Drugs based on nitroarene, aromatic N-
oxide or
quinone structures are frequently reduced by cellular
reductases to toxic products. Reduction often involves
free radicals as intermediates which react rapidly with
oxygen to form
superoxide radicals, inhibiting
drug reduction. The elevation of cellular oxidative stress accompanying
oxygen inhibition of reduction is generally less damaging than
drug reduction to toxic products, so the drugs offer selective toxicity to hypoxic cells. Since such cells are resistant to
radiotherapy, these bioreductive drugs offer potential in tumour
therapy. The basis for the selectivity of action entails kinetic competition involving the contesting reaction pathways. The reduction potential of the
drug, radical pKa and nature of radical/radical decay kinetics all influence
drug activity and selectivity, including the range of
oxygen tensions over which the
drug offers selective toxicity. These properties may be quantified using generation of radicals by pulse radiolysis, presenting a physicochemical basis for rational
drug design.