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This work shows that S-atom substitution in phosphate, controls the directionality of hole transfer processes between base and sugar-phosphate backbone in DNA systems. The investigation combines synthesis, electron spin resonance (ESR) studies in supercooled homogeneous solution, pulse radiolysis in aqueous solution at ambient temperature and density functional theory (DFT) calculations of in-house synthesized model compound dimethylphosphorothioate (DMTP(O(−))=S) and nucleotide (5’-O-methoxyphosphorothioyl-2’-deoxyguanosine (G-P(O(−))=S)). ESR investigations show that DMTP(O(−))=S reacts with Cl(2)(•−) to form the σ(2)σ*(1) adduct radical -P-S∸Cl which subsequently reacts with DMTP(O(−))=S to produce [-P-S∸S-P-](−). -P-S∸Cl in G-P(O(−))=S undergoes hole transfer to Gua forming the cation radical (G(•+)) via thermally activated hopping. However, pulse radiolysis measurements show that DMTP(O(−))=S forms the thiyl radical (-P-S•) by one-electron oxidation which did not produce [-P-S∸S-P-](−). Gua in G-P(O(−))=S is oxidized unimolecularly by -P-S• intermediate in sub-picosecond range. DFT thermochemical calculations explain the differences in ESR and pulse radiolysis results obtained at different temperatures.

Invited for the cover of this issue are the groups of Roman Dembinski, Mehran Mostafavi, and Amitava Adhikary at the Polish Academy of Sciences, Université Paris-Saclay, and Oakland University. The image depicts a doughnut as a way of illustrating the hole transfer process. Read the full text of the article at 10.1002/chem.202000247.

The directionality of the hole-transfer processes between DNA backbone and base was investigated by using phosphorodithioate [P(S- )=S] components. ESR spectroscopy in homogeneous frozen aqueous solutions and pulse radiolysis in aqueous solution at ambient temperature confirmed initial formation of G.+ -P(S- )=S. The ionization potential of G-P(S- )=S was calculated to be slightly lower than that of guanine in 5'-dGMP. Subsequent thermally activated hole transfer from G.+ to P(S- )=S led to dithiyl radical (P-2S. ) formation on the μs timescale. In parallel, ESR spectroscopy, pulse radiolysis, and density functional theory (DFT) calculations confirmed P-2S. formation in an abasic phosphorodithioate model compound. ESR investigations at low temperatures and higher G-P(S- )=S concentrations showed a bimolecular conversion of P-2S. to the σ2 -σ*1 -bonded dimer anion radical [-P-2S - . 2S-P-]- [ΔG (150 K, DFT)=-7.2 kcal mol-1 ]. However, [-P-2S - . 2S-P-]- formation was not observed by pulse radiolysis [ΔG° (298 K, DFT)=-1.4 kcal mol-1 ]. Neither P-2S. nor [-P-2S - . 2S-P-]- oxidized guanine base; only base-to-backbone hole transfer occurs in phosphorodithioate.