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 analogues which are radiosensitizers and bioreductively activated cytotoxins

Journal Article · Sat Sep 01 00:00:00 EDT 1990 · Journal of Medicinal Chemistry; (USA)

DOI:https://doi.org/10.1021/jm00171a040· OSTI ID:6509587

Jenkins, T C; Naylor, M A; O'Neill, P; Threadgill, M D; Cole, S; Stratford, I J; Adams, G E; Fielden, E M; Suto, M J; Stier, M A ^[1]

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1. Medical Research Council Radiobiology Unit, Didcot, Oxfordshire (England)

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.

• OSTI ID: 6509587
• Journal Information: Journal of Medicinal Chemistry; (USA), Journal Name: Journal of Medicinal Chemistry; (USA) Vol. 33:9; ISSN JMCMA; ISSN 0022-2623
• Country of Publication: United States
• Language: English

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