SYNTHESIS AND EVALUATION OF ALPHA-[[(2-HALOETHYL)AMINO]METHYL]-2-NITRO-1H-IMIDAZOLE-1-ETHANOLS AS PRODRUGS OF ALPHA-[(1-AZIRIDINYL)METHYL]-2-NITRO-1H-IMIDAZOLE-1-ETHANOL (RSU-1069) AND ITS ANALOGS WHICH ARE RADIOSENSITIZERS AND BIOREDUCTIVELY ACTIVATED CYTOTOXINS

α-[(1-AziridinyOmethyl]-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 ~6 were found to increase with increasing methyl substitution and to depend on the nature of the leaving group (I — Br = Cl» F). A competing reaction of ImCH2CH(OH)CH2+NH2CH2CH2X X-(X = C1, Br) with aqueous HC03-ions gives 3-[2-hyroxy-3-(2-nitro-1H-imidazol-1-y1)propy1]-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. © 1990, American Chemical Society. All rights reserved.