Theoretical investigations on the thermal decomposition mechanism of 5-hydroxy-6-hydroperoxy-5,6-dihydrothymidine in water.

The main primary product of DNA oxidation by free radicals is 5-hydroxy-6- hydroperoxy-5,6-dihydrothymidine (5-OH-6-OOH-DHT), whose further degradation can yield the other mutagenic products and amplify the spectrum of DNA damage. In this study, to illustrate the thermal stability of 5-OH-6-OOH-DHT in DNA, the decomposition mechanism of 5-OH-6-OOH-DHT was identified based on the cis-(5R,6S) diastereomer. Optimized structures for all of the stationary points in the gas phase were investigated at the B3LYP/6-31+G(d,p) level of theory. Four pathways were characterized. The decomposition mechanism of 5-OH-6-OOH-DHT was proposed to involve either dehydration for paths A and B or the cleavage of a glycosidic bond for paths C and D. Moreover, to simulate the title reaction in aqueous solution, a water-mediated mechanism and cluster-continuum model, based on the SCRF/CPCM model, were taken into account. The results indicate that the most favorable reaction pathways for paths A and B both involve a sort of eight-membered ring transition structure formed by two (path A) or one (path B) auxiliary water molecules, suggesting that the thermal decomposition of 5-OH-6-OOH-DHT can be significantly facilitated by water molecules. Path A is the most feasible mechanism reported for the decomposition of 5-OH-6-OOH-DHT in the aqueous solution, which is slightly more favorable than path B. However, the unimolecular decomposition mechanisms (paths C and D) both have high-energy barriers and are largely endothermic, suggesting that the cleavage of the N-glycosidic bond via unimolecular decomposition is thermodynamically and kinetically unfavorable. These studies have shed light on the chemical properties of 5-OH-6-OOH-DHT in free radical reactions and thereby have provided new insights into the complex mechanism of oxidative DNA damage.