A new class of analogues of the bifunctional radiosensitizer alpha-(1-aziridinylmethyl)-2-nitro-1H-imidazole-1-ethanol (RSU 1069): The cycloalkylaziridines
- Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI (USA)
A series of compounds related to alpha-(1-aziridinylmethyl)-2-nitro-1H-imidazole-1-ethanol (RSU 1069, 1) were synthesized and evaluated as selective hypoxic cell cytotoxic agents and as radiosensitizers. The aziridine moiety was replaced with a number of other potential alkylating groups including cycloalkylaziridines and azetidines. The data indicated that modification of the aziridine of 1 resulted in a substantial decrease in the ability of the compounds to selectively kill hypoxic cells. However, these modifications did not affect the compounds' in vitro radiosensitizing activity since many of the derivatives were as potent as 1. All of the compounds that were evaluated in vivo were less toxic than 1, and several members of this series had significant activity. The best compound was trans-alpha-(((4-bromotetrahydro-2H-pyran-3-yl) amino)methyl)-2-nitro-1H-imidazole-1-ethanol (18), which, due to its activity and log P value, is a candidate for additional in vivo studies.
- OSTI ID:
- 5262260
- Journal Information:
- Journal of Medicinal Chemistry; (United States), Journal Name: Journal of Medicinal Chemistry; (United States) Vol. 34:8; ISSN JMCMA; ISSN 0022-2623
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMALS
ANOXIA
CELL KILLING
CHEMICAL PREPARATION
DRUGS
EVALUATION
HAMSTERS
MAMMALS
MICE
RADIOSENSITIZERS
RODENTS
STRUCTURE-ACTIVITY RELATIONSHIPS
SYNTHESIS
VERTEBRATES