Formation of S–Cl Phosphorothioate Adduct Radicals in dsDNA S‑Oligomers: Hole Transfer to Guanine vs Disulfide Anion Radical Formation

In phosphorothioate-containing dsDNA oligomers (S-oligomers), one of the two nonbridging oxygen atoms in the phosphate moiety of the sugar–phosphate backbone is replaced by sulfur. In this work, electron spin resonance (ESR) studies of one-electron oxidation of several S-oligomers by Cl₂^•– at low temperatures are performed. Electrophilic addition of Cl₂^•– to phosphoro­thioate with elimination of Cl^– leads to the formation of a two-center three-electron σ²σ*¹-bonded adduct radical (‑P‑S‑̇Cl). In AT S-oligomers with multiple phosphoro­thioates, i.e., d­[ATATAsTsAsT]₂, ‑P‑S‑̇Cl reacts with a neighboring phosphoro­thioate to form the σ²σ*¹-bonded disulfide anion radical ([‑P‑S‑̇S‑P‑]⁻). With AT S-oligomers with a single phosphoro­thioate, i.e., d­[ATTTAsAAT]₂, reduced levels of conversion of ‑P‑S‑̇Cl to [‑P‑S‑̇S‑P‑]⁻ are found. For guanine-containing S-oligomers containing one phosphoro­thioate, ‑P‑S‑̇Cl results in one-electron oxidation of guanine base but not of A, C, or T, thereby leading to selective hole transfer to G. The redox potential of ‑P‑S‑̇Cl is thus higher than that of G but is lower than those of A, C, and T. Spectral assignments to ‑P‑S‑̇Cl and [‑P‑S‑̇S‑P‑]⁻ are based on reaction of Cl₂^•– with the model compound diisopropyl phosphoro­thioate. The results found for d­[TGCGsCsGCGCA]₂ suggest that [‑P‑S‑̇S‑P‑]⁻ undergoes electron transfer to the one-electron-oxidized G, healing the base but producing a cyclic disulfide-bonded backbone with a substantial bond strength (50 kcal/mol). Formation of ‑P‑S‑̇Cl and its conversion to [‑P‑S‑̇S‑P‑]⁻ are found to be unaffected by O₂, and this is supported by the theoretically calculated electron affinities and reduction potentials of [‑P‑S‑S‑P‑] and O₂.