Linked Life Data

1507207

Source:http://linkedlifedata.com/resource/pubmed/id/1507207

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
17
pubmed:dateCreated
1992-9-22
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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
21
pubmed:volume
35
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3214-22
pubmed:dateRevised
2008-11-21
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
pubmed:year
1992
pubmed:articleTitle
Hypoxia-selective antitumor agents. 5. Synthesis of water-soluble nitroaniline mustards with selective cytotoxicity for hypoxic mammalian cells.
pubmed:affiliation
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't