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-O-2 collision events that generate singlet oxygen (S = 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 (G(ET) = -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.