Mechanism of methylation of 8-oxoguanine due to its reaction with methyldiazonium ion

摘要

Anticancer drugs such as temozolomide (TMZ) and decarbazine (DTIC) and several detrimental methylating agents methylate DNA via the formation of methyldiazonium ion. In the present contribution, density functional theory calculations have been carried out to investigate the mechanism of reactions of at the various nucleophilic sites of 8-oxoguanine (8-oxoG), which is formed extensively in oxidatively damaged DNA and can cause ageing, mutation and cancer. The reactant complexes, transition states and product complexes involved in different reactions have been fully optimised at the B3LYP/6-31G(d,p) level of theory in gas phase. Single-point energy calculations using each of the optimised geometries have been carried out at the B3LYP/aug-cc-pVDZ and M06-2X/aug-cc-pVDZ levels of theory in gas phase and at the polarizable continuum model (PCM)-B3LYP/aug-cc-pVDZ level of theory in aqueous media. Our calculations predict that the O8, O6 and N7 sites of 8-oxoG can easily get methylated by with the O8 site being the most favourable site for methylation. This prediction is supported by the fact that the 6-methoxy-9-methyl-8-oxoguanine and several such secondary metabolites have been observed in the Red Sea marine tunicate Symplegma rubra Monniot, 1972, a natural source. It is found that methylation pattern is appreciably modified in going from guanine to 8-oxoG and guanine is more reactive towards than 8-oxoG. Biological implications of 8-oxoG methylation including effect of O6-methylation on 8-oxoG:adenine mispair have also been discussed. Thus, the present study suggests that intensive experimental studies be performed to ascertain whether 8-oxoG methylation occurs in biological media efficiently as it may be helpful in unravelling the mechanism of action of anticancer methylating agents which act via formation of such as TMZ and DTIC.