Dalton Transactions Dynamic Article Links Cite this: Dalton Trans., 2011, 40, 2006 www.rsc.org/dalton PAPER Structure, solution chemistry, antiproliferative actions and protein binding properties of non-conventional platinum(II) compounds with sulfur and phosphorus donors†‡ Carolin M¨ ugge,§ a Claudia Rothenburger,§ a Antje Beyer, a Helmar G ¨ orls, a Chiara Gabbiani, b Angela Casini, c Elena Michelucci, d Ida Landini, e Stefania Nobili, e Enrico Mini, e Luigi Messori* b and Wolfgang Weigand* a Received 14th July 2010, Accepted 8th December 2010 DOI: 10.1039/c0dt00845a Twelve Pt(II) complexes with cis-PtP 2 S 2 pharmacophores (where P 2 refers to two monodentate or one bidentate phosphane ligand and S 2 is a dithiolato ligand) were prepared, characterized and evaluated as potential antiproliferative agents. The various compounds were first studied from the structural point of view; afterward, their solubility properties as well as their solution behaviour were analyzed in detail. Antiproliferative properties were specifically evaluated against A2780 human ovarian carcinoma cells, either resistant or sensitive to cisplatin. For comparison purposes similar studies were carried out on four parent cis-dichloro bisphosphane Pt(II)complexes. On the whole, the cis-PtP 2 S 2 compounds displayed significant antiproliferative properties while the cis-PtP 2 Cl 2 (cis-dichloro bisphosphane Pt(II)) compounds revealed quite poor biological performances. To gain further insight into the molecular mechanisms of these bisphosphane Pt(II) compounds, the reactions of selected complexes against the model protein cytochrome c were investigated by ESI-MS and their adduct formation explored. A relevant reactivity with cyt c was obtained only for cis-PtP 2 Cl 2 compounds, whereas cis-PtP 2 S 2 compounds turned out to be nearly unreactive. The obtained results are interpreted and discussed in the frame of the current knowledge of anticancer platinum compounds and their structure–activity-relationships. The observation of appreciable antiproliferative effects for the relatively inert cis-PtP 2 S 2 compounds strongly suggests that these compounds will undergo specific activation within the cellular environment. Introduction Platinum compounds play a crucial role in modern anticancer chemotherapy. However, in spite of the numerous studies now a Institute of Inorganic and Analytical Chemistry, Friedrich-Schiller- University Jena, August-Bebel-Strasse 2, 07743, Jena, Germany. E-mail: wolfgang.weigand@uni-jena.de; Fax: (+49) 3641 948102 b Laboratory of Metals in Medicine, Department of Chemistry, University of Florence, Via della Lastruccia 3, 50019, Sesto Fiorentino, Firenze, Italy. E-mail: luigi.messori@unifi.it; Fax: (+39) 055 4573385 c Institut des Sciences et Ing´ eniere Chimiques, Ecole Polytechnique F´ ed´ erale de Lausanne (EPFL)CH-1015, Lausanne, Switzerland d Mass Spectrometry Center (CISM), University of Florence, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy e Department of Preclinical and Clinical Pharmacology, University of Flo- rence, Viale Pieraccini 6, 50139, Firenze, Italy † This paper is dedicated to Dr. Janina Altman on the occasion of her 80 th birthday. ‡Electronic supplementary information (ESI) available: 31 P{ 1 H} spectra of 7 and 8; molecular structures of 6–10; crystallographic data for 6–10; ESI-MS spectra of cyt c interacting with compounds 1–4. CCDC reference numbers: 776102 for 6, 776103 for 7, 776104 for 8, 776105 for 9 and 776106 for 10. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c0dt00845a § These Authors contributed equally to this work. available on this issue and the thousands of compounds tested so far, only very few platinum drugs have successfully reached clinical use. 1,2 Strikingly, the approved platinum compounds share some common structural features such as the presence of two NLG (non leaving groups, typically nitrogen ligands) and two LG (leaving groups, e.g. halides or carboxylates) in the cis position. 3,4 This type of configuration allows, in principle, bidentate coordination to adjacent nucleobases of the DNA double helix. 5 Remarkably, cytotoxic platinum complexes are in most cases prodrugs and their activation is a normal prerequisite for biological activity. Activation is normally attained through the release of one or more labile ligands. 6 The above observations have prompted scientists since early times to try to establish the precise SAR (structure–activity- relationships) for anticancer platinum compounds that might be useful for the design of new active molecules. These rules were first reported by Hoeschele et al. 7 and rapidly became very popular within the scientific community. Now, as a far greater number of platinum compounds are available with known chemical and biological profiles, it is evident that those original rules suffer many exceptions and limitations. Indeed, numerous “rule-breaker” platinum-based drugs have been prepared and 2006 | Dalton Trans., 2011, 40, 2006–2016 This journal is © The Royal Society of Chemistry 2011 Downloaded by UNIVERSITA DI FIRENZE on 06 October 2011 Published on 06 January 2011 on http://pubs.rsc.org | doi:10.1039/C0DT00845A View Online