Estudo computacional dos mecanismos de redução de compostos de platina(IV) a platina(II) em solução aquosa

Abstract

Platinum compounds are widely used as chemotherapeutics worldwide. One of the most important is cis-diamminedichloroplatinum(II), known as cisplatin. However, it has side effects and there are limitations on its administration. In this sense, a new class of platinum(IV) compounds has been studied following a prodrug approach in their development. It is believed that for these compounds to become therapeutically active, they must undergo prior reduction from Pt(IV) to Pt(II). However, what happens in this reduction process is still poorly explored in the literature, and there are several doubts. The prodrug approach indicates that in a reduction process, axial ligands leave the coordination sphere of platinum, forming a compound with irreversible characteristics. In this work, computational methods were used to investigate the reduction process of two platinum(IV) compounds: cis-diamminetetrachloroplatinum(IV) and bis(acetato)amino(n-butylamino)dichloroplatinum(IV), the latter in two different conformations. Their structural, electronic, and thermodynamic characteristics were studied to elucidate this reduction pathway. The MP2 and DFT levels of theory (M06-2x functional) were used for calculations in gas phase and with solvent inclusion by the IEFPCM method. The first compound has a LUMO orbital with dz2 symmetry, suggesting the traditional reduction mechanism for octahedral compounds, d6. The second compound has a LUMO orbital with dx2-y2 symmetry, which may indicate a different reduction mechanism from the traditional one, with the departure of equatorial ligands. The thermodynamic analyses performed indicate processes with a decrease in ΔG and an increase in entropy for most of the compounds studied. Other electronic and thermodynamic analyses were also performed and interpreted. Similar results were obtained with the inclusion of the solvent effect. Calculations were also performed with explicit solvation method by Monte Carlo methodology. These calculations yield results that indicate the stabilization of products in the aqueous phase, the formation of at least 2 solvation layers in the compounds studied, and possible hydrogen bonding. Statistical correlation analyses were performed to extract the smallest possible number of configurations that represent water-solute interactions. The results were obtained by combining functionals to find the best method, but limitations were found in the calculations, probably due to the high degree of freedom of the system and convergence problems.