Modulation of Nucleotide Binding of trans Platinum(II) Complexes by Planar Ligands. A Combined Proton NMR and Molecular Mechanics Study

Abstract

Nonclassical trans platinum complexes containing planar nitrogen bases show biological activity different from that of trans-diamminedichloroplatinum(II) (trans-DDP). In search of the mechanism of action of such compounds, a comparative study on the nucleobase chemistry of trans-DDP and trans-[PtCl(2)(NH(3))(quinoline)] (trans-QUIN) was performed using 1D and 2D NMR spectroscopy and molecular modeling techniques. The two simple monofunctional adducts trans-[PtCl(9-ethylguanine-N7)(NH(3))L]NO(3) (L = NH(3), 1; L = quinoline, 2) were synthesized by employing the AgNO(3)/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 (1)H NMR spectra of 2 and the bifunctional adducts trans-[Pt(9-EtGua-N7)(5'-GMP-N7)(NH(3))L] (4) andtrans-[Pt(9-EtGua-N7)(2)(NH(3))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.