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V Simposio Pharmaco-Bio-Metallics Oral Communication Nuovi farmaci inorganici in oncologia COINAGE METAL COMPLEXES CONTAINING NEW SCORPIONATE LIGANDS WITH BIOLOGICAL ACTIVITY M. Mancini1, A. Burini2, R. Galassi2, G. Gioia Lobbia2, C. Marzano3, M. Pellei2, C. Santini2, F. Tisato4 1. C.I.R.C.M.S.B. - Unità di Ricerca di Camerino 2. Dipartimento di Scienze Chimiche, Università di Camerino 3. Dipartimento di Scienze Farmaceutiche, Università di Padova 4. ICIS-C.N.R., Corso Stati Uniti, 4, Padova e-mail: [email protected] Introduction The coordination chemistry of coinage metals with a wide variety of ligands is an important area of chemical research because of the potential use of copper, silver and gold functionalized complexes as therapeutic agents. Gold complexes have been used for biomedical applications in the treatment of rheumatoid arthritis and in chemotherapy [1], and some mixed chelate copper-based drugs have exhibited greater antineoplastic potency than cisplatin in in vitro and in vivo studies of a variety of tumor cell lines [2]. Phosphane and phosphanoethane ligands are broadly used in the synthesis of gold, silver and copper complexes, and they play an important role in the design and development of metal complexes for biomedical applications and for tumoricidal properties [3]. Scorpionate ligands have been successfully used as supporting ligands for bioinorganic synthetic studies: as an extension of the coordination chemistry of new heteroscorpionate ligands (Figure 1) toward coinage metal acceptors, here we describe the synthesis, the spectroscopic and analytic characterization of new scorpionate complexes containing gold(I), copper(I), silver(I) and water soluble phosphane coligands. H N N S C SLi H N N N N C O C OLi H H C N N N N N N N O2N Li[S2CCH(3,5-Me2Pz)2] COONa B NO2 [H2B(TzNO2)2]- Li[O2CCH(3,5-Me2Pz)2] Figure 1. Scorpionate ligands 1 CH N N N N N N Na[HC(CO2)(Tz)2] N V Simposio Pharmaco-Bio-Metallics Oral Communication Nuovi farmaci inorganici in oncologia Results and Discussion In order to develop specific ligand systems to produce water-soluble, kinetically inert, and in vivo stable gold complexes, we have studied the coordination chemistry of new anionic ligands, bis(3,5dimethylpyrazol-1-yl)dithioacetate and bis(3,5-dimethylpyrazol-1-yl)acetate, toward gold(I) complexes containing phosphane ligands such as tris(hydroxymethyl)phosphane (THP) and 1,3,5triaza-7-phosphaadamantane (TPA) [4]. Studies of biological activity are in progress in order to obtain a structure-activity relationship for the compounds (THP)AuCl, (TPA)AuCl and [(THP)4Au]Cl. Moreover we have designed and synthesized the new triazole-based and water soluble bis(triazol-1yl)acetate, and the new nitro-substituted heteroscorpionate ligand, dihydridobis(3-nitro-1,2,4triazolyl)borate. New Cu(I) and Ag(I) complexes containing these scorpionates and phosphane coligands have been synthesized and fully characterized. The cytotoxic activity of selected hydrophilic Cu(I) complexes and the corresponding uncoordinated ligands has also been evaluated against a panel of human tumor cell lines containing examples of ovarian (2008), cervix (A431) and lung (A549) cancer, melanoma (A375) and leukemia (HL60); for comparison purpose, cisplatin was tested under the same experimental condition. All the tested Cu(I) complexes exhibited IC50 values appreciably lower than those of cisplatin against all human tumor cell lines. Further studies are in progress to elucidate the mechanism of action of these new class of water soluble copper complexes. Acknowledgements The authors are grateful to CIRCMSB for the fellowship to M. M. and to University of Camerino for financial support (FAR). References [1] [2] [3] [4] C. Frank Shaw III Chem. Rev. 1999, 99, 2589-2600. A. De Vizcaya-Ruiz, A. Rivero-Mueller, L. Ruiz-Ramırez, G.E.N. Kass, L. R. Kelland, R.M. Orr, M. Dobrota Toxicol. In Vitro 2000, 14, 1-5. S.J. Berners-Price, R.J. Bowen, P. Galettis, P.C. Healy, M.J. McKeage Coordin. Chem. Rev. 1999, 185-186, 823-836. a) D. Saravana Bharathi, M.A. Sridhar, J. Shashidhara Prasad, Ashoka G. Samuelson Inorg. Chem. Comm. 2001, 4, 490-492; b) Z. Assefa, B. G. McBurnett, R. J. Staples, J. P. Fackler Jr. Inorg. Chem. 1995, 34, 75-83. 2