Radiation-chemical Properties of the Hypoxic Cell Radiosensitizer Doranidazole (PR-350)

Abstract

This study was performed to confirm the radiation-chemical properties of the 2-nitroimidazole derivative doranidazole, (±)-(2RS,3SR)-3-[(2-nitroimdazol-1-yl)-methoxy]butane-1,2,4-triol [CAS 137339–64–1], PR-350, which was synthesized as a hypoxic cell radiosensitizer with low toxicity. Radiation-chemical experiments using doranidazole showed that (1) unlike O₂, it had high reactivity toward not only hydrated electrons (e_aq^-), but also hydroxyl radicals (·OH), (2) the reduced intermediates of doranidasole had no ability to induce immediate strand breaks of colE1 plasmid DNA, (3) doranidazole enhanced radiation-induced DNA strand breaks of colE1 plasmid DNA in the aqueous state, whereas it did not enhance the base alteration, such as 8-oxo-deoxyguanosine, (4) it enhanced the radiation-induced formation of strand breaks with 3'-phosophate and 3'- phosphoglycolate termini, and (5) it was bound to DNA after irradiation. These facts revealed that the majority of radiation-chemical properties of doranidazole, except for the high reactivity toward ·OH, were similar to those of oxygen.