The development of some nitroimidazoles as hypoxic cell sensitizers.

The most promising hypoxic cell sensitizer for use in radiotherapy is, at present, the 2-nitroimidazole, misonidazole, although neurotoxicity prevents its use at dosages necessary for optimum results. In the search for agents with better therapeutic ratios, we have investigated several classes of substituted 2-, 4-, and 5-nitroimidazoles. In general, 2-nitro derivatives are the most efficient in line with electron affinity considerations. However, notable exceptions include some 4-nitroimidazoles substituted in the 5-position by various sulphonamide or sulphonate groups. Some of these compounds are as efficient as oxygen on a concentration basis and display activity greater than predicted from their electron affinities. Cellular studies with these compounds will be described. Further, in the 2-nitroimidazole series the effect of the chain length of the N1 side chain terminated with a morpholine, piperidine, and pyrrolidine group has been studied. Notwithstanding the fairly constant electron affinities in these compounds, results show that systematic changes in sensitizing efficiency and cytotoxicity can occur with varying chain length, which indicates possible potential for increasing therapeutic ratio. These and other studies will be used as examples of the methods used in the search for better hypoxic cell sensitizers.