pKa values of aqua ligands of platinum (II) anticancer complexes: [1H, 15N] and 195Pt NMR Studies of cis- and trans- [PtCl2 (NH3) (Cyclohexylamine)]

Syntheses and NMR studies are reported of two 15N-labelled Pt(II) complexes of anticancer interest: cis-PtCl2(15NH3)(c-C6H1115NH2), a metabolite of the orally-active Pt(IV) complex cis,trans,cis-[PtCl2(acetate)2(c-C6H11NH2)(NH3), and trans-[PtCl2(15NH3)(c-C6H1115NH2), a reduction product of the active Pt(IV) complex trans,trans,trans-[PtCl2(OH)2(c-C6H11NH2). For cis-[PtCl2(15NH3)(c-C6H1115NH2), hydrolysis was faster for the chloride ligand trans to cyclohexylamine, and the pKa values determined by [1H, 15N NMR spectroscopy for the two cis monoaqua isomers were the same (6.73). The trans monoaqua complex was a stronger acid with pKa of 5.4 (determined by 195Pt NMR). For the cis diaqua complex, pKa values of 5.68 and 7.68 were determined.

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

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.

Co-acquisition of hyperpolarised 13C and 15N NMR spectra

Recent developments in dynamic nuclear polarisation now allow significant enhancements to be generated in the cryo solid state and transferred to the liquid state for detection at high resolution. We demonstrate that the Ardenkjaer-Larsen method can be extended by taking advantage of the properties of the trityl radicals used. It is possible to hyperpolarise 13C and 15N simultaneously in the solid state, and to maintain these hyperpolarisations through rapid dissolution into the liquid state. We demonstrate the almost simultaneous measurement of hyperpolarised 13C and hyperpolarised 15N NMR spectra. The prospects for further improvement of the method using contemporary technology are also discussed.