Síntese, caracterização e avaliação da atividade biológica de derivados obtidos de complexos de rutênio-areno

Abstract

The present work aims the study of organometallics compounds of Ru(II)(η6-p-cymene), including ligands such as triarylphosphines (PAr3), mono and 3,5-disubstituted and N heterocyclic 3-methylpyridine (N). For this purpose, the synthesis of the ligand Ar= 3,5-di-tert-butylphenyl (L1) and its reactivity with O, S, Se were performed, in order to obtain its novel and stable derivatives E = PAr3 (L5-L7). In addition to L1, the ligands with the group Ar= 3,5-dimethylphenyl (L2), 4-methoxy-3,5-dimethylphenyl (L3) and 4-methoxyphenyl (L4) were used in the synthesis of a series of neutral complexes, [Ru(η6-p-cymene)PAr3Cl2] (1-4), and cationic, Ru(η6-p-cymene)PAr3NCl] (5-8). The composition and structure of the compounds were elucidated based on elementary analysis, spectroscopic techniques, such as 31P{1H}, 1H, 13C{1H} NMR, FTIR, UV-Vis, in addition to molar conductivity. Among the complexes obtained, only 4 is reported in the literature, however, without crystallographic characterization and biological studies. Theoretical calculations obtained by the DFT technique evaluated the stereochemistry and the effect of the L1 steric hidrance. The crystallographic structures of complexes 1-4 and 5-8 were elucidated by monocrystal X ray diffractometry and the DFT calculations of these complexes helped to determine the molecular and electronic structures, in order to assist in the interpretation of the results of UV-Vis spectroscopy and cyclic voltammetry, and the results of these techniques indicate that the PAr3 and N ligands stabilize the Ru (II)-(η6-p-cymene) unit. The complexes were subjected to evaluation of cytotoxic activity against the cell lines MRC-5 (non-tumor lung), A549 (lung cancer), MDA-MB-231 (breast cancer), U2-OS (human bone cancer) and the results revealed that 1, 2 and 4 show high cytotoxicity, with 1 being inactive in relation to the MRC-5 cell line, indicating good selectivity. Complexes 5-8 showed promising activity. The antibacterial tests performed by diffusion disc and by determining the minimum inhibitory concentration (MIC), against Gram positive (S.aureus and B.subtilis) and Gram negative (E.coli) bacteria models, demonstrated low MIC values, mainly for some complexes in the series (5-8). From these preliminary, but promising results, a probable mechanism of action through viscosity was investigated in order to evaluate the interaction of complexes with DNA. Data obtained from fluorescence microscopy and microfluidics techniques indicated that the possible interaction of these complexes in the biological environment can be with cell membranes. Thus, studies of Langmuir monolayers were performed with cancer membrane models (DPPS = 1,2-dipal-mitoil-sn-glycero-3-phospho-L-serine sodium), of bacteria (S. aureus with 55% 1,2-dioleoyl-sn-glycerol-3-phosphatidylglycerol (DOPG) and 45% cardiolipin (CL)) and healthy cells (DOPC= 2-dioleoyl-sn-glycero-3-phospho-choline). By pressure and potential isotherm measurements, it was noted that the complexes altered the ordering of the membranes, indicating possible interaction, correlating with their biological potential.