Structural and solution chemistry, protein binding and antiproliferative profiles of gold(I)/(III) complexes bearing the saccharinato ligand Laura Maiore a , Maria Agostina Cinellu a, ⁎, Elena Michelucci b , Gloriano Moneti b , Stefania Nobili c , Ida Landini c , Enrico Mini c , Annalisa Guerri d , Chiara Gabbiani d , Luigi Messori d, ⁎ a Department of Chemistry, University of Sassari, Via Vienna 2, 07100 Sassari (SS), Italy b Mass Spectrometry Centre, University of Florence, Via U. Schiff 6, 50019 Sesto Fiorentino (FI), Italy c Department of Pharmacology, University of Florence, V.le Pieraccini 6, 50139 Florence, Italy d Department of Chemistry, University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino (FI), Italy abstract article info Article history: Received 26 July 2010 Received in revised form 23 November 2010 Accepted 23 November 2010 Available online xxxx Keywords: Gold compound Protein interactions Cytotoxicity A series of new gold(I) and gold(III) complexes based on the saccharinate (sac) ligand, namely M[Au(sac) 2 ] (with M being Na + ,K + or NH 4 + ), [(PTA)Au(sac)], K[Au(sac) 3 Cl] and Na[Au(sac) 4 ], were synthesized and characterized, and some aspects of their biological profile investigated. Spectrophotometric analysis revealed that these gold compounds, upon dissolution in aqueous media, at physiological pH, manifest a rather favourable balance between stability and reactivity. Their reactions with the model proteins cytochrome c and lysozyme were monitored by mass spectrometry to predict their likely interactions with protein targets. In the case of disaccharinato gold(I) complexes, cytochrome c adducts bearing four coordinated gold(I) ions were preferentially formed in high yield. In contrast, [(PTA)Au(sac)] (PTA = 1,3,5-triaza-7-phosphaadaman- tane) turned out to be poorly effective, only producing a mono-metalated adduct in very low amount. In turn, the gold(III) saccharinate derivatives were less reactive than their gold(I) analogues: K[Au(sac) 3 Cl] and Na[Au (sac) 4 ] caused moderate protein metalation, again with evidence of formation of tetragold adducts. Finally, the above mentioned gold compounds were challenged against the reference human tumor cell line A2780S and its cisplatin resistant subline A2780R and their respective cytotoxic profiles determined. [(PTA)Au(sac)] turned out to be highly cytotoxic whereas moderate cytotoxicities were observed for the gold(III) complexes and only modest activities for disaccharinato gold(I) complexes. The implications of these results are thoroughly discussed in the light of current knowledge on gold based drugs. © 2010 Elsevier Inc. All rights reserved. 1. Introduction Nowadays, gold compounds are drawing a great deal of attention within the Metals in Medicine community owing to their outstanding antiproliferative properties, and are being intensely investigated as a rich source of innovative cytotoxic drugs for cancer treatment [1–3]. Notably, during the last decade, a large number of gold compounds were synthesized and characterized; some of them showing very promising anticancer properties, both in vitro and in vivo. We like to remind here gold(III) porphyrins [4], gold(III) dithiocarbamates [5], some dinuclear gold(III) complexes with bipyridyl ligands [6], a few selected organogold(III) compounds [7–10]. Pairwise, a variety of gold (I) compounds manifested very attractive pharmacological profiles [11–17]. A major issue in the bioinorganic chemistry of gold(III)/(I) compounds, of potential use as anticancer agents, is the obtainment of gold species characterized by a sufficient degree of stability under physiological-like conditions and by the concomitant retention of a still appreciable reactivity toward biomolecular targets as it is usually required for metal-based prodrugs. These goals may be afforded through an appropriate selection of gold(III)/(I) ligands capable of tuning finely the reactivity of the metal center. In any case, a reasonable, sometimes difficult, compromise must be met between stability and reactivity. In addition, an acceptable solubility profile within aqueous solutions is typically required for optimal candidate drugs. With this in mind we have prepared a few novel gold compounds, based on the presence of the saccharinate anion (sac - ) as a ligand, and analysed their solution behaviour within a standard buffer. Their reactions with cytochrome c and with lysozyme, used here as model proteins, were investigated in detail by ESI MS (electrospray ionization mass spectrometry) according to established protocols; their anti- proliferative properties were specifically evaluated against A2780S/R human ovarian carcinoma cells. The choice of saccharinate as a ligand was motivated by a number of reasons. First of all, sodium saccharinate is a compound widely used Journal of Inorganic Biochemistry 105 (2011) 230–237 ⁎ Corresponding authors. Fax: +39 0554573385. E-mail addresses: cinellu@uniss.it (M.A. Cinellu), luigi.messori@unifi.it (L. Messori). 0162-0134/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.jinorgbio.2010.11.016 Contents lists available at ScienceDirect Journal of Inorganic Biochemistry journal homepage: www.elsevier.com/locate/jinorgbio