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 mer-[Ru­(L3)­(N-N)­X]­[Y]n (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-S; Y = Cl, PF6, or CF3SO3; 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] (3Cl), [Ru­(Cl-tpy)­(en)­(dmso-S)]­[Y]2 [Y =
PF6 (6PF6), CF3SO3 (6OTf)] and [Ru­(Cl-tpy)­(bpy)­(dmso-S)]­[CF3SO3]2 (8OTf), the X-ray structure was also determined. The new terpyridine complexes,
with the exception of 8, 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 (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.