Metabolic and radiolytic reduction of 4-alkylamino-5-nitroquinoline bioreductive drugs: Relationship to hypoxia-selective cytotoxicity

Abstract

The 4-alkylamino-5-nitroquinolines (5NQs) are a new series of bioreductive drugs that exhibit varying degrees of selective toxicity (up to 60-fold) under hypoxic conditions in cell culture. This study tested the hypothesis that differences in hypoxia-selective cytotoxicity in this series reflect differences in the efficiency with which oxygen inhibits metabolic reduction. The products of reduction of six 5NQs were characterized and rates of reduction compared in aerobic and hypoxic AA8 cells. The major stable products of both radiolytic and metabolic reduction under anoxic conditions were the corresponding amines, which were not responsible for the toxicity of the parent nitro compounds. Metabolism of each compound was inhibited completely in aerobic cells, indicating that differences in hypoxia-selective toxicity in this series are not due to variations in efficiency as substrates for oxygen-insensitive nitro reduction. Rates of hypoxic metabolism correlated broadly with hypoxia-selective cytotoxicity; the 5NQ derivatives with high rates of hypoxic metabolism had good hypoxia-selective cytotoxicity, whereas the compounds with low rates of reduction (the 3,6-dimethyl and 8-methylamino compounds; 3,6diMe-5NQ and 8NHMe-5NQ) were non-selective. Low rates of drug-induced oxygen consumption by 3,6diMe-5NQ and 8NHMe-5NQ in respiration-inhibited cells confirmed that these compounds are poor substrates for enzymatic nitro reduction. While there was an overall correlation between one-electron reduction potential at pH 7 (E 1 7 ) and rate of metabolic reduction, the relatively high E 1 7 of 3,6diMe-5NQ (-367mV) indicates that rates of reduction, and hypoxic selectivity of cytotoxicity, cannot be predicted from reduction potential alone. 3,6diMe-5NQ and 8NHMe-5NQ are cytotoxic through a non-bioreductive mechanism, the variable contribution of which may underlie the differences in hypoxia-selective cytotoxicity within this series of bioreductive drugs.