Oxidation of 5′-dGMP, 5′-dGDP, and 5′-dGTP by a platinum(IV) complex

Abstract

We previously reported that a Pt(IV) complex, [Pt^IV(dach)Cl₄] [trans-d,l-1,2-diaminocyclohexanetetrachloroplatinum(IV)] binds to the N₇ of 5′-dGMP (deoxyguanosine-5′-monophosphate) at a relatively fast rate and oxidizes it to 8-oxo-5′-dGMP. Here, we further studied the kinetics of the oxidation of 5′-dGMP by the Pt^IV complex. The electron transfer rate constants between 5′-dGMP and Pt^IV in [H₈-5′-dGMP–Pt^IV] and [D₈-5′-dGMP–Pt^IV] were similar, giving a small value of the kinetic isotope effect (KIE: 1.2 ± 0.2). This small KIE indicates that the deprotonation of H₈ in [H₈-5′-dGMP–Pt^IV] is not involved in the rate-determining step in the electron transfer between guanine (G) and Pt^IV. We also studied the reaction of 5′-dGDP (deoxyguanosine-5′-diphosphate) and 5′-dGTP (deoxyguanosine-5′-triphosphate) with the Pt^IV complex. Our results showed that [Pt^IV(dach)Cl₄] oxidized 5′-dGDP and 5′-dGTP to 8-oxo-5′-dGDP and 8-oxo-5′-dGTP, respectively, by the same mechanism and kinetics as for 5′-dGMP. The Pt^IV complex binds to N₇ followed by a two-electron inner sphere electron transfer from G to Pt^IV. The reaction was catalyzed by Pt^II and occurred faster at higher pH. The electron transfer was initiated by either an intramolecular nucleophilic attack by any of the phosphate groups or an intermolecular nucleophilic attack by free OH⁻ in the solution. The rates of reactions for the three nucleotides followed the order: 5′-dGMP > 5′-dGDP > 5′-dGTP, indicating that the bulkier the phosphate groups are, the slower the reaction is, due to the larger steric hindrance and rotational barrier of the phosphate groups.