Donor atom preferences in substitution reactions of trans-platinum mononucleobase compounds: Implications for DNA-protein selectivity

摘要

The competitive reactions of mononucleobase cations SP-4-2-[PtCl(9-EtGua)(NH3)(quinoline)](+), 1, and trans-[PtCl(9-EtGua)(pyridine)(2)](+), 2, with 5'-guanosine monophosphate (5'-GMP) and N-Acetylmethionine (N-AcMet) were studied by H-1 NMR Spectroscopy. The results confirmed the previously observed kinetic selectivity for sulfur over nitrogen binding. The symmetric bis(pyridine) complex reacted faster than the ammine/quinoline moiety - the estimated half-times for reaction with 5'-GMP and N-AcMet were, respectively, 7.4 and 2.3 h for 1 and 4.90 and < 0.75 h for 2. Thus modification of the planar amine can enhance sulfur selectivity - based on the observed rates a S/N selectivity ratio of 3.2 is obtained for 1 but > 6.5 for 2. Applications of these findings were extended to study the reaction of I and 2 with Ubiquitin. One principal adduct corresponding to chloride displacement is observed for both species and in this case little difference in rate is observed. The likely binding site is the unique methionine residue. The percentage of platinum-bound ubiquitin is higher for 1 and 2 than the parent dichlorides trans-[PtCl2(NH3)(quinoline)] and trans-[PtCl2(pyridine)(2)]. The results suggest that systematic ligand modification can modulate sulfur donor specificity and suggest possible structural features for design of platinum-based bifunctional DNA-protein cross-linking agents, rather than the DNA-DNA cross-linking principally adopted by the anticancer drug cisplatin and congeners. (c) 2006 Elsevier B.V. All rights reserved.