title: Cytotoxic gold compounds: synthesis, biological characterization and investigation of their inhibition properties of the zinc finger protein PARP-1.
abstract: The new gold(III) complexes: [Au{2-(2'-pyridyl)imidazolate}Cl(2)] and [Au{2,6-bis(2'-benzimidazolate)pyridine}(OCOCH(3))] and the mono- and binuclear gold(I) complexes: [Au{2-(2'-pyridyl)imidazole}(PPh(3))](PF(6)), [Au(2-phenylimidazolate)(DAPTA)] (DAPTA = 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane), [(PPh(3)Au)(2)(2-R-imidazolate)](PF(6)) (R = 2-C(5)H(4)N, Ph) have been synthesized and characterized. The structure of the [(PPh(3)Au)(2){2-(2'-pyridyl)imidazolate)](PF(6)) complex was also characterized by X-ray crystallography. The antiproliferative properties of the complexes were assayed against human ovarian carcinoma cell lines, either sensitive (A2780) or resistant to cisplatin (A2780cisR), human mammary carcinoma cells (MCF7) and non-tumorigenic human kidney (HEK293) cells. Most of the studied compounds showed important cytotoxic effects. Interestingly, the compounds containing the 2-(2'-pyridyl)imidazolate ligand showed selectivity towards cancer cells with respect to the non-tumorigenic ones, with the dinuclear compound [(PPh(3)Au)(2){2-(2'-pyridyl)imidazolate)](PF(6)) being the most active. Some compounds were also screened for their inhibitory effect of the zinc-finger protein PARP-1, essential for DNA repair and relevant to the mechanisms of cancer cell resistance to cisplatin. Interaction studies of the compounds with the model protein ubiquitin were undertaken by electrospray ionization mass spectrometry (ESI MS). The results are discussed in relation to the putative mechanisms of action of the cytotoxic gold compounds.
authors.affiliation: Department of Chemistry, University of Sassari, Sassari, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Serratrice
authors.forename: Fabio
authors.initials: F
authors.lastname: Edafe
authors.forename: Filipa
authors.initials: F
authors.lastname: Mendes
authors.forename: Rosario
authors.initials: R
authors.lastname: Scopelliti
authors.forename: Shaik Mohammed
authors.initials: SM
authors.lastname: Zakeeruddin
authors.forename: Michael
authors.initials: M
authors.lastname: Grätzel
authors.forename: Isabel
authors.initials: I
authors.lastname: Santos
authors.forename: Maria Agostina
authors.initials: MA
authors.lastname: Cinellu
authors.forename: Angela
authors.initials: A
authors.lastname: Casini
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003603:Cytotoxins / Q000138:chemical synthesis*; D005260:Female; D006801:Humans; D050607:Organogold Compounds / Q000138:chemical synthesis / Q000633:toxicity*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
chemical_list: D003603:Cytotoxins; D050607:Organogold Compounds; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1