Caracterização e investigação biológica de complexos de Ir(III) com potencial atividade anticancerígena

Abstract

Currently, most metallodrugs used in anticancer treatment are platinum-based complexes. Despite their clinical success, these complexes have restrictions such as, high toxicity causing side effects and resistance to some cancer cell lines. These issues stimulated the search for new metals with different mechanisms of action. In this study, nine (9) organometallic complexes of Ir (III) of the type [Cp * Ir (XY) Z]0/+/+2, where XY = bipyridine, phenanthroline, dipyridophenazine and phenylpyridine and Z = NO2-, indazole and 7-azaindole were synthesised. These compounds were prepared aiming to modulate the cytotoxicity by structural replacements, which were investigated for anti-cancer activity in a screening using three cancer cell lines. Interestingly, three iridium complexes containing distinct chelating ligands did not show any enhancement on anti-cancer activity using as a NO2- ligand. However, for the complex containing dipyridophenazine (dppz) as a chelating agent, it was observed almost double of cytotoxic activity in all cancer cell lines when compared with already active precursor containing chloride. Beside those results, using 7-azaindole as Z ligand, it was observed moderate activity and much higher when compared with inactive precursor containing chloride and also analogous containing indazole. Aiming to understand the mechanism of action for these complexes, it was investigated, preliminarily, DNA as a molecular target. Both complexes containing dppz as chelating ligand showed nuclease activity using plasmid DNA monitored by agarose gel electrophoresis, and also an enhanced activity when subjected to ultraviolet light irradiation (290nm) for 30 minutes. The complex 1-ain had also its interaction with DNA investigated by agarose gel electrophoresis, but it did not show similar differences with indazole or any expressive activity. So, it is possible to expect a different biological target to explain its expressive increase in cytotoxicity. A complex containing 7-azaindole and dppz chelator was synthesized (3-ain) exhibiting nuclease activity, hypochromic effect upon titration with CT-DNA and displacement of ethidium bromide bound to CT-DNA supporting a possible mode of interaction to DNA through intercalation. All together these results support our structural strategy can generate new anti-cancer agents.