Theoretical studies on the reactions of thymine with six methylating agents

Abstract The reaction mechanisms of the three carcinogenic methylating agents, dimethyl sulfate (DMS), methyl methanesulfonate (MMS), and iodomethane (MeI), with keto and enol tautomers of thymine (K-thymine and E-thymine) were studied by using the B3LYP method in the 6-311+G (d, p) basic set. Using the same method, reactions of K- and E-thymine were explored with the three common methylating agents, dimethyl carbonate (DMC), methyl fluorosulfonate (MFS), and methyl trifluorosulfonate (MTFS). The solvent effects were examined using the polarizable continuum model (PCM) in water, acetone, and carbon tetrachloride. Our calculations found that K-thymine is appreciably more stable than the enol form in the gas phase and the three solvents. The calculated results show that the reactions of K-thymine with MeI, MFS, and MTFS are a two-step mechanism, while those of K-thymine with DMS, MMS and DMC are a one-step mechanism. Moreover, all reactions of E-thymine with the six methylating agents are a one-step mechanism. The reaction barriers of K-thymine with three carcinogenic methylating agents range from 211.2 to 267.6 kJ/mol. For K-thymine with DMC, MFS and MTFS, the reaction barriers range from 191.1 to 287.6 kJ/mol. These results indicate that all reactions mentioned above could not efficiently occured in biological organism in the absence of the catalyst. Our conclusion is in agreement with the previous study on the reactions of guanine with methyl chloride and methyl bromide.