RESUMO
(C^N) and (C^N^C) cyclometalated Au(iii) represent a highly promising class of potential anticancer agents. We report here the synthesis of seven new cyclometalated Au(iii) complexes with five of them bearing an acridine moiety attached via (N^O) or (N^N) chelates, acyclic amino carbenes (AAC) and N-heterocyclic carbenes (NHC). The antiproliferative properties of the different complexes were evaluated in vitro on a panel of cancer cells including leukaemia, lung and breast cancer cells. We observed a trend between the cytotoxicity and the intracellular gold uptake of some representative compounds of the series. Some of the acridine-decorated complexes were demonstrated to interact with ds-DNA using FRET-melting techniques.
Assuntos
Acridinas/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Compostos Organoáuricos/síntese química , Compostos Organoáuricos/farmacologia , Antineoplásicos/química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , DNA/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Glutationa/metabolismo , Humanos , Modelos Moleculares , Conformação Molecular , Compostos Organoáuricos/química , Compostos Organoáuricos/metabolismoRESUMO
A series of cationic mixed cyclometallated (C^N)Au(iii) dithiocarbamate complexes has been synthesized in good yields [HC^N = 2-(p-t-butylphenyl)pyridine]. The crystal structure of [(C^N)AuS2CNEt2]PF6 (3) has been determined. The cytotoxic properties of the new complexes have been evaluated in vitro against a panel of human cancer cell lines and healthy cells and compared with a neutral mixed (C^C)Au(iii) dithiocarbamate complex (C^C = 4,4'-di-t-butylbiphenyl-2,2'-diyl). The complexes appeared to be susceptible to reduction by glutathione but were stable in the presence of N-acetyl cysteine. The potential mechanism of action of this class of compounds has been investigated by measuring the intracellular uptake of some selected complexes, by determining their interactions with higher order DNA structures, and by assessing the ability to inhibit thioredoxin reductase. The complexes proved unable to induce the formation of reactive oxygen species. The investigations add to the picture of the possible mode of action of this class of complexes.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/química , Compostos de Ouro/farmacologia , Ouro/química , Tiocarbamatos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Compostos de Ouro/química , Humanos , Células Tumorais CultivadasRESUMO
Gold(III) complexes have emerged as a versatile and effective class of metal-based anticancer agents. The development of various types of ligands capable of stabilizing the AuIII cation and preventing its reduction under physiological conditions, such as chelating nitrogen-donors, dithiocarbamates and C^N cyclometalled ligands, has opened the way for the exploration of their potential intracellular targets and action mechanisms. At the same time, the bioconjugation of AuIII complexes has emerged as a promising strategy for improving the selectivity of this class of compounds for cancer cells over healthy tissues, and recent developments have shown that combining gold complexes with molecular structures that are specifically recognized by the cell can exploit the cell's own transport mechanisms to improve selective metal uptake.
Assuntos
Antineoplásicos/farmacologia , Ouro/química , Compostos Organoáuricos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Humanos , Estrutura Molecular , Compostos Organoáuricos/químicaRESUMO
A series of cyclometallated gold(iii) complexes supported by pyrazine-based (C^Npz^C)-type pincer ligands were synthesized via two different pathways. Nucleophilic attack on the isocyanide complex [(C^Npz^C)Au(C[triple bond, length as m-dash]NC6H3Me2-2,6)]SbF6 (2) gave [(C^Npz^C)Au(ACC)]SbF6 complexes with aniline (4·SbF6), adamantylamine (5), glycine ethyl ester (6), alanine methyl ester (7), valine methyl ester (8), phenylglycine methyl ester (9) and methionine methyl ester (10) substituents (ACC = acyclic carbene). The pathway via isocyanide insertion into gold-amide bonds was also investigated; e.g. the reaction of xylyl isocyanide with (C^Npz^C)AuNHPh followed by protonation with HBF4·OEt2 gave the acyclic carbene complex 4·BF4. To the best of our knowledge compounds 6-10 represent the first examples of gold(iii) acyclic carbene complexes bearing amino acid functions. The compounds provide a versatile platform for the study of the anti-proliferative properties of gold(iii) complexes. Tests against human adenoma-type lung cancer cells identified 5, 6, 7 and 10 as particularly promising and demonstrate the synthetic flexibility of acyclic carbene complexes and the potential of that class of compounds for anticancer applications. Compared to cisplatin, amino ester-containing ACC complexes showed improved selectivity for MCF-7 breast cancer cells over that for healthy fibroblasts.