Strong inhibition of thioredoxin reductase by highly cytotoxic gold(I) complexes. DNA binding studies

• Aminophosphine gold(I) thiolates show excellent cytotoxic activity.
• HeLa and MCF-7 cell lines were tested.
• Very strong inhibition of the thioredoxin reductase has been found.
• DNA binding interactions of the complexes with DNA were investigated.
• Interactions of complexes with calf thymus (CT-) DNA have been verified.
• These interactions do not cause significant changes in its structure.

Biological properties of a series of aminophosphine-thiolate gold(I) complexes [Au(SR)(PPh2NHpy)] [Ph2PNHpy = 2-(diphenylphosphinoamino)pyridine; HSR = 2-mercaptopyridine (2-HSpy) (3), 2-mercaptonicotinic acid (2-H2-mna) (4), 2-thiouracil (2-HTU) (5) or 2-thiocytosine (2-HTC) (6)] and [Au(SR){PPh2NH(Htrz)}] [Ph2PNH(Htrz) = 3-(diphenylphosphinoamino)-1,2,4-triazole]; HSR = 2-mercaptopyridine (2-HSpy) (7), 2-thiocytosine (2-HTC) (8) or 6-thioguanine (6-HTG) (9) have been studied. Their antitumor properties have been tested in vitro against two tumor human cell lines, HeLa (derived from cervical cancer) and MCF-7 (derived from breast cancer), using a metabolic activity test (3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide, MTT). Some of them showed excellent cytotoxic activity. With the aim to obtain more information about the mechanisms of action of these derivatives, the interactions of complexes 3, 5, 7 and 9 with thioredoxin reductase in HeLa cells were studied. They showed a potent inhibition of thioredoxin reductase activity. In order to complete this study, interactions of the complexes with calf thymus (CT-) DNA and with different bacterial DNAs, namely the plasmid pEMBL9 and the promoter region of the furA (ferric uptake regulator A) gene from Anabaena sp. PCC 7120 were investigated. Although interactions of complexes with CT-DNA have been verified, none of them cause significant changes in its structure.

Aminophosphine gold(I) thiolate complexes showed strong cytotoxic activity and strong inhibition of thioredoxin reductase. Coordination studies to DNA were performed.Figure optionsDownload as PowerPoint slide