 8-methoxyguanosine 5 as oxidation product, as well as guanine (6) and 1-methoxyribose 7 by deglycosylation (total yield ca. 30%). The dioxetane-derived reduction product constitutes the 1,2-diol 4a, while the major dioxetane-derived product (85%) is ω-methoxyacetophenone (3a). A Grob-type fragmentation is made responsible for the exclusive formation of the dioxetane cleavage products in the reactions with the acetylated nucleosides 8-10 derived from adenine, cytosine, and thymine. Rather than redox chemistry, this guanosine oxidation, unprecedented for peroxides, is proposed to involve nucleophilic attack by the N-7 atom of the nucleosides on the peroxide bond of the dioxetane 1a electrophile to generate a zwitterionic intermediate. S(N)2 attack by methanol at the C-8 position of the guanine moiety in the zwitterionic intermediate leads to the 8-methoxyguanosine 5 and the diol 4a. Alternatively, heterolytic cleavage of the glycosidic bond affords the methoxylated ribose 7 (after methanol trapping) and the N-7-alkoxylated guanine. The latter, after protonation, subsequently undergoes Grob fragmentation into guanine (6) and the dioxetane decomposition products ω-methoxyacetophenone (3a) and formaldehyde. We propose that the present novel oxidation of guanosine is general for electrophilic peroxides and may constitute a prominent route of oxidative DNA damage. In contrast, the corresponding 3-(bromomethyl)-3-phenyl-1,2-dioxetane (1b) gave with the guanosine 2 an intractable, complex product mixture, for which presumably the bromo substituent is responsible on account of competitive alkylation chemistry. However, with the 2'-deoxythymidine 10, a novel acid-catalyzed ring-opening of the bromo-substituted dioxetane 1b to its β-methoxy hydroperoxide 11b is observed, a reaction which does not take place for the methoxy-substituted dioxetane 1a. This unusual process for simple dioxetanes is rationalized in terms of stabilization of the intermediary benzylic cation by the adjacent β-bromo substituent through neighboring group participation.