DIAZIQUONE-GLUTATHIONE CONJUGATES - CHARACTERIZATION AND MECHANISMS OF FORMATION

The antitumor agent diaziquone (AZQ) reacts with reduced glutathione ( GSH) in aqueous solutions and under aerobic conditions to give rise to the glutathionyl and hydroxyl free radicals, as well as the AZQ semiq uinone. Under anaerobic conditions, the only radical observed was the glutathionyl radical. These radicals are quickly abrogated when supero xide dismutase and catalase are coincubated. Separately, superoxide di smutase favors the formation of thiyl radicals while catalase favors t he formation of hydroxyl radicals and AZQ semiquinone. The metal chela tor diethylenetriaminepentaacetic acid favors the production of hydrox yl radicals and AZQ semiquinone. The reaction of AZQ with GSH at pH 7. 2 and 5.5 results in a variety of conjugates. These conjugates include addition of glutathione to both aziridines, displacement of the aziri dines by GSH, and a combination of both. The majority of the conjugate s are formed by nucleophilic attack of GSH to the AZQ aziridines or by 1,4-Michael addition to the AZQ quinone or a combination of both. The re may be a small free radical component in conjugate formation, but t he majority of the free radicals observed are from redox reactions tha t involve the oxidation of glutathione and the reduction and autoxidat ion of AZQ to produce oxygen radicals and hydrogen peroxide, a process that is enhanced by trace metal ions.