Mechanism for the decomposition of 5-aza-2′-deoxycytidine: a theoretical study using Monte Carlo simulation plus local microhydration model

The decomposition mechanism of 5-aza-2'-deoxycytidine (decitabine) has been investigated using the Monte Carlo simulation with free energy perturbation technique based on the local microhydration model. The irreversible deformylation process (process 2) was firstly evaluated. Four possible pathways, two stepwise (paths 1 and 3) and two concerted (paths 2 and 4) were examined. In two stepwise pathways, a tetrahedral intermediate is given by the addition of H2O to the C-(1)=O-(2) bond, followed by the proton shift to the N-(3) atom leading to the final products. In two concerted pathways, the nucleophilic attack of H2O at the C-(1) atom and the simultaneous movement of hydroxyl H to the N-(3) atom induce the cleavage of the C-(1)-N-(3) single bond. The potential energy profiles along the minimum energy path for four pathways in the gas phase and in water were obtained. Our computed results exhibit that two stepwise mechanisms (paths 1 and 3) are more favorable than two concerted mechanisms (paths 2 and 4) when the solvent effects of bulk water are taken into account. Then, in collaboration with the previous study (Gao et al. in Theor Chem Acc 131: 1108-1123, 2012), the whole decomposition processes of decitabine were discussed. Two possible pathways were considered: pathway t1 be made up of B-path 2 (in process 1) and path 1 as well as pathway t2 be composed of B-path 3 (in process 1) and path 3. The results clearly manifest that pathway t2 is more favorable than pathway t1 in the decomposition reaction of decitabine, which leads to IM-dR2 and GuaUre-dR2 as ring-opening-formylated intermediate and decomposition product, respectively. The third step is the rate-controlling step with the free energy barrier height of 29.8 kcal/mol, which is in agreement with the experimentally determined activation free energy (25.4 kcal/mol).