Kinetic and Equilibrium Studies on Formation of Hydroxo-bridged Dinuclear Platinum Complexes and Their Chemical Reactivities

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Ciplatin is one of the most active antitumor drugs. Its active species has been believed to be cis-diamminediaquaplatinum(II) ion. It is a diprotic acid and forms a dihydroxo-bridged dinuclear complex in neutral pH region. In this research project, kinetic and equilibrium studies on the formation of the dinuclear platinum(II) complexes were carried out by potentiometry, and the reaction of dinuclear complexes with guanosine-5'-monophosphate as a model of deoxyribonucleic acid, which is the likely target for platinum complexes in tumor cells, was investigated by high-performance liquid chromatography, circular dichromism spectrometry, and proton nuclear magnetic resonance spectrometry.In the kinetic sutudy, the observed second order rate constants for the dinuclear complex formation were calculated from the analysis of the hydrogen concentration variation at the early stage of the reaction after a small amount of potassium hydroxide was added to the solution of diaquaplatinum(II) complexes. The rate constants for several platinum(II) complexes containing ethylendiamine and its derivatives were determined. The formation of the hydroxo-bridged dinuclear complexes is found to be influenced by the basicity of amine ligands.The reactivities of the dinuclear complex derived from cisplatin with species. The formation of monohydroxo-bridged platinum complex containing 5' -GMP was suggested as an intermediate in the former reaction.The above information is useful to understand the mechanism of the tumor inhibitory action of cisplatin and the biological activities of the dinuclear platinum(II) complexes.