Complexos de In(III) com ligantes bioativos: propriedades físico-químicas e atividade antineoplásica de alguns complexos

Abstract

In the present work indium(III) complexes with the ligands lapachol (lap), lausone (lau), naringenin (nar) and 2-formyl-8-hidroxiquinoline-derived hydrazones were obtained and their physico-chemical properties were investigated. The antineoplastic effects of selected complexes against breast tumor cells were evaluated. Novel complexes [In(lap)Cl2]·4H2O (1), [In(lap)2Cl]·Et3N (2), [In(lap)3]·2H2O (3), cis-[In(lap)(bipy)Cl2] (4) bipy = 2,2’- bipyridine and cis- [In(lap)(phen)Cl2] (5) phen= 1,10-phenanthroline were synthesized. Lapachol did not show significant cytotoxic effects against MCF-7 ad MDA-MB-231 tumor cells. The cytotoxic effects did not increase upon coordination to indium(III) in complexes (1-3), but significantly increased in complex cis-[In(lap)(phen)Cl2] (5). Although both complexes (4) and (5) interacted with DNA in vitro by an intercalative mode, only (5) exhibited cytotoxicity against MCF-7 and MDA-MB breast tumor cells. 1,10-phenanthroline and complex (5) presented cytotoxic effects against MCF-7 and MDA-MB cells, with complex (5) being three-fold more active than 1,10-phenanthroline on MCF-7 cells. In addition, complex (5) significantly reduced the formation of MDA-MB-231 colonies in a clonogenicity assay. cis-[In(lap)(phen)Cl2] (5) showed cytotoxic effects against non-malignant HEK-293 cells, but its selectivity index, was 30-fold higher than that of doxorrubicin used as control on MCF-7 and 7-fold more active than doxorubicin against MDA-MB-231 cells. The results suggest that the presence of 1,10-phenanthroline exerted a crucial role in the cytotoxic effects of complex (5) and that the inclusion of 1,10-phenanthroline as co-ligant proved to be a valuable strategy for increasing cytotoxicity due to its own cytotoxic effects and to its ability to vectorize the complex to DNA. Complexes [In(lau)(bipy)Cl2] (6) and [In(lau)(phen)Cl2] (7) were synthesized with lausone. The crystal structure of [In(lau)(bipy)Cl2] (6) was determined. Complexes [In(nar)Cl2]·6H2O (8) and [In(nar)2Cl]·Et3N (9) with naringenin were obtained as well. The reaction of indium(III) chloride with 2-formyl-8-hydroxyquinoline-4-nitroimidazole hydrazone (H2L1) in ethanol gave [In(H2L1)(HL1)Cl2], complex (1) as the product. The reaction with 2-formyl-8-hydroxyquinoline-4-nitrobenzene hydrazone (H2L2) in methanol gave [In(HL2)Cl2(CH3OH)], complex (2), as the product while [In(HL2)Cl2]·CH3CH2OH, complex (3), was formed as the product using ethanol as solvent. The crystal structure of the complex [In(HL2)Cl2(CH3OH)] (2) was determined. Theoretical DFT calculations suggested that complex [In(H2L1)(HL1)Cl2] (1) presents coordination number (CN) 8, with one neutral and one anionic ligand coordinated to the metal center through the O-Npy-N tridentate chelating system together with two chloride ions. Experimental data indicated that in complexes [In(HL2)Cl2(CH3OH)] (2) and [In(HL2)Cl2]·CH3CH2OH (3) one anionic ligand is attached to the indium(III) center through the O-Npy-N-O tetradentate chelating system along with two chlorides. A coordinated methanol molecule completes the indium(III) coordination sphere in complex [In(HL2)Cl2CH3OH] (2). DFT calculations revealed that complex [In(HL2)Cl2(CH3OH)] (2) presents CN 7, with bond lengths in accordance with the experimental values. The calculated electronic spectra of complexes [In(H2L1)(HL1)Cl2] (1) and [In(HL2)Cl2(CH3OH)] (2) were in agreement with the experimental spectra and allowed the attribution of the absorption peaks to π - π* transitions. The present work is an important contribution to understanding indium(III) coordination chemistry and the antitumoral properties of indium(III) complexes.