Síntese e caracterização de complexos de Ag(I) e Au(I) contendo ligantes carbenos N-heterocíclicos, potenciais agentes anticâncer e o estudo de seus possíveis mecanismos de ação

Abstract

Cancer is one of the major public health challenges worldwide, leading to a significant demand for more effective and less toxic medications. Rational strategies and approaches are employed to optimize the design and synthesis of potential new drugs. Knowing the anticancer activity of well-known antifungal agents like Clotrimazole (CTZ) and Ketoconazole (KTZ), the study aimed to investigate whether the coordination type would influence the biological activity of different metal complexes containing these azoles and their N-heterocyclic carbene (NHC) derivatives as ligands. To address this, two imidazolic salts, L1 [(CTZ-Me)I] and L2 [(KTZMe)I], were synthesized and characterized by reactions between the azole of interest and iodomethane. Additionally, the synthesis and characterization of all ligands with silver(I) Ag(L1)(I)].H2O (1), [Ag(L1)2]I.4CH2Cl2 (2), [Ag(CTZ)2]NO3 (3), [Ag(L2)(I)] (4), [Ag(L2)2]I.2CH2Cl2 (5), and [Ag(KTZ)2]NO3 (6), as well as gold(I) [Au(L1)(Cl)].2CH2Cl2 (7), [Au(CTZ)(Cl)] (8), [Au(L2)(Cl)] (9), and [Au(KTZ)(Cl)] (10) complexes, were carried out. All metal complexes and their original ligands were characterized, when possible, using infrared (IR) and ultraviolet-visible (UV-Vis) spectroscopies, electrospray ionization mass spectrometry (ESI-MS), nuclear magnetic resonance (1H and 13C NMR), and elemental analysis of carbon, hydrogen, and nitrogen (CHN). Their structures were proposed based on the analysis of all data, and, in the case of metal complex 7, through the elucidation of the crystallographic structure of its crystals. Cytotoxicity studies demonstrated the effects of these compounds on different tumor and non-tumor cells. Results revealed that the silver(I) complex derived from ligand L1 (1) exhibited ten times greater cytotoxicity than its original ligand against human metastatic breast adenocarcinoma cells, a highly aggressive lineage. It was also at least fifteen times more active against murine breast carcinoma cells (4TI). The gold(I) complex (7) showed six times more cytotoxicity than its original ligand against MDA-MB-231 cells. Silver(I) complexes were more active than free ligands, with complexes 4 and 5 being the most selective for the B16-F1 cancer cell lineage. These results strongly suggest that the coordination of the ligand to the metal ion may have influenced the biological activity of the compounds in the studied lineages. Furthermore, the interaction of the synthesized metal complexes with DNA, bovine serum albumin (BSA) (only for silver(I) complexes), and glutathione (GSH) (only for gold(I) complexes) was evaluated. DNA interaction studies using techniques such as spectrophotometric titration, viscosity, and electrophoresis (for silver(I) compounds) indicated that DNA is not the target of these compounds, suggesting that cytotoxicity may be related to another biomolecular target. In interactions with BSA, silver(I) complexes demonstrated electrostatic interaction, suggesting potential interaction, transport, or retention of these compounds by the protein. Experiments with GSH and gold(I) complexes (7-10) revealed strong interaction with glutathione, indicating a rapid reaction of these complexes with this biomolecule, potentially affecting its stability in the cell. The notable interaction with glutathione also suggests high reactivity with other enzymes, such as TrxR, which also contains cysteines in its structure.