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Title: A new class of analogues of the bifunctional radiosensitizer alpha-(1-aziridinylmethyl)-2-nitro-1H-imidazole-1-ethanol (RSU 1069): The cycloalkylaziridines

Abstract

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.

Authors:
; ; ; ; ; ;  [1]
  1. Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI (USA)
Publication Date:
OSTI Identifier:
5262260
Resource Type:
Journal Article
Journal Name:
Journal of Medicinal Chemistry; (United States)
Additional Journal Information:
Journal Volume: 34:8; Journal ID: ISSN 0022-2623
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.; RADIOSENSITIZERS; EVALUATION; ANOXIA; CELL KILLING; CHEMICAL PREPARATION; HAMSTERS; MICE; STRUCTURE-ACTIVITY RELATIONSHIPS; ANIMALS; DRUGS; MAMMALS; RODENTS; SYNTHESIS; VERTEBRATES; 560152* - Radiation Effects on Animals- Animals

Citation Formats

Suto, M J, Stier, M A, Werbel, L M, Arundel-Suto, C M, Leopold, W R, Elliott, W E, and Sebolt-Leopold, J S. A new class of analogues of the bifunctional radiosensitizer alpha-(1-aziridinylmethyl)-2-nitro-1H-imidazole-1-ethanol (RSU 1069): The cycloalkylaziridines. United States: N. p., 1991. Web. doi:10.1021/jm00112a026.
Suto, M J, Stier, M A, Werbel, L M, Arundel-Suto, C M, Leopold, W R, Elliott, W E, & Sebolt-Leopold, J S. A new class of analogues of the bifunctional radiosensitizer alpha-(1-aziridinylmethyl)-2-nitro-1H-imidazole-1-ethanol (RSU 1069): The cycloalkylaziridines. United States. doi:10.1021/jm00112a026.
Suto, M J, Stier, M A, Werbel, L M, Arundel-Suto, C M, Leopold, W R, Elliott, W E, and Sebolt-Leopold, J S. Thu . "A new class of analogues of the bifunctional radiosensitizer alpha-(1-aziridinylmethyl)-2-nitro-1H-imidazole-1-ethanol (RSU 1069): The cycloalkylaziridines". United States. doi:10.1021/jm00112a026.
@article{osti_5262260,
title = {A new class of analogues of the bifunctional radiosensitizer alpha-(1-aziridinylmethyl)-2-nitro-1H-imidazole-1-ethanol (RSU 1069): The cycloalkylaziridines},
author = {Suto, M J and Stier, M A and Werbel, L M and Arundel-Suto, C M and Leopold, W R and Elliott, W E and Sebolt-Leopold, J S},
abstractNote = {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.},
doi = {10.1021/jm00112a026},
journal = {Journal of Medicinal Chemistry; (United States)},
issn = {0022-2623},
number = ,
volume = 34:8,
place = {United States},
year = {1991},
month = {8}
}