Complexos de ouro(I) derivados do adamantano: síntese, atividade citotóxica e potencial de inibição da tiorredoxina redutase

Abstract

This work describes the synthesis, characterization, cytotoxic activity and potential inhibition of thioredoxin reductase (TrxR) of four new gold (I) complexes with novel ligands derived from adamantine, 1,3,4-oxadiazole or 1,3-thiazolidine-2-thionering and alkyl or aryl phosphines. The cytotoxicity of compounds was investigated in three tumor cell lines and one normal cell to determine the inhibitory concentration of fifty percent of cell viability (IC50) and selectivity index (SI). One of the most important applications for metal complexes such as Cisplatin [cis-diamindichloroplatinum(II)] and derivatives is in cancer treatment. However, there are several problems associated with their use, especially cellular resistance, developed by some tumor cells, and serious side effects. Those problems create a demand for new compounds more active against cancer and less toxic to patient. In this context, the search for complexes with other metals that present different cellular targets appeared to circumvent such problems. The action of platinum complexes occurs preferentially on DNA while the gold action is related to the inhibition of the enzyme TrxR which participates in intracellular redox balance. To enhance biological activity of gold complexes we prepared ligands containing adamantane with heterocyclic ring oxadiazole or thiazolidine and phosphines (trimethyl or triphenyl) which are present in bioactive substances. The synthesized compounds were characterized by CHN, 1H and 13C NMR, IR, Raman, TG and X-ray diffraction for ligands and complex 1 {triphenylphosphin[5-adamantyl-1,3,4-oxadiazole-2- thiolate(κS)]gold(I)}. All complexes were more active against tumor cells compared to the free ligands and more efficient and selective than cisplatin for melanoma cell line (B16-F10). The complex 4 {Triethylphosphine chloride[(metyl-1-adamantane)1,3-thiazolidine-2- thione(κS)]gold(I)} showed IC50 values near Auranofin [2,3,4,6-tetra-o-acetyl-1-thio-β-Dglycopyranosate- trietylphosphingold(I)] and higher selectivity. The ability to inhibit TrxR was most relevant for the complexes with ethyl phosphine reaching the inhibition promoted by Auranofin. We have observed a relationship among the capacity to inhibit TrxR, structure and cytotoxicity which contributes to confirm the mechanism of action for gold compounds. Thus, this study is an important contribution to the coordination chemistry of gold(I) complexes.