NAD(P)H dependent
cytochrome P450's and other haemoproteins under
hypoxia, mediate two-electron reduction of a wide range of structurally dissimilar N-
oxides to their respective tertiary
amines. Metabolic reduction can be utilised, in acute and chronic
hypoxia, to convert N-
oxides of
DNA affinic agents to potent and persistent
cytotoxins. In this respect a knowledge of N-
oxide bioreduction and the importance of the cationic nature of agents that bind to
DNA by intercalation can be combined to rationalise N-
oxides as
prodrugs of
DNA binding agents. The concept is illustrated using the alkylaminoanthraquinones which are a group of
cytotoxic agents with
DNA binding affinity that is dependent on the cationic nature of these compounds. The actions of the alkylaminoanthraquinones involve
drug intercalation into
DNA (and
double stranded RNA) and inhibition of both
DNA and
RNA polymerases and topoisomerase Type I and II. A di-N-
oxide analogue of
mitoxantrone, 1,4-bis([2-(dimethylamino-N-
oxide)ethyl]amino)5,8-dihydroxyanthracene -9,10- dione (
AQ4N) has been shown to possess no intrinsic binding affinity for
DNA and has low toxicity. Yet in the absence of air
AQ4N can be reduced in vitro to
a DNA affinic agent with up to 1000-fold increase in cytotoxic potency. Importantly the reduction product, AQ4, is stable under oxic conditions. Studies in vivo indicate that antitumour activity of
AQ4N is manifest under conditions that promote transient
hypoxia and/or diminish the oxic tumour fraction. The advantage of utilising the reductive environment of hypoxic tumours to reduce N-
oxides is that, unlike conventional bioreductive agents, the resulting products will remain active even if the
hypoxia that led to bioactivation is transient or the active compounds, once formed, diffuse away from the hypoxic tumour regions. Furthermore, the
DNA affinic nature of the active compounds should ensure their localisation in tumour tissue.