title: In vitro antitumour activity of water soluble Cu(I), Ag(I) and Au(I) complexes supported by hydrophilic alkyl phosphine ligands.
abstract: Hydrophilic, monocationic [M(L)(4)]PF(6) 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(CH(3)CN)(4)]PF(6) or AgPF(6) precursors at room temperature in the presence of an excess of the relevant phosphine. The related [Au(L)(4)]PF(6) 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 TlPF(6). The three series of complexes [M(L)(4)]PF(6) 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)]PF(6) 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.
authors.affiliation: School of Science and Technology-Chemistry Division, Università di Camerino, via S. Agostino 1, 62032 Camerino, Macerata, Italy. carlo.santini@unicam.it
authors.forename: Carlo
authors.initials: C
authors.lastname: Santini
authors.forename: Maura
authors.initials: M
authors.lastname: Pellei
authors.forename: Grazia
authors.initials: G
authors.lastname: Papini
authors.forename: Barbara
authors.initials: B
authors.lastname: Morresi
authors.forename: Rossana
authors.initials: R
authors.lastname: Galassi
authors.forename: Simone
authors.initials: S
authors.lastname: Ricci
authors.forename: Francesco
authors.initials: F
authors.lastname: Tisato
authors.forename: Marina
authors.initials: M
authors.lastname: Porchia
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Rigobello
authors.forename: Valentina
authors.initials: V
authors.lastname: Gandin
authors.forename: Cristina
authors.initials: C
authors.lastname: Marzano
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003300:Copper; D004354:Drug Screening Assays, Antitumor; D006046:Gold; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008024:Ligands; D010720:Phosphines / Q000737:chemistry*; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D051381:Rats; D012834:Silver; D013329:Structure-Activity Relationship; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors
chemical_list: D056831:Coordination Complexes; D008024:Ligands; D010720:Phosphines; D061988:Proteasome Inhibitors; D012834:Silver; D006046:Gold; D003300:Copper; D013880:Thioredoxin-Disulfide Reductase; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease