A DFT study of reactions of Ru(III) anticancer drug KP1019 with 8-oxoguanine and 8-oxoadenine

The cytotoxic activities of KP1019 and other Ru(III) drugs are believed to be associated with their binding with DNA. Here, we report the density functional theory (DFT) study of reactions of KP1019 drug at the O6 and O8 sites of 8-oxoguanine (8-oxoG) and the O8 site of 8-oxoadenine (8-oxoA). 8-OxoG is predominantly formed in oxidative stress and can cause mutation and cancer. It is found that the barrier free energies (ΔGb) of these reactions obey the following trend: O8 (8-oxoG) < O8 (8-oxoA) < O6 (8-oxoG), at different levels of theory in gas phase and aqueous media. The ΔGb of reaction at the O8 (8-oxoG) is found to be 10.96 (13.81) kcal/mol at the M06-2X/(LanL2DZ+6-311+G**) level of theory in gas phase (aqueous media). The rate constant of reaction at the O8 (8-oxoG) site in aqueous media is 4.6 × 102 s−1. The reaction free energies (ΔGf) and reaction enthalpies (ΔHf) of all the reactions are appreciably negative in both gas phase and aqueous media which indicate that the reaction of mono-aquated KP1019 at the O6 and O8 sites of 8-oxoG as well as at the O8 site of 8-oxoA would occur spontaneously. Further, our calculations demonstrate that KP1019 would react with 8-oxoG more favourably as compared with guanine. Thus, it predicts that the main mechanism of the action of KP1019 drug might be due to its binding with the O8 site of 8-oxoG in biological media.