The Kinetics of the Reaction of ‘Anomalous’ 4-nitroimidazole Radiosensitizers with Thiols

Nitroimidazoles as hypoxic cell radiosensitizers and hypoxia probes: misonidazole, myths and mistakes

“…49 The explanation was much simpler: cellular thiols were displacing the halide 'leaving group' (in a reaction catalysed by glutathione-S-transferases); the behaviour was also exhibited by other 4-nitroimidazoles with substituents such as -SO 2 CH 3 . [50][51][52][53][54] Some nitro compounds, including 1-methyl-2-nitroimidazole substituted with 5-CHO ( Figure 1) (16), a 2-nitrobenzimidazole (17), and the 5-nitrofuran nifurtimox (3) react with thiols with the nitro substituent being displaced as nitrite. 53,55 Other, broadly similar examples of radiosensitization by thiol-reactive nitroimidazoles were reported in different laboratories, for brevity not further discussed here.…”

“…In practice, ensuring the test system is thoroughly de-oxygenated takes time and a modified testing procedure would be required. Importantly, even where direct thiol reactivity of the nitro compound is very slow (and it certainly is with misonidazole), 51 as soon as the test cells become hypoxic, cellular nitroreductases 'kick in' , and the resulting metabolism produces, via the radical-anion, the nitroso 2-electron reduction product which is highly reactive towards thiols. Synthesis of 1-methyl-2nitrosoimidazole ( Figure 1) (18) (and painstaking identification of 'downstream' reduction products and their properties) enabled the properties of the thiol-depleting intermediate(s) to be studies in detail.…”