Vinyl epoxides: reagents for radical-induced DNA cleavage

Abstract

Allyloxyl radicals, formed by addition of thiyl radicals to vinyl epoxides, function as DNA-cleaving agents. Radical-induced damage to DNA is normally caused either by hydrogen-atom abstraction from, deoxyribose or addition to the π-bonds of the heterocyclic bases. Model studies showed that allyloxyl radicals could effect both hydrogen-atom abstraction and addition to simple alkene π-bonds (but no product of addition to the π-bonds of adenine was observed). Importantly, this model chemistry could be performed in water at room temperature, and using enzymic formation of glutathionyl radicals. An intercalating vinyl epoxide 35 bound to ΦX174 supercoiled DNA caused cleavage when activated by glutathionyl radicals. The potential use of epoxide 35 in reversing the radiation resistance of tumours with a high local concentration of glutathione is discussed.