title: Strong inhibition of thioredoxin reductase by highly cytotoxic gold(I) complexes. DNA binding studies.
abstract: 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.
authors.affiliation: Departamento de Química Inorgánica, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), Universidad de Zaragoza-CSIC, E-50009 Zaragoza, Spain.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Ortego
authors.forename: Fátima
authors.initials: F
authors.lastname: Cardoso
authors.forename: Soraia
authors.initials: S
authors.lastname: Martins
authors.forename: María F
authors.initials: MF
authors.lastname: Fillat
authors.forename: Antonio
authors.initials: A
authors.lastname: Laguna
authors.forename: Margarida
authors.initials: M
authors.lastname: Meireles
authors.forename: M Dolores
authors.initials: MD
authors.lastname: Villacampa
authors.forename: M Concepción
authors.initials: MC
authors.lastname: Gimeno
mesh_terms: D017033:Anabaena / Q000235:genetics; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006046:Gold / Q000737:chemistry*; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells / Q000187:drug effects; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; D006046:Gold; D004247:DNA; C427203:calf thymus DNA; D013880:Thioredoxin-Disulfide Reductase
keywords: Aminophosphine ligands; Antitumor properties; DNA binding; Gold(I); Thiolate compounds; Thioredoxin reductase