[~1H,~(15)N] N.M.R. Kinetic Studies of Reactions of cis- and trans-[PtCl_2(~(15)NH_3)(c-C_6H_(11)~(15)NH_2)] with Guanosine 5'-Monophosphate

摘要

cis-[PtCl_2(~(15)NH_3)(c-C_6H_(11)NH_2)] is an active metabolite of the oral platinum (IV) anticancer drug cis, trans, cis-[PtCl_2(CH_3CO_2)_2(NH_3)(c-C_6H_(11)NH_2)]. 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 [~1H, ~(15)N] n.m.r. methods. Reactions of the trans isomer are reported for comparison. The reactions proceed via equated intermediates, and, for the cis isomer, the rates of aquation and substitution of H_2O by 5'-GMP are 2-5 times faster trans to the amine ligand (c-C_6H_(11)NH_2) compared to trans to NH_3 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 N 7 of 5'-GMP) is comparable to that trans to NH_3. These findings have implications for the courses of reactions with DNA.