New Water-Soluble Ruthenium(II) Terpyridine Complexes for Anticancer Activity: Synthesis, Characterization, Activation Kinetics, and Interaction with Guanine Derivatives Ana Rilak, †,‡ Ioannis Bratsos,* ,‡,§ Ennio Zangrando, ‡ Jakob Kljun, ∥,⊥ Iztok Turel, ∥ Z ̌ ivadin D. Bugarc ̌ ic ́ , † and Enzo Alessio* ,‡ † Faculty of Science, University of Kragujevac, R. Domanovic ́ a 12, P.O. Box 60, 34000 Kragujevac, Serbia ‡ Dipartimento di Scienze Chimiche e Farmaceutiche, Universita ̀ di Trieste, Via L. Giorgieri 1, 34127 Trieste, Italy ∥ Faculty of Chemistry and Chemical Technology, University of Ljubljana, As ̌ kerč eva 5, SI-1000 Ljubljana, Slovenia ⊥ EN→FIST Centre of Excellence, Dunajska 156, SI-1000 Ljubljana, Slovenia * S Supporting Information ABSTRACT: With the aim of assessing whether ruthenium(II) compounds with meridional geometry might be utilized as potential antitumor agents, a series of new, water-soluble, monofunctional ruthenium(II) complexes of the general formula mer- [Ru(L 3 )(N-N)X][Y] n (where L 3 = 2,2′:6′,2″-terpyridine (tpy) or 4′-chloro-2,2′:6′,2″-terpyridine (Cl-tpy), N-N = 1,2- diaminoethane (en), 1,2-diaminocyclohexane (dach), or 2,2′-bipyridine (bpy); X = Cl or dmso-S; Y = Cl, PF 6 , or CF 3 SO 3 ; n =1 or 2, depending on the nature of X) were synthesized. All complexes were fully characterized by elemental analysis and spectroscopic techniques (IR, UV/visible, and 1D and 2D NMR), and for three of them, i.e., [Ru(Cl-tpy)(bpy)Cl][Cl] (3 Cl ), [Ru(Cl-tpy)(en)(dmso-S)][Y] 2 [Y = PF 6 (6 PF 6 ), CF 3 SO 3 (6 OTf )] and [Ru(Cl-tpy)(bpy)(dmso-S)][CF 3 SO 3 ] 2 (8 OTf ), the X-ray structure was also determined. The new terpyridine complexes, with the exception of 8, are well soluble in water (>25 mg/mL). 1 H and 31 P NMR spectroscopy studies performed on the three selected complexes [Ru(Cl-tpy)(N-N)Cl] + [N-N = en (1), dach (2), and bpy (3)] demonstrated that, after hydrolysis of the Cl ligand, they are capable of interacting with guanine derivatives [i.e., 9-methylguanine (9MeG) or guanosine-5′-monophosphate (5′-GMP)] through N7, forming monofunctional adducts with rates and extents that depend strongly on the nature of N-N: 1 ≈ 2 ≫ 3. In addition, compound 1 shows high selectivity toward 5′-GMP compared to adenosine-5′-monophosphate (5′-AMP), in a competition experiment. Quantitative kinetic investigations on 1 and 2 were performed by means of UV/visible spectroscopy. Overall, the complexes with bidentate aliphatic diamines proved to be superior to those with bpy in terms of solubility and reactivity (i.e., release of Cl − and capability to bind guanine derivatives). Contrary to the chlorido compounds, the corresponding dmso derivatives proved to be inert (viz., they do not release the monodentate ligand) in aqueous media. ■ INTRODUCTION In the search for nonplatinum antitumor drugs with a different spectrum of activity and fewer side effects than those of cisplatin and its analogues, ruthenium compounds appear to be the front runners, 1 especially after the introduction of two ruthenium(III) complexes, namely, [indH]trans-[RuCl 4 (ind) 2 ] (ind = indazole, KP1019) and [imH]trans-[RuCl 4 (dmso- S)(im)] (im = imidazole, NAMI-A), into clinical trials. 2,3 During the last decades, a large interest in ruthenium polypyridyl complexes as structure- and site-specific DNA binding agents with attractive photophysical properties has grown. 4,5 Studies on ruthenium polypyridyl complexes that feature at least one coordination site occupied by a good Received: March 6, 2014 Article pubs.acs.org/IC © XXXX American Chemical Society A dx.doi.org/10.1021/ic5005215 | Inorg. Chem. XXXX, XXX, XXX−XXX