title: Chemistry and biology of two novel gold(I) carbene complexes as prospective anticancer agents.
abstract: Two novel gold carbene compounds, namely, chlorido (1-butyl-3-methyl-imidazole-2-ylidene) gold(I) (1) and bis(1-butyl-3-methyl-imidazole-2-ylidene) gold(I) (2), were prepared and characterized as prospective anticancer drug candidates. These compounds consist of a gold(I) center linearly coordinated either to one N-heterocyclic carbene (NHC) and one chloride ligand (1) or to two identical NHC ligands (2). Crystal structures were solved for both compounds, the resulting structural data being in good agreement with expectations. We wondered whether the presence of two tight carbene ligands in 2 might lead to biological properties distinct from those of the monocarbene complex 1. Notably, in spite of their appreciable structural differences, these two compounds manifested similarly potent cytotoxic actions in vitro when challenged against A2780 human ovarian carcinoma cells. In addition, both were able to overcome resistance to cisplatin in the A2780R line. Solution studies revealed that these gold carbene complexes are highly stable in aqueous buffers at physiological pH. Their reactivity with proteins was explored: no adduct formation was detected even upon a long incubation with the model proteins cytochrome c and lysozyme; in contrast, both compounds were able to metalate, to a large extent, the copper chaperone Atox-1, bearing a characteristic CXXC motif. The precise nature of the resulting gold-Atox-1 adducts was elucidated through ESI-MS analysis. On the basis of these findings, it is proposed that the investigated gold(I) carbene compounds are promising antiproliferative agents warranting a wider pharmacological evaluation. Most likely these gold compounds produce their potent biological effects through selective metalation and impairment of a few crucial cellular proteins.
authors.affiliation: Laboratory of Metals in Medicine, Department of Chemistry, University of Florence , via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Messori
authors.forename: Lorella
authors.initials: L
authors.lastname: Marchetti
authors.forename: Lara
authors.initials: L
authors.lastname: Massai
authors.forename: Federica
authors.initials: F
authors.lastname: Scaletti
authors.forename: Annalisa
authors.initials: A
authors.lastname: Guerri
authors.forename: Ida
authors.initials: I
authors.lastname: Landini
authors.forename: Stefania
authors.initials: S
authors.lastname: Nobili
authors.forename: Gabriele
authors.initials: G
authors.lastname: Perrone
authors.forename: Enrico
authors.initials: E
authors.lastname: Mini
authors.forename: Piero
authors.initials: P
authors.lastname: Leoni
authors.forename: Marco
authors.initials: M
authors.lastname: Pasquali
authors.forename: Chiara
authors.initials: C
authors.lastname: Gabbiani
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005260:Female; D006046:Gold / Q000737:chemistry*; D006801:Humans; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry; D015394:Molecular Structure; D010051:Ovarian Neoplasms / Q000188:drug therapy
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; C030011:carbene; D006046:Gold; D008697:Methane