In vitro antitumour activity of water soluble Cu(I), Ag(I) and Au(I) complexes supported by hydrophilic alkyl phosphine ligands

Hydrophilic, monocationic [M(L)4]PF6 complexes (M=Cu or Ag; L: thp = tris(hydroxymethyl)phosphine, L: PTA = 1,3,5-triaza-7-phosphaadamantane, L: thpp=tris(hydroxypropyl)phosphine) were synthesized by ligand exchange reaction starting from [Cu(CH3CN)4]PF6 or AgPF6 precursors at room temperature in the presence of an excess of the relevant phosphine. The related [Au(L)4]PF6 complexes (L=thp, PTA or thpp) were synthesized by metathesis reactions starting from [Au(L)4]Cl at room temperature in the presence of equimolar quantity of TlPF6. The three series of complexes [M(L)4]PF6 were tested as cytotoxic agents against a panel of several human tumour cell lines also including a defined cisplatin resistant cell line. These investigations have been carried out in comparison with the clinically used metallodrug cisplatin and preliminary structure–activity relationships are presented. The best results in terms of in vitro antitumour activity were achieved with metal-thp species and, among the coinage metal complexes, copper derivatives were found to be the most efficient drugs. Preliminary studies concerning the mechanism of action of these [M(L)4]PF6 species pointed to thioredoxin reductase as one of the putative cellular targets of gold and silver complexes and provided evidence that copper derivatives mediated their cytotoxic effect through proteasome inhibition.