Estudo teórico de propriedades eletroquímicas e interação com possíveis alvos biológicos de complexos baseados em Ru com potencial atividade antitumoral

Abstract

Ruthenium (II and III) Complexes have attracted the interest of the scientific community as potential antitumor drugs, due to their low toxicity and ability to overcome drug resistance. Although Ru metallodrugs exhibit antitumor activity in both oxidation states, metal Ru(III) ion will likely reduce to Ru (II) in vivo. Thus, Ru (III) complexes would act as a prodrug, which is activated by reduction in vivo to bind more efficiently the biological target. Thus ruthenium (III) [Ru (NH3)4(H2O)(pyz)]3+ compounds and the iconic: trans-tetrachloro (dimethylsulfoxide) imidazole ruthenate(III) [Im]trans-[RuCl4(Im)(DMSO)] (NAMI-A) and trans-[tetrachlorobis (1H-indazole) ruthenate(III) [IndH]trans-[RuCl4(Ind)2] (KP1019), were investigated in the present study due to their antineoplastic activities. This mechanism associated with the Ru (III) complexes, are activated by reduction and chloride ligands exchange by water molecules in the solvent (hydrolysis or aquation), have two important steps for anti-tumor function of such metallodrugs. Based on experimental observations, three events are connected to the biological activity of such compounds: i) reduction of the Ru (III) center, (ii) reaction of exchange chloride with water molecules of the solvent medium and (iii) interaction of the targets biological. The sequence of the events will depend, on the reactions kinetics and also on species potential reduction, chloride concentration and thermodynamic stability of the complexes formed. Density Functional Theory (DFT) calculations, at the TPSSh/Def2-TZVP level, in combination with the SMD continuum solvation model, were performed to investigate the electrochemistry and their hydrolysis products as well as the thermodynamics of biological molecules interactions with S-donor (cystine (Cys), glutathione (GSH)) and N-donor (guanine at the coordination sites N3 and N7). Our results show that the compounds exhibit different electrochemical behavior upon hydrolysis. While the reduction potential of [Ru(NH3)3(Pz)(Cl)]3+ and NAMI-A are sensitive to ligand exchange. NAMI-A complex increases to 0.8V after hydrolysis and the reduction potential of KP1019 remains almost constant after the first hydrolysis. The NAMI-A and KP1019 complexes have thermodynamic preference to reduce before undergoing hydrolysis and strong preference to undergo successive hydrolysis rather than interacting with donor S and donor N ligands. Interaction with S-donor ligands in the unprotonated form is highly unfavorable, with the free energy in solution (ΔGsol) ≥ 18 kcal mol-1. For both complexes, the interaction with the guanine and glutathione are of the same magnitude (ΔGsol ca. –0.6 kcal mol-1) meaning that these ligands can compete for binding to the metallodrug. In contrast to the complexes presented above, the Gibbs variation energy in gas phase is energetically favorable to virtually all adducts. The H2O/NO ligand exchange reaction of the NAMI-H2O complex with NO was investigated at the B3LYP/DEF2-TZVP theory level and will through the use of multiconfigurational calculations such as CASSCF. Our results showed that mechanism goes through a triple reactant and transition state and the singlet product formation. The corrected electronic energies present values respectively by 7.53 and 30 kcal mol-1. The transitions between spin states have studied by MECP's obtained at the B3LYP / def2-TZVP level of theory. It was observed that the intersection between systems with consequent coupling of electronic spins must happen at the point of MECP-III, where concomitantly there will be NO  Ru charge transfer and configuration product formation [RuIINO+].