Single-Electron-Transfer (SET) Leading to Radical Species in the Redox Reactions of Cyclic Peroxides with Biological Substrates

Abstract

In view of the genotoxicity [1] of 1,2-dioxetanes 1, which are efficient thermal sources of triplet excited carbonyl products [2], it was of interest to establish whether the DNA damage was of photochemical character or the result of redox reactions of such cyclic peroxides uith cell components. The living cell guards itself against such “oxidative stress” by deactivation of theh oxidants, e.g. the glutathione defense mechanism [3]. Indeed, the cyclic peroxides 1– 3 are efficiently reduced to their respective dihydroxy products by thiols, particularly glutathione and cysteine. With sulfides, e.g. thionine, oxygen transfer is observed, resulting in sulfoxides and the corresponding deoxygenated products of the cyclic peroxides [1]. As minor pathways, the 1,2-dioxetanes suffer catalytic decomposition [4], while C-H insertion products are formed by all three cyclic peroxides 1–3 with thiomethyl substrates. As initial step for this transformation a single-electron-tranfer process is proposed [1], leading to a radical ion pair, from which all the observed products can readily be rationalized (eq 1). A variety of biologically significant substrates can serve as electron donors, including 2-mercapto-4-methy1pyrimidine, phenothiazines , chloropromazine, ascorbic acid, tocopherol, β-carotene, N-benzyl dihydronicotinamide, NADH, and aromatic amines such as tetramethylphenylenediamine, dimethyl-p-anisidine, tetramethyl-4,4′-diaminodipheny1, 9-methylacridine, etc. For the phenothiazine the characteristic radical cation was detected, while efficient chemiluminescence was observed for aromatic amines uith low oxidation potentials, presumably via the CIEEL mechanism [5]. The mechanistic details of this novel single-electron-transfer process and the biological implications will be discussed.