Síntese e avaliação do potencial antitumoral de complexos de cobre(II) e níquel(II) contendo ligantes de interesse biológico

Abstract

The discovery of the antitumor properties of cisplatin represented an advance in the fight against cancer, since there has been a significant increase in cure rates for some cancers. However, besides the cisplatin having serious side effects, there is also intrinsic or acquired resistance, which compromises the efficiency of the treatment, making it necessary to develop new drugs with different mechanisms of action that are also safer and more effective. In this perspective, thirteen new NiII and CuII complexes coordinated to different classes of ligands such as β-diketone, hydrazide and iminopyridine were synthesized and characterized by elemental analysis, conductivity and magnetic susceptibility measurements, high-resolution electrospray ionization mass spectrometry (HRESIMS), spectroscopy techniques (UV-vis, diffuse reflectance, FT-IR and EPR) and by single crystal X-ray analysis. Afterwards, the antitumoral activity of these complexes were evaluated against different breast cancer cell lines (MCF-7 e MDA-MB-231). As to the structures, the Ni(II) complexes coordinated to the β-diketone, phenanthroline and nitrate ligands of the type [Ni(η2-NO3)(O,O)(phen)] (O,O = 4.4, 4-trifluoro-1-phenyl-1,3-butanedione (bta), 4-chlorophenyl-4,4,4-trifluoro-1,3-butanedione (btc), 4,4,4-trifluoro-1- (2 -furil) -1,3-butanedione (btf) and phen = phenanthroline), showed a distorted octahedral geometry with all ligands coordinated in a bidentate mode, as verified by single crystal analysis of the complex [Ni(η2-NO3)(btc)(phen)]. Three other Cu(II) complexes of the type [Cu(bth)(N-donor)](NO3)2 (bth = 4-benzopyran[4,3]thiophene-2-carboxylic acid hydrazide; N-donor = phenanthroline, dimethoxybipyridine or terpyridine) were also obtained and the spectroscopic data indicate that the ligands coordinate in a bidentate or tridentate mode. Posteriorly, the third class of Cu(II) compounds of the type [Cu(N,N)2(NO3)2] and [Cu(N,N)(N,N,N)](PF6)2 (N,N = 4-chloro-N-(pyryridine-2-methylene) aniline (Clmp), 2,6-diethyl-N-(pyriridine-2 methylene) aniline (diemp), 2,6-diisopropyl-N-(pyryridine-2-methylene) aniline (diipmp), 4-methyl-N-(pyryridine-2-methylene) aniline (memp) and N,N,N = 4-methylphenylterpyridine) was synthesized and characterized. Regarding biological activity, the most promising results of cytotoxicity against cell lines MCF-7 and MDA-MB-231 were obtained with the Ni(II) and Cu(II) complexes coordinated to β-diketone and hydrazide, respectively, since they exhibited IC50 values in the micromolar range. DNA binding studies were perfomed by the techniques such as UV-vis, dichroism and fluorescence spectroscopy. These techniques suggest an electrostatic interaction or/and a bond in the DNA groove of the Ni(II) and Cu(II) compounds coordinated to β-diketone and hydrazide. The data from molecular docking followed by semi-empirical simulations of the Ni(II) compounds reinforce that they are capable of binding in the minor groove of the double helix of ct-DNA in an A-T rich region. DNA cleavage studies indicated that the complex [Ni(η2-NO3)(btc)(phen)] cleaves plasmid DNA in the presence of H2O2. Posteriorly, it was verified that the compounds [Ni(η2-NO3)(bta)(phen)] and [Ni(η2-NO3)(btc)(phen)] induces late apoptosis in MCF-7 cells. Additionally, in vitro cell migration studies have shown that Cu(II) compounds with bth hydrazide have remarkable antimetastatic activity in the MCF-7 and MDA-MB-231 cells.