Oxidation of a guanine derivative coordinated to a Pt(iv) complex initiated by intermolecular nucleophilic attacks

Abstract

In this study we report that fac-[Pt^IV(dach)(9-EtG)Cl₃]⁺ (dach = d,l-1,2-diaminocyclohexane, 9-EtG = 9-ethylguanine) in high pH (pH 12) or phosphate solution (pH 7.4) produces 8-oxo-9-EtG and Pt^II species. The reaction in H₂¹⁸O revealed that the oxygen atom in hydroxide or phosphate ends up at the C8 position of 8-oxo-G. The kinetics of the redox reaction was first order with respect to both Pt^IV-G and free nucleophiles (OH⁻ and phosphate). The oxidation of G initiated by hydroxide was approximately 30∼50 times faster than by phosphate in 100 mM NaCl solutions. The large entropy of activation of OH⁻¹ (ΔS^‡ = 26.6 ± 4.3 J mol⁻¹ K⁻¹) due to the smaller size of OH⁻ is interpreted to be responsible for the faster kinetics compared to phosphate (ΔS^‡ = −195.5 ± 11.1 J mol⁻¹ K⁻¹). The enthalpy of activation for phosphate reaction is more favorable relative to the OH⁻ reaction (ΔH^‡ = 35.4 ± 3.5 kJ mol⁻¹ for phosphate vs. 96.6 ± 11.4 kJ mol⁻¹ for OH⁻¹). The kinetic isotope effect of H8 was determined to be 7.2 ± 0.2. The rate law, kinetic isotope effect, and isotopic labeling are consistent with a mechanism involving proton ionization at the C8 position as the rate determining step followed by two-electron transfer from G to Pt^IV.