Equilibrium, kinetic and HPLC study of the reactions between platinum(II) complexes and DNA constituents in the presence and absence of glutathione.

The complex formation equilibria of Pt(SMC)(H(2)O)(2) and Pt(terpy)H(2)O, where SMC =S-methyl-L-cysteine and terpy = 2,2':6',2"-terpyridine, with some biologically relevant ligands such as inosine (INO), inosine-5'-monophosphate (5'-IMP), guanosine-5'-monophosphate (5'-GMP) and glutathione (GSH) were studied. The stoichiometry and stability constants of the complexes formed are reported, and the concentration distribution of the various complex species have been evaluated as a function of pH. Also the kinetics and mechanism of the complex formation reactions were studied as a function of nucleophile concentration and temperature. For the complex Pt(SMC)(H(2)O)(2), two consecutive reaction steps, which both depend on the nucleophile concentration, were observed under all conditions. The negative entropies of activation support an associative complex formation mechanism. Reaction of guanosine-5'-monophosphate (5'-GMP) with Pt(II) complexes was carried out in the presence and absence of glutathione (GSH) at neutral pH. The rate constants clearly showed a kinetic preference toward GSH at neutral pH. The reactions were also monitored by HPLC. However, only a small amount of coordinated 5'-GMP was detected in the HPLC trace. The products were isolated and characterized by MALDI-TOF mass spectrometry.