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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
19
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pubmed:dateCreated |
1992-10-26
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pubmed:abstractText |
A series of 2-nitroimidazoles bearing side chains terminating in or containing aziridinyl and oxiranyl groups has been prepared, and the compounds were evaluated in vitro as hypoxia-selective bioreductively-activated cytotoxins and selected compounds tested for their radiosensitizing properties toward hypoxic mammalian cells. Compounds were either the regioisomers of analogues of the potent dual-functional 2-nitroimidiazole alpha-[(1-aziridinyl)-methyl]-2-nitro-1H-imidazole-1- ethanol (RSU-1069, 1) with additional methyl groups or related oxiranes of varying side-chain length and type. Oxiranyl derivatives showed little differential toxicity, and those tested were less effective as radiosensitizers, and although these properties were influenced by side-chain length, differences were not great. Aziridinyl compounds related to 1 but with increased side-chain lengths were unstable. Methylation of 1 in various regions had little effect on radiosensitization and no clear advantages over 1 as differential cytotoxic drugs. Progressive methylation at C-3 was found to increase toxicity but decrease hypoxia selectivity. Incorporation of a cyclohexane side chain in 1,2-cis-2,3-trans-3-aziridin-1-yl-2-hydroxy-1-(2-nitroimidazol+ ++-1- yl)cyclohexane (26) abolished hypoxia-selective toxicity and unexpectedly reduced radiosensitizing efficiency. Of the aziridines, 1-(2-nitro-1-imidazolyl)-2-methyl-3-(1-aziridinyl)-2-propanol (20) was comparable in efficacy to 1 as a bioreductively-activated cytotoxin with slightly lower aerobic toxicity; however, the prodrugs of 1 remain as preferred candidates for clinical evaluation.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical | |
pubmed:status |
MEDLINE
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pubmed:month |
Sep
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pubmed:issn |
0022-2623
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
18
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pubmed:volume |
35
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3573-8
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:1404237-Antibiotics, Antineoplastic,
pubmed-meshheading:1404237-Aziridines,
pubmed-meshheading:1404237-Isomerism,
pubmed-meshheading:1404237-Nitroimidazoles,
pubmed-meshheading:1404237-Radiation Tolerance,
pubmed-meshheading:1404237-Structure-Activity Relationship,
pubmed-meshheading:1404237-Tumor Cells, Cultured
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pubmed:year |
1992
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pubmed:articleTitle |
2-Nitroimidazole dual-function bioreductive drugs: studies on the effects of regioisomerism and side-chain structural modifications on differential cytotoxicity and radiosensitization by aziridinyl and oxiranyl derivatives.
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pubmed:affiliation |
MRC Radiobiology Unit, Chilton, Didcot, Oxon, United Kingdom.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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