alpha-[(1-Aziridinyl)methyl]-2-nitro-1H-imidazole-1-ethanols, of general formula ImCH2CH(OH)CH2NCR1R2CR3R4, 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(+)-NH2CR1R2CR3R4X X-, 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 approximately 6 were found to increase with increasing methyl substitution and to depend on the nature of the leaving group (I approximately Br greater than Cl much greater than F). A competing reaction of ImCH2CH(OH)CH2+NH2CH2CH2X X- (X = Cl, Br) with aqueous HCO3- ions gives 3-[2-hyroxy-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. alpha-[[(2-Bromoethyl)amino]methyl]-2-nitro-1H-imidazole-1- ethanol (RB 6145, 10), the prodrug of alpha-[(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.
A series of 3,5-disubstituted-2,1-benzisoxazole-4,7-diones was synthesized and evaluated as radiosensitizers both in vitro and in vivo. These compounds were designed as non-nitro electron-affinic agents in an effort to alleviate some of the toxicities seen with the 2-nitroimidazole radiosensitizers evaluated in the clinic. Several compounds in this series were potent radiosensitizers in vitro, with sensitizer enhancement ratios of 2.0-2.3 at concentrations less than 0.5 mM. Compounds with potent in vitro activity were also evaluated in vivo. However, none of these compounds showed radiosensitizing activity in vivo. The reduction potentials of these compounds were determined by cyclic voltammetry and compared to other electron-affinic radiosensitizers. In general, the reduction potentials of this series of compounds was slightly more positive than the 2-nitroimidazoles, but they fell within the range postulated as acceptable to yield in vivo activity. The results suggest that factors other than reduction potential may be responsible for the lack of in vivo radiosensitizing activity observed for this class of radiosensitizers.
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