Modulation of nucleotide binding of trans platinum(II) complexes by planar ligands. A combined proton NMR and molecular mechanics study

Nonclassical trans platinum complexes containing planar nitrogen bases show biological activity different from that of trans-diamminedichloroplatinum(ll) (trans-DDP). In search of the mechanism of action of such compounds, a comparative study on the nucleobase chemistry of trans-DDP and trans-[PtCl2(NH3)(quinoline)] (trans-QUIN) was performed using 1D and 2D MMR spectroscopy and molecular modeling techniques. The two simple monofunctional adducts trans-[PtCl(9-ethylguanine-N7)(NH3)L]NO3 (L = NH3, 1; L = quinoline, 2) were synthesized by employing the AgNO3/DMF method. Reactions of these species with 5 guanosine monophosphate (5'-GMP) and 5'-cytidine monophosphate (5'-CMP) were used to simulate potential second binding steps on DNA. Guanine-N7 proved to be the kinetically preferred binding site for both 1 and 2. Reactions with 2 proceeded significantly slower than those with 1 under the same conditions. These differences in reactivity are attributed to an altered hydrolytic behavior of 2 due to steric influences of quinoline upon associative substitution reactions. This is supported by interligand NOEs observed in the 2D NOESY spectrum of 2 and by AMBER-based geometries for different conformers of 2. Signal splittings observed in the H-1 NMR spectra of 2 and the bifunctional adducts trans-[Pt(s-EtGua-N7)(5'-GMP-NT)(NH3)L] (4) and trans-[Pt(9-EtGua-N7)(2)(NH3)L](2+) (6) (L = quinoline) indicate hindered rotation about the Pt-N (guanine and quinoline) bonds. Temperature-dependent NMR spectra and molecular mechanics results are in agreement with frozen rotamers in solution at room temperature where unfavorable repulsive interligand interactions result in different head-to-head and head-to-tail orientations of the bases. For the different rotamers of 4, a high barrier of interconversion of 87 kJ mol(-1) was estimated from NMR data. The consequences of these kinetic and geometric effects with respect to target DNA are discussed.