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-diamminedichlor oplatinum(ll) (trans-DDP). In search of the mechanism of action of suc h 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]NO 3 (L = NH3, 1; L = quinoline, 2) were synthesized by employing the AgN O3/DMF method. Reactions of these species with 5 guanosine monophospha te (5'-GMP) and 5'-cytidine monophosphate (5'-CMP) were used to simula te 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 condit ions. These differences in reactivity are attributed to an altered hyd rolytic behavior of 2 due to steric influences of quinoline upon assoc iative substitution reactions. This is supported by interligand NOEs o bserved in the 2D NOESY spectrum of 2 and by AMBER-based geometries fo r 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'-GM P-NT)(NH3)L] (4) and trans-[Pt(9-EtGua-N7)(2)(NH3)L](2+) (6) (L = quin oline) indicate hindered rotation about the Pt-N (guanine and quinolin e) bonds. Temperature-dependent NMR spectra and molecular mechanics re sults are in agreement with frozen rotamers in solution at room temper ature where unfavorable repulsive interligand interactions result in d ifferent head-to-head and head-to-tail orientations of the bases. For the different rotamers of 4, a high barrier of interconversion of 87 k J mol(-1) was estimated from NMR data. The consequences of these kinet ic and geometric effects with respect to target DNA are discussed.