Estabilidade molecular de compostos de inclusão baseados em ciclodextrinas e complexos de platina(ii) com atividade antitumoral

Abstract

Cisplatin and its derivatives are widely used as antitumor agents to treat several types of cancers. Despite their efficacy, these compounds have several side effects that can interrupt the treatment. Nonetheless, various studies propose modifications to reduce these disadvantages associated with platinum(II) complexes. A quite simple approach is the encapsulation of the drug in cyclodextrins. The inclusion complexes have the goal of improving the aqueous solubility of apolar drugs, in addition to preventing their deactivation before achieving their cellular target. In this dissertation project, density functional calculations were performed to evaluate the relation between structure-stability in the gaseous and aqueous phase of 44 inclusion compounds of the drugs cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, and heptaplatin with host macromolecules β-cyclodextrin and γ-cyclodextrin. After the optimization calculations, it was possible to notice a ring deformation on the cyclodextrins associated with a minimization of repulsive electronic effects while favoring intermolecular hydrogen bonds between the monomers. Intramolecular hydrogen bonds of the secondary hydroxyl groups in the cyclodextrins also contribute to the system stabilization. With the model reaction considered, all the inclusion compounds were thermodynamically favorable in the aqueous phase, applying the implicit solvent model in association with M06-2X/LANL2DZ/def2-SVP level. This result suggests that the chemical structures could represent a small set of structures in a dynamic equilibrium of the system in an aqueous phase. The calculations of 1H NMR chemical shifts in the aqueous phase revealed that it was possible to estimate the relative position of the platinum(II) complex in the cyclodextrin cavity and identify the structural deformations suffered by the host macromolecule.