Hydrolysis mechanism of anticancer Pd(II) complexes with coumarin derivatives: a theoretical investigation

The hydrolysis reaction mechanisms of a new generation Pd(II) anticancer drugs containing coumarin derivatives have been investigated combining density functional theory with the conductor-like dielectric continuum model approach. The first and the second aquation processes have been explored for the cis and trans counterpart of title PdL2 complex. Two possibilities for the second hydrolysis process have been analyzed for both compounds. From our data emerge that cis and trans PdL2 compounds have a different behavior in water. cis-isomer readily undergo first hydrolysis process generating a mono-aqua complex while both the pathways investigated for the second aquation reaction are more energetically demanding, suggesting that the mono-aqua complex could act as active species. On the contrary, for trans-compound, both the investigated reactions for the second aquation process occur by overcoming activation barriers comparable with that found for the first hydrolysis reaction. According to our data, trans-oriented PdL2 drug could undergo degradation process generating non-active compounds with the consequent lack of pharmacological activity.