[1H,15N] N.M.R. Kinetic Studies of Reactions of cis- and trans-[PtCl2(15NH3)(c-C6H1115NH2)] with Guanosine 5'-Monophosphate

Abstract

cis-[PtCl₂(¹⁵NH₃)(c-C₆H₁₁NH₂)] is an active metabolite of the oral platinum(IV) anticancer drug cis,trans,cis-[PtCl₂(CH₃CO₂)₂(NH₂)(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 [¹H, ¹⁵N] 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.