RESUMO
Three ruthenium(II) phosphine/diimine/picolinate complexes were selected aimed at investigating anticancer activity against several cancer cell lines and the capacity of inhibiting the supercoiled DNA relaxation mediated by human topoisomerase IB (Top 1). The structure-lipophilicity relationship in membrane permeability using the Caco-2 cells have also been evaluated in this study. SCAR 5 was found to present 45 times more cytotoxicity against breast cancer cell when compared to cisplatin. SCAR 4 and 5 were both found to be capable of inhibiting the supercoiled DNA relaxation mediated by Top 1. Interaction studies showed that SCAR 4 and 5 can bind to DNA through electrostatic interactions while SCAR 6 is able to bind covalently to DNA. The complexes SCAR were found to interact differently with bovine serum albumin (BSA) suggesting hydrophobic interactions with albumin. The permeability of all complexes was seen to be dependent on their lipophilicity. SCAR 4 and 5 exhibited high membrane permeability (P app > 10 × 10-6 cm·s-1) in the presence of BSA. The complexes may pass through Caco-2 monolayer via passive diffusion mechanism and our results suggest that lipophilicity and interaction with BSA may influence the complexes permeation. In conclusion, we demonstrated that complexes have powerful pharmacological activity, with different results for each complex depending on the combination of their ligands.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , DNA Topoisomerases Tipo I/metabolismo , Compostos Organometálicos/farmacologia , Rutênio/farmacologia , Inibidores da Topoisomerase/administração & dosagem , Inibidores da Topoisomerase/farmacologia , Administração Oral , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , Bovinos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA/antagonistas & inibidores , DNA/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Rutênio/administração & dosagem , Rutênio/química , Soroalbumina Bovina/antagonistas & inibidores , Soroalbumina Bovina/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/químicaRESUMO
Despite the resistance developed by the Mycobacterium tuberculosis (MTb) strains, isoniazid (INH) has been recognized as one of the best drug for treatment of Tuberculosis (Tb). The coordination of INH to ruthenium metal centers was investigated as a strategy to enhance the activity of this drug against the sensitive and resistant strains of MTb. The complexes trans-[Ru(NH3)4(L)(INH)](2+) (L=SO2 or NH3) were isolated and their chemical and antituberculosis properties studied. The minimal inhibitory concentration (MIC) data show that [Ru(NH3)5(INH)](2+) was active in both resistant and sensitive strains, whereas free INH (non-coordinated) showed to be active only against the sensitive strain. The coordination of INH to the metal center in both [Ru(NH3)5(INH)](2+) and trans-[Ru(NH3)4(SO2)(INH)](2+) complexes led to a shift in the INH oxidation potential to less positive values compared to free INH. Despite, the ease of oxidation of INH did not lead to an increase in the in vitro INH activity against MTb, it might have provided sensitivity toward resistant strains. Furthermore, ruthenium complexes with chemical structures analogous to those described above were synthesized using the oxidation products of INH as ligands (namely, isonicotinic acid and isonicotinamide). These last compounds were not active against any strains of MTb. Moreover, according to DFT calculations the formation of the acyl radical, a proposed intermediate in the INH oxidation, is favored in the [Ru(NH3)5(INH)](2+) complex by 50.7kcalmol(-1) with respect to the free INH. This result suggests that the stabilization of the acyl radical promoted by the metal center would be a more important feature than the oxidation potential of the INH for the antituberculosis activity against resistant strains.