Reactivity and Biological Properties of a Series of Cytotoxic PtI 2 (amine) 2 Complexes, Either cis or trans Configured Luigi Messori, † Leticia Cubo, ‡ Chiara Gabbiani, † Amparo A ́ lvarez-Valde ́ s, ‡ Elena Michelucci, § Giuseppe Pieraccini, § Carla Ríos-Luci, ∥ Leticia G. Leó n, ∥ Jose ́ M. Padró n, ∥ Carmen Navarro-Ranninger, ‡ Angela Casini,* ,⊥,# and Adoració n G. Quiroga* ,‡ † Dipartimento di Chimica, Universita ̀ di Firenze, Via della Lastruccia 3, 50019 Sesto Fiorentino, Italy ‡ Department of Inorganic Chemistry, Universidad Autó noma de Madrid, C/Francisco Toma ́ s y Valiente, 7, 28049 Madrid, Spain § Mass Spectrometry Centre (CISM), Universita ̀ di Firenze, Via U. Schiff 6, 50019 Sesto Fiorentino, Italy ∥ Instituto Universitario de Bio-Orga ́ nica “Antonio Gonza ́ lez” (IUBO-AG), Universidad de La Laguna, C/Astrofísico Francisco Sa ́ nchez 2, 38206 La Laguna, Spain ⊥ Institut des Sciences et Ingé nierie Chimiques Ecole Polytechnique Fé de ́ rale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland # Research Institute of Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands * S Supporting Information ABSTRACT: Six diiodido−diamine platinum(II) complexes, either cis or trans configured, were prepared, differing only in the nature of the amine ligand (isopropylamine, dimethylamine, or methylamine), and their antiproliferative properties were evaluated against a panel of human tumor cell lines. Both series of complexes manifested pronounced cytotoxic effects, with the trans isomers being, generally, more effective than their cis counterparts. Cell cycle analysis revealed different modes of action for these new Pt(II) complexes with respect to cisplatin. The reactivity of these platinum compounds with a number of biomolecules, including cytochrome c, two sulfur containing modified amino acids, 9-ethylguanine, and a single strand oligonucleotide, was analyzed in depth by mass spectrometry and NMR spectroscopy. Interestingly, significant differences in the reactivity of the investigated compounds toward the various model biomolecules were observed: in particular we observed that trans complexes preferentially release their iodide ligands upon biomolecule binding, while the cis isomers may release the amine ligands with retention of iodides. Such differences in reactivity may have important mechanistic implications and a relevant impact on the respective pharmacological profiles. ■ INTRODUCTION Since the discovery of its outstanding antitumor properties and its introduction in the clinic, cisplatin has been considered a primary anticancer drug lead. 1 Several attempts were made to modify its chemical structure with the goal of obtaining more effective and less toxic antitumor platinum compounds. 2 Rather stringent structural requirements were thus defined for anticancer platinum(II) agents such as the presence of two labile ligands (leaving groups) in cis position and the need of two inert amine ligands (nonleaving groups or spectator ligands) in the two remaining coordination positions. 3−5 Nonetheless, several examples of active Pt(II) complexes were reported later that do not obey established structure−activity rules. 6−8 A few of these compounds, bearing aliphatic amines as nonleaving groups, of general formula trans-[PtCl 2 LL′] (where L and L′ = aliphatic amines) were developed by some of us and were shown to overcome cisplatin resistance in tumor cells overexpressing the ras oncogene, as well as producing promising effects in tumor xenografts. 9,10 Within this frame, we recently reconsidered the possibility of replacing chlorides with iodides within classical square planar platinum(II) complexes. In particular, we investigated the cis- diiodido-diisopropylamine platinum(II) complex (1, Chart 1) Received: September 19, 2011 Published: January 6, 2012 Chart 1. Schematic Representation of cis and trans Pt(II) Complexes Studied in This Work Article pubs.acs.org/IC © 2012 American Chemical Society 1717 dx.doi.org/10.1021/ic202036c | Inorg. Chem. 2012, 51, 1717−1726