The Triplet State of 6-thio-2′-deoxyguanosine: Intrinsic Properties and Reactivity Toward Molecular Oxygen

Thiopurine prodrugs are currently among the leading treatment options for leukemia, immunosuppression, and arthritis. Patients undergoing long‐term thiopurine treatment are at a higher risk of developing sunlight‐induced skin cancers than the general population. This side effect originates from the cellular metabolization of thiopurine prodrugs to form 6‐thio‐2′‐deoxyguanosine, which can absorb UVA radiation, populating its reactive triplet state and leading to oxidatively generated damage. However, the photo‐oxidation mechanism is not fully understood. In this contribution, the oxidation potential and the adiabatic triplet energy of 6‐thio‐2′‐deoxyguanosine are estimated computationally, whereas the intrinsic rate of triple‐state decay and the rate constant for triplet quenching by molecular oxygen are determined using time‐resolved spectroscopic techniques. A singlet oxygen quantum yield of 0.24 ± 0.02 is measured in aqueous solution (0.29 ± 0.02 in acetonitrile). Its magnitude correlates with the relatively low percentage of triplet‐O2 collision events that generate singlet oxygen (SΔ = 37%). This behavior is rationalized as being due to the exergonic driving force for electron transfer between the triplet state of 6‐thio‐2′‐deoxyguanosine and molecular oxygen (ΔGET = −69.7 kJ mol−1), resulting in the formation of a charge‐transfer complex that favors nonradiative decay to the ground state over triplet energy transfer. 6‐thio‐2′‐deoxyguanosine is a common metabolite of the widely prescribed thiopurine prodrugs. The triplet state of 6‐thio‐2′‐deoxyguanosine is populated upon UVA absorption, which can lead to cytotoxic side‐effects. A mechanism is presented wherein the interaction between the triplet state of 6‐thio‐2′‐deoxyguanosine and molecular oxygen leads to two competitive pathways—triplet‐energy transfer or the formation of a charge‐transfer complex. The former pathway generates singlet oxygen, whereas the latter decays back to the ground state. The identification of these two competitive relaxation pathways can assist in evaluating the primary mode of photosensitization that leads to the phototoxicity of 6‐thio‐2′‐deoxyguanosine in biological environments.