Novos Complexos de Rutênio Contendo Derivados Imidazólicos: Síntese, Caracterização e Avaliação do Potencial Terapêutico

Abstract

Ruthenium (II) complexes have been under intense research in the last decades due to their high pharmacological potential in the treatment of different diseases, especially cancer. Moreover, coordination compounds containing imidazole derivatives and NOx-like ligands also have been considered as promising systems, based on their versatility and wide range of therapeutic applications (anticancer, bactericidal, antihypertensive, for example). Considering that, the main goal of this work is synthetize new complexes with general formula cis-[RuII(bpy)2L1L2]n+, where bpy=2,2’-bipyridine, L1=2-methylimidazole (2-MIM) or ethylenethiourea (ETU), L2=Cl-, NO_2^-, NO+. The characterization was held using spectroscopic techniques (vibrational spectroscopy in the region of infrared, mass spectroscopy and electronic spectroscopy), 1H nuclear magnetic resonance, cyclic voltammetry and elemental analysis, agreeing with the proposed structures. The nitric oxide (NO0) releasing capability of the synthetized nitrosyl complexes was evaluated under different conditions. The spectroscopic monitoring during the application of electric potential and under blue light irradiation (λmax=460 nm) has indicated aquo-complex formation, suggesting NO0 releasing. cPTIO and Metmyoglobin (Fe3+) were also used as probes for nitric oxide detection and they evidenced the presence of NO during light irradiation, but suggest the formation of nitroxyl (HNO) through reduction with thiols (GSH and L-cysteine). Spectrophotometric titration has showed that compounds cis-[Ru(bpy)2(2-MIM)(NO)]3+ and cis-[Ru(bpy)2(ETU)(NO)]3+ presented NO+/NO_2^- conversion pH value equal to 5,67 and 6,28, respectively. In addition, reactivity of nitrosyl complexes facing superoxide and hydroxyl radicals was studied. The results suggested that both compounds presented antioxidant activity against free radicals. In vitro cytotoxicity assays showed that nitrosyl complexes have low antineoplasic effect, but the compounds cis-[Ru(bpy)2(2-MIM)2]2+ and cis-[Ru(bpy)2(ETU)Cl]+ showed promising results. However, the species cis-[Ru(bpy)2(2-MIM)(NO)]3+ and cis-[Ru(bpy)2(ETU)(NO)]3+, and their respective precursors as well, were very effective during vascular relaxament assays, demonstrating excellent hypotensive action. Taken together, these results evidence the synthesis of new candidates for metallopharmaceuticals with potential application as anticancer and antihypertensive drugs.