Dalton Transactions PAPER Cite this: Dalton Trans., 2013, 42, 15457 Received 22nd July 2013, Accepted 22nd August 2013 DOI: 10.1039/c3dt51991k www.rsc.org/dalton Synthesis, molecular structure, computational study and in vitro anticancer activity of dinuclear thiolato- bridged pentamethylcyclopentadienyl Rh(III) and Ir(III) complexes† Gajendra Gupta, a Amine Garci, a Benjamin S. Murray, b Paul J. Dyson, b Gabin Fabre, c,d Patrick Trouillas, c,d,e Federico Giannini, a,f Julien Furrer, f Georg Süss-Fink a and Bruno Therrien* a Neutral dinuclear dithiolato-bridged pentamethylcyclopentadienyl Rh(III) complexes of the type (C 5 Me 5 ) 2 Rh 2 (μ-SR) 2 Cl 2 (R = CH 2 Ph, 1; R = CH 2 CH 2 Ph, 2) and cationic dinuclear trithiolato-bridged penta- methylcyclopentadienyl Rh(III) and Ir(III) complexes of the type [(C 5 Me 5 ) 2 M 2 (μ-SR) 3 ] + (M = Rh, R = CH 2 Ph, 3; M = Rh, R = CH 2 CH 2 Ph, 5; M = Rh, R = CH 2 C 6 H 4 -p- t Bu, 7: M = Ir, R = CH 2 Ph, 4; M = Ir, R = CH 2 CH 2 Ph, 6; M = Ir, R = CH 2 C 6 H 4 -p- t Bu, 8) have been synthesized from the chloro-bridged pentamethylcyclopentadienyl Rh(III) and Ir(III) dimers (C 5 Me 5 ) 2 M 2 (μ-Cl) 2 Cl 2 by reaction with the corresponding thiol derivative (RSH). Complexes 3–8 were isolated as chloride salts.All complexes were obtained in good yield and were fully characterized by spectroscopic methods. The molecular structures of the neutral complexes (1 and 2) show interesting fea- tures: the two rhodium atoms are bridged by two thiolato ligands with no metal–metal bonds and the penta- methylcyclopentadienyl and chlorido ligands are oriented syn to each other, an uncommon conformation for such dinuclear complexes. These structural features were rationalized using DFT calculations. Additionally, the antiproliferative activity of the complexes was evaluated against the cancerous A2780 (cisplatin sensitive) and A2780cisR (cisplatin resistant) human ovarian cell lines and on the noncancerous HEK293 human embryonic kidney cells. All complexes were found to be active and the cationic iridium complexes 4, 6 and 8 are particularly cytotoxic, with IC 50 values in the nanomolar range (IC 50 < 0.1 μM). The catalytic activity of the complexes for the oxidation of glutathione (GSH) to GSSG was evaluated by NMR spectroscopy. Introduction Cancer is now the second largest killer in developed nations and according to health organizations, by 2030 the annual death toll will exceed 13 million. 1 Among chemotherapeutic agents, cisplatin and the other platinum-based drugs have occupied for 35 years an enviable position. 2 Indeed, platinum- based drugs are clinically used on a daily basis to treat cancers. Even today, despite limitations and new therapeutic strategies, about two thirds of cancer patients are getting a platinum-based drug during their treatment. The limitations of platinum-based drugs, 3 namely dose-dependent side effects (such as emetogenesis, neuro-, hepato- and nephrotoxicity) and development of drug resistance mechanisms (intrinsic and acquired), have boosted the research for finding other metal-based drugs. 4 Among metals, ruthenium is probably the one showing the greatest promise. 5 Ruthenium appears to be less toxic than platinum, and several biological studies have indicated that ruthenium complexes possess diverse modes of action. 6 Since the first synthesis of (C 6 H 6 ) 2 Ru 2 (μ-Cl) 2 Cl 2 by Win- khaus and Singer in 1967, 7 the chemistry of arene ruthenium complexes has been extensively studied, traditionally in the field of catalysis 8 and nowadays in biology. 9 Early on, it was † Electronic supplementary information (ESI) available: Synthesis and character- ization of complexes 1–8; single-crystal X-ray structure analyses details for 1, 2 and [6]Cl; computational methods; biological methods; catalytic study. CCDC 939466–939468. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3dt51991k a Institute of Chemistry, University of Neuchatel, Ave de Bellevaux 51, CH-2000 Neuchatel, Switzerland. E-mail: bruno.therrien@unine.ch; Fax: (+41) 32 718 2511; Tel: (+41) 32 718 2499 b Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland c LCSN-EA1069, Faculté de Pharmacie, Université de Limoges, 2 rue du Dr. Marcland, 87025 Limoges, France d Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, University of Olomouc, tř. 17. listopadu 12, 771 46 Olomouc, Czech Republic e Laboratoire de Chimie des Matériaux Nouveaux, Université de Mons, Place du Parc 20, 7000 Mons, Belgium f Department für Chemie und Biochemie, Universität Bern, CH-3012 Bern, Switzerland This journal is © The Royal Society of Chemistry 2013 Dalton Trans., 2013, 42, 15457–15463 | 15457