Synthesis and Evaluation of α-methyl>-2-nitro-1H-imidazole-1-ethanols as Prodrugs of α--2-nitro-1H-imidazole-1-ethanol (RSU-1069) and Its Analogues Which Are Radiosensitizers and Bioreductively Activated Cytotoxins

Article abstract of DOI:10.1021/jm00171a040

α-<(1-Aziridinyl)methyl>-2-nitro-1H-imidazole-1-ethanols, of general formula , where Im = 2-nitroimidazole and R¹, R², R³, R⁴ = H, Me, are radiosensitizers and selective bioreductively activated cytotoxins toward hypoxic tumor cells in vitro and in vivo.Treatment of the aziridines with hydrogen halide in acetone or aqueous acetone gave the corresponding 2-haloethylamines of general formula ImCH2CH(OH)CH2⁺-NH2CR¹R²CR³R⁴XX^-, where R¹, R², R³, R⁴ = H, Me, and X = F, Cl, Br, I.These 2-haloethylamines were evaluated as prodrugs of the parent aziridines.The rates of ring closure in aqueous solution at pH ca. 6 were found to increase with increasing methyl substitution and to depend on the nature of the leaving group (I ca.Br > Cl >> F).A competing reaction of ImCH2CH(OH)CH2⁺NH2CH2CH2XX^- (X = Cl, Br) with aqueous HCO3^- ions gives 3-<2-hydroxy-3-(2-nitro-1H-imidazol-1-yl)propyl>-2-oxazolidinone.The activities of these prodrugs as radiosensitizers or as bioreductively activated cytotoxins were consistent with the proportion converted to the parent aziridine during the course of the experiment. α-<<(2-bromoethyl)amino>methyl>-2-nitro-1H-imidazole-1-ethanol (RB 6145, 10), the prodrug of α-<(1-aziridinyl)methyl>-2-nitro-1H-imidazole-1-ethanol (RSU-1069, 3), is identified as the most useful compound in terms of biological activity and rate of ring closure under physiological conditions.