Chelating agents as antitumour drugs: Formation of chelating agents from the antitumour pro-drug, razoxane

Abstract

The hydrolysis of the antitumour drug Razoxane, i.e. 1,2-bis(3,5-dioxopiperazin-1-yl)propane, in the presence of copper(II) has been studied by pH stat methods at 25 °C, in the pH range 4–5, at metal ion concentrations 0.018–0.053 M, and ionic strength 0.3 M. In all cases the concentration of Razoxane was 5.7 × 10 −3 M and the solvent system used was DMF/H 2O (1:2 1 2 ). Under these conditions the reaction rate was found to be first order in Razoxane, hydroxide ion and metal ion concentrations indicating that base hydrolysis of an incompletely formed copper(II)-Razoxane complex was being observed. At copper(II) concentrations of 0.018 , 0.036 and 0.053 M the second order rate constants for base hydrolysis are 1.1 × 10 8, 2.3 × 10 8 and 4.0 × 10 8 M −1 min −1 respectively. The last of these is 2.2 × 10 8 faster than the second order rate constant for hydrolysis of the free ligand for which k 2 is approximately 1.8 M −1 min −1 at 25 °C, ionic strength 0.3 M. Since there is only limited formation of the copper(II)-Razoxane complex the rate enhancement due to the metal ion is vastly in excess of 2.2 × 10 8. The reaction mechanism involves nucleophilic attack by a hydroxy ligand on the juxtaposed carbonyl group to give a strained intermediate which then undergoes rapid decomposition. Only one of the imide rings in Razoxane is hydrolysed in this reaction. Nevertheless a strong chelating agent is produced. The mode of action of Razoxane as an antitumour drug may involve hydrolytic metabolism to such a chelating agent.