REACTIVITY OF CHLORO(DIETHYLENETRIAMINE)PLATINUM(II) AND AQUA(DIETHYLENETRIAMINE)PLATINUM(II) IONS WITH GLUTATHIONE, S-METHYLGLUTATHIONE, AND GUANOSINE 5'-MONOPHOSPHATE IN RELATION TO THE ANTITUMOR-ACTIVITY AND TOXICITY OF PLATINUM COMPLEXES

The reactivity of the two platinum(II) complexes [Pt(dien)Cl]+ and [Pt(dien)(H2O)]2+ with glutathione (GSH), S-methylglutathione (GS-Me), and guanosine 5'-monophosphate (5'-GMP) has been investigated and compared. The reactions of GSH and GS-Me with the two platinum complexes are second order, i.e. with a direct nucleophilic attack by the entering ligand on the platinum. For the reaction of 5'-GMP with [Pt(dien)Cl]+ the rate-determining step is the formation of [Pt(dien)(H2O)]2+ followed by a rapid nucleophilic substitution of 5'-GMP, through its N7 atom. The kinetic data show that 5'-GMP has a strong kinetic preference for [Pt(dien)(H2O)]2+ compared with GSH and GS-Me. On the contrary, [Pt(dien)Cl]+ reacts more rapidly with GSH and GS-Me. The obtained kinetic data have been analyzed in relation to the antitumor activity and toxicity of platinum complexes. As a result, a new strategy for the development of novel platinum drugs with improved antitumor properties and lower toxicities has been suggested.