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]

---

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), Vol. 33:9; ISSN 0022-2623
• Country of Publication: United States
• Language: English

Related Subjects

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
RADIOSENSITIZERS
EVALUATION
EXPERIMENTAL NEOPLASMS
IN VITRO
IN VIVO
MICE
TUMOR CELLS
ANIMAL CELLS
ANIMALS
DRUGS
MAMMALS
RODENTS
VERTEBRATES
560120* - Radiation Effects on Biochemicals
Cells
& Tissue Culture
560152 - Radiation Effects on Animals- Animals