Factors in Determining the Chemo-Selective Reactions at Thymine in One-Electron Oxidation of DNA: Identification of an Intramolecular Proton Coupled Electron Transfer Pathway via a Full-Carbon Spin Centre Shift

Oxidation of DNA causes chemical reactions at nucleobase that ultimately result in DNA damage via mutation. The reaction site could prefer at thymine through one-electron oxidation in “guanine poor regions” or in the presence of Cu(II) with guanine. Two competitive processes of H2O/O2 addition to the thymine radical cation C5-C6 double bond and a proton loss via proton-coupled electron transfer (PCET) at methyl group were proposed for elucidation of the complex reaction mechanism at thymine. The DNA repairability of the mutation resulted by the latter process is uncertain, and the factors in determining the divergent pathways are not yet clear. A future better understanding is in great need for managing the possible oxidation stress caused perinatal carcinogenic side effects of the thymine-containing drug Azidothymidine (AZT), and for future rational design of new anti-virus drugs for covid-19 treatment in case Molnupiravir-mutated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses with a high proportion of G-to-A and C-to-T mutations evolves into a new dominant variant. A systematic study of photocatalyzed thymine/thymidine oxidation reactions, hydration of pyrimidines, direct β-alkylation of aldehydes/ketones via photoredox organocatalysis, direct C-H functionalization of indole benzylic sp3 carbon via photocatalysis, and photo-induced sugar transformations via spin-centre shift (SCS) was carried out to evaluate the role of water, ions and functional groups. Non-nucleophilic anions were found to play an essential role in favoring the PCET pathway as an excellent hydrogen bond acceptor. Systematic experimental evidences support a “build-in amine catalysis” of intramolecular PCET via a full-carbon SCS, as a new alternative pathway through one-electron oxidation at thymine. The direction role of carbonyl group of thymine in water wire-mediated proton transfer was also identified. A bioinspired full-carbon SCS mechanism with an assistance of acetate anion in radical migration was proposed for explaining the unique “5πe−carbonyl activation mode” in photoredox organocatalysis. The systematic study also demonstrated that both a biomimetic design of a general one-electron oxidation activation mode named as “Radical Cation Induced Addition (RCIA)” toward catalytic asymmetric hydration, and a biomimetic design of transient-metal-free catalytic C-H functionalization of benzylic sp3 carbon of indoles, would be feasible via a similar one-electron transfer mechanism.