O

Scheme 22

hydroxylamines, nitroso groups, nitro groups, and azo dyes can all be reduced by cytochrome P450, especially under anaerobic conditions.

N-Oxide metabolites are generally nontoxic or less toxic than the parent drug. Their lack of toxicity coupled to the likely regeneration of the parent in a hypoxic bio-environment suggested a prodrug strategy for treating solid tumors (for an extensive discussion of prodrugs, see 5.44 Prodrug Objectives and Design). Administration of an N-oxide-containing anticancer agent should reduce systemic toxicity but maintain the effectiveness of the drug, since reduction of the N-oxide back to the parent compound at the tumor site would be highly probable. This strategy has been successfully employed220'221 with the anthraquinone derivative AQ4N (199), which is currently in clinical trials (Scheme 22). After reaching the hypoxic regions of the solid tumor, the drug undergoes two sequential two-electron reductions. The reductions (CYP3A4) generate AQ4M (200), the mono-N-oxide, followed by AQ4 (201), the di-tertiary amine, and active anticancer agent. The cytotoxic potency of 201 is of the order of 1000-fold greater than that of 199.220

The reduction of an aromatic nitro group to an amine, a process that is frequently associated with toxicity, proceeds through the nitroso compound and the hydroxylamine. Early on it was established222 that nitrobenzene (202), nitrosobenzene (203), and phenylhydroxylamine (204) could all be reduced to aniline (205) by cytochrome P450 (Scheme 23). Cytochrome P450 under anaerobic conditions also appears to play a central role in the reductive

metabolism of the carcinogens 1-nitropyrene,223 2-nitropyrene, 4-nitrobiphenyl, and 1-nitronaphthalene224 to the corresponding hydroxylamines and amines. In a somewhat similar vein, the 3'-azido group of the anti-HIV drug zidovudine (206) has been shown to be susceptible to reduction to its toxic 3'-amino metabolite 207 under anaerobic conditions both by cytochrome P450 and by cytochrome b5 and its reductase (Scheme 24).225

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