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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
4
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pubmed:dateCreated |
1998-3-17
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pubmed:abstractText |
A series of 4(6)-(benzyloxy)-2,6(4)-diamino-5-(nitro or nitroso)pyrimidine derivatives and analogues of which 4(6)-benzyloxy groups were replaced with a (2-, 3-, or 4-fluorobenzyl)oxy or (2-, 3-, or 4-pyridylmethyl)oxy group, was synthesized. The abilities of these compounds to inhibit human O6-alkylguanine-DNA alkyltransferase (AGAT) in vitro and to potentiate the cytotoxicity of 1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl) -3-nitrosourea (ACNU) toward HeLa S3 cells were evaluated. 2,4-Diamino-6-[(2-fluorobenzyl)oxy]-5-nitropyrimidine (3) and 2,4-diamino-5-nitro-6-(2-pyridylmethoxy)pyrimidine (6), whose ortho positions of the 6-substituent are modified, were much weaker in terms of these abilities than the corresponding meta- or para-modified compounds. These results are consistent with those of our previous study using a series of O6-benzylguanine derivatives. All 5-nitrosopyrimidine derivatives examined exerted both stronger AGAT-inhibition and ACNU-enhancement abilities than the corresponding 5-nitro derivatives. Among a variety of compounds that we have examined to date, 2,4-diamino-6-[(4-fluorobenzyl)oxy]-5-nitrosopyrimidine (10) exhibited the strongest ability to inhibit AGAT, and its magnitude was 2.5 and 50 times those of 4-(benzyloxy)-2,6-diamino-5-nitrosopyrimidine (9) and O6-benzylguanine (1), respectively. A strong positive correlation was observed between the ability to inhibit AGAT and to potentiate the cytotoxicity of ACNU. This strongly indicates that 4(6)-(benzyloxy)pyrimidine derivatives and their analogues potentiate ACNU cytotoxicity by inhibiting AGAT activity. To characterize the reactivity of test compounds, alkyl-transfer reactions were also carried out using the biomimetic alkyl-transfer system.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/1-(2-chloroethyl)-1-nitrosourea,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Ethylnitrosourea,
http://linkedlifedata.com/resource/pubmed/chemical/Indicators and Reagents,
http://linkedlifedata.com/resource/pubmed/chemical/O(6)-Methylguanine-DNA...,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrimidines,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
0022-2623
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
12
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pubmed:volume |
41
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
503-8
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:9484500-Cell Survival,
pubmed-meshheading:9484500-Cloning, Molecular,
pubmed-meshheading:9484500-Drug Synergism,
pubmed-meshheading:9484500-Enzyme Inhibitors,
pubmed-meshheading:9484500-Ethylnitrosourea,
pubmed-meshheading:9484500-HeLa Cells,
pubmed-meshheading:9484500-Humans,
pubmed-meshheading:9484500-Indicators and Reagents,
pubmed-meshheading:9484500-Kinetics,
pubmed-meshheading:9484500-O(6)-Methylguanine-DNA Methyltransferase,
pubmed-meshheading:9484500-Pyrimidines,
pubmed-meshheading:9484500-Recombinant Proteins,
pubmed-meshheading:9484500-Structure-Activity Relationship
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pubmed:year |
1998
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pubmed:articleTitle |
Inhibition of human O6-alkylguanine-DNA alkyltransferase and potentiation of the cytotoxicity of chloroethylnitrosourea by 4(6)-(benzyloxy)-2,6(4)-diamino-5-(nitro or nitroso)pyrimidine derivatives and analogues.
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pubmed:affiliation |
Faculty of Pharmaceutical Sciences, Nagoya City University, Japan.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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