Theoretical criteria for the production of long-lived populations of cytotoxic free radicals

Abstract

Populations of cytotoxic semiquinone and ascorbyl free radicals with half-lives in excess of 103 seconds result from the interaction of 2, 6-dimethoxy-p-quinone with ascorbate at pH 7.4. Kinetics for these ascorbyl and semiquinone free radical populations have been determined experimentally by electron spin resonance spectroscopy (ESR). Neither transition metals nor oxygen were found to be involved in the generation or decay of these free radicals and no evidence for the formation of other more reactive species such as OH radicals could be found by spin trapping. A theoretical model is presented that accounts for the observed production of free radicals and their kinetics. The formation and decay of semiquinone radicals can be explained by a conproportionation-disproportionation pseudoequifibrium existing between quinone and hydroquinone in the reaction mixture. The presence of ascorbyl radicals cannot be explained in this way, however, and these radicals apparently result from one electron reductions of quinone by ascorbate. Criteria for the selection of other pairs of electron donors and acceptors capable of synergistic production of long-lived free radical populations for applications such as chemotherapy are discussed.