The chemistry of singlet O2 toward guanine nucleoside is highly relevant to DNA lesion, mutation, cell death, and pathological conditions. This oxidatively generated damage has been assumed to be initiated by the formation of a transient 4,8-endoperoxide via a Diels-Alder cycloaddition of singlet O2 to the guanine imidazole ring. However, no endoperoxide formation was directly detected in native guanosine. In this work, 9-methylguanine (9MG) was utilized as a model substrate to mimic the correlation between singlet O2 oxidation of guanosine and its ionization states, both in the absence and in the presence of water solvation. Potential energy surface exploration, kinetic modeling and direct dynamics trajectory simulation were carried out to characterize formation and transformation of reaction intermediates. Two reaction pathways were identified and neither follows the literature proposed oxidation mechanism for neutral guanosine: 1) single O2 oxidation of protonated 9MG begins by a concerted cycloaddition, but is mediated by a 5,8-endoperoxide; 2) by contrast, a concerted cycloaddition does not occur for deprotonated 9MG. The latter involves a stepwise addition starting with the formation of an 8-peroxide which subsequently evolves to a 4,8-endoperoxide. Guided by theory and capitalizing on a guided-ion-beam tandem mass spectrometer, transient peroxide intermediates were captured in the gas-phase collisions of hydrated 9MG (either protonated or deprotonated) with single O2 at ambient temperature. Following detection of intermediates in the gas phase, oxidation kinetics and end-product branching ratios of 9MG were measured in aqueous solution using online mass spectrometry coupled with absorption and emission spectrophotometry. The oxidation is weak in acidic solution, increases in neutral solution, and becomes intensive in basic solution. First-order oxidation rate constants were measured to be 1.2 × 106 M-1s-1 for neutral 9MG and 4.6 − 4.9 × 107 M-1s-1 for deprotonated 9MG. 5-Guanidinohydantoin (Gh) and spiroiminodihydantoin (Sp) were detected as the major products, and Sp became dominant in basic solution. The work has pieced together the early-stage dynamics of initial guanosine-O2 adduct formation that is missing from conventional condensed-phase studies, and the late-stage kinetics that evolves from endoperoxides to end products.

Elucidating dynamics and kinetics of singlet oxygen-induced guanine nucleoside oxidation using a combination of potential energy surfaces, kinetic modeling, molecular dynamics simulations and guided-ion-beam mass spectrometry

256th National Meeting (2018)

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