Thermodynamic and Kinetic Studies on Reactions of Pt(II) Complexes with Biologically Relevant Nucleophiles

The effect of different N−N spectator ligands on the reactivity of platinum(II) complexes was investigated by studying the water lability of [Pt(diaminocyclohexane)(H2O)2]2+ (Pt(dach)), [Pt(ethylenediamine)(H2O)2]2+(Pt(en)), [Pt(aminomethylpyridine)(H2O)2]2+(Pt(amp)), and [Pt(N,N'-bipyridine)(H2O)2]2+(Pt(bpy)). Some of the selected N−N chelates form part of the coordination sphere of Pt(II) drugs in clinical use, as in Pt(dach) (oxaliplatin), or are models, regarding the nature of the amines, with higher stability in terms of substitution and hydrolysis of the diamine moiety, as in Pt(en) (cisplatin) and Pt(amp) (AMD473). The effect of π-acceptors on the reactivity was investigated by introducing one (Pt(amp)) or two pyridine rings (Pt(bpy)) in the system. The pKa values for the two water molecules (viz., Pt(dach) (pKa1 = 6.01, pKa2 = 7.69), Pt(en) (pKa1 = 5.97, pKa2 = 7.47), Pt(amp) (pKa1 = 5.82, pKa2 = 6.83), Pt(bpy) (pKa1 = 4.80, pKa2 = 6.32) show a decrease in the order Pt(dach) > Pt(en) > Pt(amp) > Pt(bpy). The substitution of both coordinated water molecules by a series of nucleophiles (viz., thiourea (tu), l-methionine (L-Met), and guanosine-5'-monophosphate (5'GMP-)) was investigated under pseudo-first-order conditions as a function of concentration, temperature, and pressure using UV−vis spectrophotometric and stopped-flow techniques and was found to occur in two subsequent reaction steps. The following k1 values for Pt(dach), Pt(en), Pt(amp), and Pt(bpy) were found: tu (25 °C, M-1 s-1) 21 ± 1, 34.0 ± 0.4, 233 ± 5, 5081 ± 275; L-Met (25 °C) 0.85 ± 0.01, 0.70 ± 0.03, 2.15 ± 0.05, 21.8 ± 0.6; 5'GMP- (40 °C) 5.8 ± 0.2, 3.9 ± 0.1, 12.5 ± 0.5, 24.4 ± 0.3. The results for k2 for Pt(dach), Pt(en), Pt(amp), and Pt(bpy) are as follows: tu (25 °C, M-1 s-1) 11.5 ± 0.5, 10.2 ± 0.2, 38 ± 1, 1119 ± 22; L-Met (25 °C, s-1) 2.5 ± 0.1, 2.0 ± 0.2, 1.2 ± 0.3, 290 ± 4; 5'GMP- (40 °C, M-1 s-1) 0.21 ± 0.02, 0.38 ± 0.02, 0.97 ± 0.02, 24 ± 1. The activation parameters for all reactions suggest an associative substitution mechanism. The pKa values and substitution rates of the complexes studied can be tuned through the nature of the N−N chelate, which is important in the development of new active compounds for cancer therapy.