[1H,15 N] NMR kinetic studies of reactions of cis- and trans-[PtCl2(15NH3)(c-C6H1115NH2)] with guanosine 5′-monophosphate

cis-[PtCl2((NH3)-N-15)(c-C6H11NH2)] is an active metabolite of the oral platinum(IV) anticancer drug cis,trans,cis-[PtCl2(CH3CO2)(2)(NH3)(c-C6H11NH2)]. Since it is likely that guanine bases on DNA are targets for this drug, we have analysed the kinetics of reaction of this platinum(II) metabolite with guanosine 5'-monophosphate (5'-GMP) at 310 K, pH 7, using [H-1, N-15] n.m.r. methods. Reactions of the trans isomer are reported for comparison. The reactions proceed via aquated intermediates, and, for the cis isomer, the rates of aquation and substitution of H2O by 5'-GMP are 2-5 times faster trans to the amine ligand (c-C6H11NH2) compared to trans to NH3 for both the first and second steps. For the trans complex, the first aquation step is c. 3 times faster than for the cis complex, as expected from the higher trans influence of Cl-?, whereas the rate of the second aquation step (trans to N7 of 5'-GMP) is comparable to that trans to NH3. These findings have implications for the courses of reactions with DNA.