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Predicate | Object |
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
17
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pubmed:dateCreated |
1992-9-22
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pubmed:abstractText |
Nitroaniline mustards have potential as hypoxia-selective cytotoxic agents, with reductive metabolism activating the nitrogen mustard by converting the electron-withdrawing nitro group to an electron-donating hydroxylamine or amine. However, the parent compounds have poor aqueous solubility, and their potencies are limited by low reduction potentials (E1/2 ca. -600 mV versus the normal hydrogen electrode) and corresponding slow rates of nitro reduction. To address these limitations, a series of 4-nitroaniline mustards bearing hydrophilic side chains attached via an electron-withdrawing carboxamide group was prepared and evaluated for hypoxia-selective cytotoxicity against Chinese hamster cell lines. The N-[(N,N-dimethylamino)ethyl]carboxamide derivatives proved to have excellent aqueous solubility and improved cytotoxic potency, but their reduction potentials, while higher than the non-carboxamide compounds, were still low and little selectivity for hypoxic cells were observed. A series of carboxamides of 2,4-dinitroaniline mustard was also prepared. These compounds had reduction potentials in the desired range (E1/2 ca. -450 mV by cyclic voltammetry) and were more toxic to hypoxic than aerobic UV4 cells. The most selective compounds were 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzamide (20, SN 23862) and its water-soluble N-[(N,N-dimethylamino)ethyl]carboxamide analogue. These showed selectivities of 60- to 70-fold for hypoxic UV4 cells. The selectivity of 20 was much superior to that of its aziridine analogue (23, CB 1954), which was only 3.6-fold more toxic to hypoxic than oxic cells in the same system. Compound 20 is a much less efficient substrate than CB 1954 for the major aerobic nitroreductase from rat Walker tumor cells, NAD(P)H:quinone oxidoreductase (DT diaphorase). Lack of aerobic bioactivation of 20 by DT diaphorases may be responsible for its higher hypoxic selectivity than that of 23.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/4-nitroaniline,
http://linkedlifedata.com/resource/pubmed/chemical/Aniline Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/Aniline Mustard,
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Mustard Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/NAD(P)H Dehydrogenase (Quinone),
http://linkedlifedata.com/resource/pubmed/chemical/Oxygen,
http://linkedlifedata.com/resource/pubmed/chemical/Water
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0022-2623
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
21
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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 |
3214-22
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pubmed:dateRevised |
2008-11-21
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pubmed:meshHeading |
pubmed-meshheading:1507207-Aniline Compounds,
pubmed-meshheading:1507207-Aniline Mustard,
pubmed-meshheading:1507207-Animals,
pubmed-meshheading:1507207-Antineoplastic Agents,
pubmed-meshheading:1507207-CHO Cells,
pubmed-meshheading:1507207-Cell Survival,
pubmed-meshheading:1507207-Chemistry, Physical,
pubmed-meshheading:1507207-Cricetinae,
pubmed-meshheading:1507207-Humans,
pubmed-meshheading:1507207-Molecular Structure,
pubmed-meshheading:1507207-Mustard Compounds,
pubmed-meshheading:1507207-NAD(P)H Dehydrogenase (Quinone),
pubmed-meshheading:1507207-Oxidation-Reduction,
pubmed-meshheading:1507207-Oxygen,
pubmed-meshheading:1507207-Physicochemical Phenomena,
pubmed-meshheading:1507207-Rats,
pubmed-meshheading:1507207-Solubility,
pubmed-meshheading:1507207-Structure-Activity Relationship,
pubmed-meshheading:1507207-Tumor Cells, Cultured,
pubmed-meshheading:1507207-Water
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pubmed:year |
1992
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pubmed:articleTitle |
Hypoxia-selective antitumor agents. 5. Synthesis of water-soluble nitroaniline mustards with selective cytotoxicity for hypoxic mammalian cells.
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pubmed:affiliation |
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
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pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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