Nitroimidazoles, cytotoxicity

Pharmacology Metronidazole, a nitroimidazole, is active against various anaerobic bacteria and protozoa. It is believed to invoke cytotoxicity on the reduced nitro group in the bacterium cell. The liberated inactive end products are believed to target the RNA, DNA, or cellular proteins of the organisms. 

Some of the sensitizing (and cytotoxic) effects of the nitro compounds can be attributed to GSH depletion. Activated chlorine maybe replaced by GS" [reaction (89) Wardman 1982 Stratford et al. 1983)], but the reaction is much more general. For example, the 2-nitroimidazoles react with GS by N02 release. These reactions are slow, but are considerably speeded up by glutathione-S-transferase (Wardman et al. 1973). 

Stillman MJ, Shaw CF III, Suzuki KT (1992) Metallothioneins. Synthesis, structure, and properties of metallothioneins, phytochelatins and metal-thiolate complexes. VCH Publishers, New York Stratford IJ, Hoe S, Adams GE, Hardy C, Williamson C (1983) Abnormal radiosensitizing and cytotoxic properties of ortho-substituted nitroimidazoles. Int J Radiat Biol 43 31-43 Stubbe J, Kozarich JW (1987) Mechanisms of bleomycin-induced DNA degradation. Chem Rev 87 1107-1136... 

One-electron reduction of misonidazole - 2-nitroimidazole radiosensitizer [891], (nitroimidazolyl)succinic esters [892] and nitroindazoles [893, 894] has been studied by ESR and polarography. Misonidazole is participated in the determination of potentiation degree of the anticancer agent cytotoxicity [891],... 

Nitroaromatic compounds (e.g. nitroimidazoles and nitro-furans) are useful against anaerobic microbial infections (1). They are also differentially toxic towards anaerobic or hypoxic mammalian cells (2) and selectively radiosensitize hypoxic cells, offering a potential new use for nitro compounds in cancer radiotherapy (3,4). The selective toxicity, i.e. the protection by O2, may arise via the one-electron transfer reaction (T), since the nitro radicals, RNO2 have been observed in anaerobic microsomal incubations (5) and the anaerobic reduction products such as hydroxylamines probably lead to cytotoxicity by binding to DNA and RNA (6) ... 

Conjugation of a 2-nitroimidazole derivative to carboxymethyl dextran allowed doxorubicin-loading with hypoxia-induced cellular uptake and cytotoxicity in vitro [110]. The dextran group for stability in the circulation and primary tumor accumulation was combined with conversion from a hydrophobic 2-nitroimidazole to a hydrophilic 2-aminoimidazole under hypoxia to promote doxorubicin release in tumor environment. This system showed a 4-fold doxorubicin accumulation in tumor over liver, lung, spleen, kidney, and heart 24 h after systemic injection and enhanced anticancer activity in vivo over free drug. 

A series of achiral hypoxia-activated prodrugs were synthesized on the basis of ifosfamide. Prodrugs, activated by 2-nitroimidazole reduction, demonstrated up to 400-fold enhanced cytotoxicity toward H-460 cells in culture under hypoxia versus their potency under aerobic conditions. The lead compound (75) has also been stable to liver microsomes and is currently being evaluated in the clinic as a promising antitumor agent. 

Brown, J.M. (1982). The mechanisms of cytotoxicity and chemosensitization by misonidazole and other nitroimidazoles. Int. J. Radiat. Oncol. Biol. Phys. 5(3-4), 675-682. 

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