CORRELATION BETWEEN METABOLIC REDUCTION RATES AND ELECTRON-AFFINITY OF NITROHETEROCYCLES

  • 1 January 1979
    • journal article
    • research article
    • Vol. 39  (11) , 4512-4515
Abstract
Nitroheterocyclic compounds can selectively sensitize hypoxic (tumor) cells to radiation damage in vitro. Results in vivo have generally been less optimistic, inasmuch as metabolic reduction of these drugs not only limits effective lifetime but also produces metabolic intermediates with marked cytotoxic and carcinogenic activity. With 3 reducing systems in vitro, Escherichia coli B/r, mouse L-929 cells and mouse liver microsomes, the rate of nitroreduction of several nitroheterocycles was proportional to their electron affinity (half-wave reduction potential). Relative to the rate of nitrofurazone reduction in each system, metronidazole (Flagyl), N-hydroxyethyl-3,5-dinitropyrrole, misonidazole, nifuroxime, nitrofurantoin and furylfuramide were metabolized about 200, 20, 2, 1.4 and 1.2 times less rapidly, while 3,5-dinitrobenzonitrile, 2,5-dinitrophenol and 5-nitro-2-furaldehyde diacetate were reduced 2, 3 and 4 times more rapidly. Since nitroreduction is correlated with subsequent cytotoxicity, DNA damage and mutagenicity, improvements in the therapeutic efficacy of nitroheterocycles (i.e., sensitization without toxicity and carcinogenicity) will depend on development of drugs with more appropriate pharmacological properties.