Electron-affinic sensitization. VI. A pulse radiolysis and ESR comparison of some 2- and 5-nitroimidazoles

The nitroimidazoles are effective radiosensitizers for both hypoxic bacterial and mammalian cells and are currently under clinical investigation as adjuncts in radiotherapy. It is known that the 2-nitroimidazoles are biologically more efficient than the 5-nitro derivatives. Some aspects of the radiation chemistry of one biologically important example of each class, together with results obtained with other related derivatives, are reported. Metronidazole (a 5-nitroimidazole) and Ro-07-0582 (a 2-nitroimidazole) react rapidly with both e-/sub aq/ and OH to produce transient absorbing species, which decay by second-order kinetics. Both compounds accept electrons from the radical anion of thymine at near diffusion-controlled rates, but not from neutral thymine radicals formed by H and OH attack. From a study of one-electron transfer reactions involving p-nitroacetophenone as an electron acceptor it is shown that the electron affinity of the 2-nitroimidazole structure is higher than that of the 5-nitroderivatives and similar to that of PNAP. Further, ESR studies of these radical anions indicate greater resonance stabilization of 2-nitroimidazoles, implying a higher electron affinity. This correlates with the greater biological effectiveness of the 2-nitroimidazoles as hypoxic cell radiosensitizers. (U.S.)