The 3-(hydroxymethyl)-3,4,4-trimethyl-1,2-dioxetane (HTMD) highly
efficiently damages DNA
compared to the merely alkyl-substituted derivative
3,3,4,4-tetramethyl-1,2-dioxetane (TMD). To elucidate
this difference in oxidative reactivity, two additional
hydroxymethyl-substituted 1,2-dioxetanes, namely
cis/trans-3-(hydroxymethyl)-3,4-dimethyl-4-(phenylmethyl)-
(1α/1β) and
3-(hydroxymethyl)-4,4-dimethyl-3-(phenylmethyl)-1,2-dioxetane (2), were investigated in regard
to their photochemical and photobiological
properties. The high genotoxic effects of the
hydroxymethyl-substituted 1,2-dioxetanes, which are
reflected
in the significant formation of single-strand breaks in plasmid pBR 322
DNA and the efficient oxidation of
guanine in calf thymus DNA and the nucleoside 2'-deoxyguanosine (dGuo),
are for the first time understood
in terms of radical chemistry. The reactivity order of the
dioxetanes 1α/1β > HTMD > 2 ≫
TMD to damage
DNA parallels the propensity of these dioxetanes to generate radicals.
These reactive species are formed in
the thermolysis of the dioxetanes through α cleavage of the
intermediary triplet-excited α-hydroxy- and α-phenyl-substituted carbonyl products. The presence of radicals was
confirmed by spin-trapping experiments with
5,5-dimethyl-1-pyrroline N-oxide and by laser-flash
photolysis. These carbon-centered radicals are
efficiently
scavenged by molecular oxygen to produce peroxyl radicals, which are
proposed as the active DNA-damaging
species in the thermal decomposition of the hydroxymethyl-substituted
1,2-dioxetanes HTMD, 1α/1β, and
2.