EFFICIENT REDOX CYCLING OF NITROQUINOLINE BIOREDUCTIVE DRUGS DUE TO AEROBIC NITROREDUCTION IN CHINESE-HAMSTER CELLS

Nitroquinoline bioreductive drugs with 4-alkylamino substituents under go one-electron reduction in mammalian cells, resulting in futile redo x cycling due to oxidation of the nitro radical anion in aerobic cultu res, and eventual reduction to the corresponding amines in the absence of oxygen. Rates of drug-induced oxygen consumption (R) due to redox cycling in cyanide-treated AA8 cell cultures were determined for 17 ni troquinolines. There was a linear dependence of log R on the one-elect ron reduction potential at pH 7 (E(7)(1)) with a slope of 7.1 V-1, exc luding compounds with substituents ortho to the nitro group. The latte r had anomalously low rates of oxygen consumption relative to E(7)(1), suggesting that interaction with the active site of nitroreductases i s impeded sterically for such compounds. Absolute values of R (and the observed E:dependence) were well predicted by a simple kinetic model that used rates of net nitroreduction to the amines under anoxia as a measure of the rates of one-electron reduction in aerobic cells. This indicates that redox cycling of 4-alkylaminonitroquinolines occurs at high efficiency in aerobic cells, suggesting that there are no quantit atively significant fates of nitro radical anions in cells other than their reaction with oxygen (or their spontaneous disproportionation un der hypoxia).