Chemical Modification of Auranofin Yields a New Family of Anticancer Drug Candidates: The Gold(I) Phosphite Analogues
Damiano Cirri,
Andrea Geri,
Lara Massai,
Michele Mannelli,
Tania Gamberi,
Francesca Magherini,
Matteo Becatti,
Chiara Gabbiani,
Alessandro Pratesi,
Luigi Messori
Affiliations
Damiano Cirri
Department of Chemistry and Industrial Chemistry, University of Pisa, Via G. Moruzzi 13, 56124 Pisa, Italy
Andrea Geri
Laboratory of Metals in Medicine (MetMed), Department of Chemistry “Ugo Schiff”, University of Florence, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, Italy
Lara Massai
Laboratory of Metals in Medicine (MetMed), Department of Chemistry “Ugo Schiff”, University of Florence, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, Italy
Michele Mannelli
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale G.B. Morgagni 50, 50134 Firenze, Italy
Tania Gamberi
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale G.B. Morgagni 50, 50134 Firenze, Italy
Francesca Magherini
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale G.B. Morgagni 50, 50134 Firenze, Italy
Matteo Becatti
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale G.B. Morgagni 50, 50134 Firenze, Italy
Chiara Gabbiani
Department of Chemistry and Industrial Chemistry, University of Pisa, Via G. Moruzzi 13, 56124 Pisa, Italy
Alessandro Pratesi
Department of Chemistry and Industrial Chemistry, University of Pisa, Via G. Moruzzi 13, 56124 Pisa, Italy
Luigi Messori
Laboratory of Metals in Medicine (MetMed), Department of Chemistry “Ugo Schiff”, University of Florence, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, Italy
A panel of four novel gold(I) complexes, inspired by the clinically established gold drug auranofin (1-Thio-β-D-glucopyranosatotriethylphosphine gold-2,3,4,6-tetraacetate), was prepared and characterized. All these compounds feature the replacement of the triethylphosphine ligand of the parent compound auranofin with a trimethylphosphite ligand. The linear coordination around the gold(I) center is completed by Cl−, Br−, I− or by the thioglucose tetraacetate ligand (SAtg). The in-solution behavior of these gold compounds as well as their interactions with some representative model proteins were comparatively analyzed through 31PNMR and ESI-MS measurements. Notably, all panel compounds turned out to be stable in aqueous media, but significant differences with respect to auranofin were disclosed in their interactions with a few leading proteins. In addition, the cytotoxic effects produced by the panel compounds toward A2780, A2780R and SKOV-3 ovarian cancer cells were quantitated and found to be in the low micromolar range, since the IC50 of all compounds was found to be between 1 μM and 10 μM. Notably, these novel gold complexes showed large and similar inhibition capabilities towards the key enzyme thioredoxin reductase, again comparable to those of auranofin. The implications of these results for the discovery of new and effective gold-based anticancer agents are discussed.
