New Water-Soluble Ruthenium(II) Terpyridine Complexes for Anticancer Activity: Synthesis, Characterization, Activation Kinetics, and Interaction with Guanine Derivatives

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 <i>mer</i>-[Ru­(L₃)­(N-N)­X]­[Y]_<i>n</i> (where L₃ = 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-<i>S</i>; Y = Cl, PF₆, or CF₃SO₃; <i>n</i> = 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] (<b>3</b>_<b>Cl</b>), [Ru­(Cl-tpy)­(en)­(dmso-<i>S</i>)]­[Y]₂ [Y = PF₆ (<b>6</b>_<b>PF₆</b>), CF₃SO₃ (<b>6</b>_<b>OTf</b>)] and [Ru­(Cl-tpy)­(bpy)­(dmso-<i>S</i>)]­[CF₃SO₃]₂ (<b>8</b>_<b>OTf</b>), the X-ray structure was also determined. The new terpyridine complexes, with the exception of <b>8</b>, are well soluble in water (>25 mg/mL). ¹H and ³¹P NMR spectroscopy studies performed on the three selected complexes [Ru­(Cl-tpy)­(N-N)­Cl]⁺ [N-N = en (<b>1</b>), dach (<b>2</b>), and bpy (<b>3</b>)] 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: <b>1</b> ≈ <b>2</b> ≫ <b>3</b>. In addition, compound <b>1</b> shows high selectivity toward 5′-GMP compared to adenosine-5′-monophosphate (5′-AMP), in a competition experiment. Quantitative kinetic investigations on <b>1</b> and <b>2</b> 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