Estudo teórico das interações da cisplatina e análogos em solução

Abstract

In this work, different theoretical methods were used to study the cisplatin substitution reaction, as well as the intermolecular interactions that occur before this reaction. Potential energy curves (PEC) between cisplatin and water, and its hydrolyzed species, [Pt(NH3)2H2OCl]+1 and cis-[Pt(NH3)2(H2O)]+2, were studied in details, providing the majorintermolecular interactions involved in the hydrolysis reaction. High level ab initio calculations were carried out, observing the PECs contributions. The effects of the correction due to basis set superposition error, BSSE, were evaluated through the Counterpoise method, particularlyconcerning to the use of effective core potential for platinum atom. In this same stage, the induction, dispersion and electrostatic contributions were described through the classical method of multipoles expansion. These results are in good agreement with electronic correlation contributions obtained with high level ab initio calculations. The importance of the electrostatic potential description, mainly for the charged species madp and dap was also found. The substitution reaction study was carried out in gas phase and in solution. Somepolarizable continuum model variations were used, including geometry optimization in solution and biological medium properties as the dielectric constant and ionic strength. The results calculated in solution are in the best agreement with the experimental data, when the reactantand products are the intermediary species of the reaction at the MP2 theoretical level. After the optimization in solution, no expressive changes were found. In the same way, the implicit inclusion of biological medium effects did not alter the results in solution. Two sets of Lennard-Jones (LJ) parameters developed for cisplatin molecule were tested for transferability to the madp and dap species. The set 1, (Pt=1.055 and Pt=3.659), was obtained through PECs with BSSE correction. The set 2 (Pt=7.010 and Pt=2.559), was developed through PECs without BSSE correction. The best general agreement was obtained when the set without BSSE correction was used. In spite of this result, classical Monte Carlo simulations were carried out for the cisplatin reaction using both LJ parameters sets. After all structural analysis of the species in solution only for the results without BSSE correction, were found two axial water molecules that is needed to stabilize these structures in solution. This fact confirms that set 2 of LJ parameters is the most applicable to the study of cisplatin and analogues in solution.