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.