Mechanism(s) of bioreductive activation. The example of diaziquone (AZQ)

Bioreduction in the activation of diaziquone (2,5-diaziridinyl-3,6-bis (carboethoxyamino)-1,4-benzoquinone) has been investigated by exploring its reduction by whole cells, rat liver microsomes and purified enzymes. The mechanism of bioreduction was further investigated by exploring the chemical and electrochemical reduction of diaziquone as well as its photochemistry. Reduced diaziquone (by several means) was then tested for activity against parent compound. It appears that reduced diaziquone in most cases is more active than the oxidized form. Diaziquone redox cycles, but it is easily reduced to the hydroquinone which oxidizes to the semiquinone yielding free radicals under aerobiosis. The most probable mechanism of action is that of bioreductive alkylation where the alkylating aziridines are protonated after reduction facilitating the opening of the aziridine rings and thus alkylation.