pubs.acs.org/IC Published on Web 01/12/2011 r 2011 American Chemical Society Inorg. Chem. 2011, 50, 873–882 873 DOI: 10.1021/ic101466u Water-Soluble Cp Ruthenium Complex Containing 1,3,5-Triaza-7-phosphaadamantane and 8-Thiotheophylline Derivatives: Synthesis, Characterization, and Antiproliferative Activity Lazhar Hajji, † Cristobal Saraiba-Bello, † Antonio Romerosa,* ,† Gaspar Segovia-Torrente, † Manuel Serrano-Ruiz, † Paola Bergamini, ‡,§ and Alessandro Canella || †  Area de Quı´mica Inorg  anica, Facultad de Ciencias Experimentales, Universidad de Almerı´a, 04071 Almerı´a, Spain, ‡ Dipartimento di Chimica dell’Universit  a di Ferrara, via L. Borsari 46, 44100 Ferrara, Italia, § Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici, Italia, and || Dipartimento di Biochimica e Biologia Molecolare dell’Universit  a di Ferrara, via L. Borsari 46, 44100 Ferrara, Italia Received July 22, 2010 The new water-soluble ruthenium(II) mononuclear complexes [RuCp(X)(PTA)(L)] (X = 8-thio-theophyllinate (TTH - ), L = PTA (1), L = PPh 3 (7)); (X = 8-methylthio-theophyllinate (8-MTT - ), L = PTA (2), L = PPh 3 (8)), (X = 8-benzylthio- theophyllinate (8-BzTT - ), L = PTA (3), L = PPh 3 (9)) and binuclear complexes [{RuCp(PTA)(L)} 2 -μ-(Y-κN7,N 0 7)] (Y = bis(S-8-thiotheophyllinate)methane (MBTT 2- ), L = PTA (4), L = PPh 3 (10)), (Y = 1,2-bis(S-8-thiotheophyllina- te)ethane (EBTT 2- ), L=PTA (5), L=PPh 3 (11)), (Y=1,3-bis(S-8-thiotheophyllinate)propane (PBTT 2- ); L=PTA (6), L=PPh 3 (12)) have been synthesized and characterized by NMR, IR spectroscopy and elemental analysis. The single crystal X-ray structure of [RuCp(8-MTT-κS)(PTA) 2 ](2) was also obtained. The antiproliferative activity of the complexes on cisplatin-sensitive T2 and cisplatin-resistant SKOV3 cell lines has been evaluated. Introduction Transition metal complexes designed to bind to DNA have been extensively studied in the last few decades. 1 The dis- covery of the anticancer properties of cisplatin 2 in the 1960s by Rosenberg proved that transition metal complexes could be toxic for tumor cells. As a consequence, a huge number of metal compounds of wide structural diversity have been tested and some of them found to be therapeutic agents for cancer treatment. Still now cisplatin and its parent analogues are among the most widely used chemotherapeutic agents. 3 Nevertheless, platinum-based drugs still present a few draw- backs like activity restricted to a limited number of tumors, severe side effects, drug resistance, 4 and so forth. Therefore the search for new metal-based drugs is still a lively field. Ruthenium complexes are promising anticancer agents 5 and two of them, NAMI-A 6 and KP1019 7 are currently under clinical trials, for the treatment of metastatic and colorectal cancers, respectively. The cytotoxicity of ruthenium compounds, as for cisplatin, correlates with their ability for DNA binding, which is based on the formation of metal containing active species mainly by aquation processes. It is known that Ru(III) complexes are *To whom correspondence should be addressed. E-mail: romerosa@ ual.es. (1) (a) Farrer, N. J.; Salassa, L.; Sadler, P. J. Dalton Trans. 2009, 48, 10690–10701. (b) Foxon, S. P.; Phillips, T.; Gill, M. R.; Towrie, M.; Parker, A. W.; Webb, M.; Thomas, J. A. Angew. Chem., Int. Ed. 2007, 46, 3686. (c) Neves, A.; Lanznaster, M.; Bortoluzzi, A. J.; Peralta, R. A.; Casellato, A.; Castellano, E. E.; Herrald, P.; Riley, M. J.; Schenk, G. J. Am. Chem. Soc. 2007, 129, 7486. (d) Metcalfe, C.; Thomas, J. A. Chem. Soc. Rev. 2003, 32, 215. (e) Clarke, M. J.; Zhu, F.; Frasca, D. R. Chem. Rev. 1999, 99, 2511. (f) Zeglis, B. M.; Pierre, V. C.; Barton, J. K. Chem. Commun. 2007, 4565. (g) Reedijk, J. Proc. Natl. Acad. Sci. U. S. A. 2003, 100, 3611. 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