Linked Life Data

2296009

Source:http://linkedlifedata.com/resource/pubmed/id/2296009

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
1990-2-22
pubmed:abstractText
A series of aniline mustards with a wide range of electron-donating and -withdrawing substituents in the 3- and 4-positions has been synthesized and evaluated for cytotoxicity in cell culture to examine the potential of using nitro group deactivated nitrogen mustards for the design of novel hypoxia-selective anticancer drugs (Denny, W. A.; Wilson, W. R. J. Med. Chem. 1986, 29, 879). Hydrolytic half-lives in tissue culture media, determined by bioassay against a cell line (UV4) defective in the repair of DNA interstrand cross-links showed the expected dependence on the Hammett electronic parameter, sigma, varying from 0.13 h for the 4-amino analogue to greater than 100 h for analogues with strongly electron-withdrawing substituents. Cytotoxic potencies in aerobic UV4 cultures showed a similar dependence on sigma. This dependence predicted that the 4-nitroaniline mustard would be 7200-fold less potent than its potential six-electron reduction product, the 4-amino compound, in growth inhibition assays using a 1-h drug exposure. The measured differential was much lower (225-fold) because of the instability of the latter compound, but a differential of 17,500-fold was observed in the initial rate of killing by using a clonogenic assay. The potential for formation of reactive mustards by reduction to the amine or hydroxylamine was demonstrated by the 4-nitroso compound, which had an aerobic toxicity similar to that of the amine. Although these features confirmed the original rationale, the 3-nitro- and 4-nitroaniline mustards had only minimal hypoxic selectivity against UV cells. Toxicity to hypoxic cells appears to be limited by the low reduction potentials of these compounds and consequent lack of enzymatic nitroreduction. However, this study has demonstrated that nitro groups can be used to latentiate aromatic nitrogen mustards and indicates that examples with higher reduction potentials could provide useful hypoxia-selective therapeutic agents.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:volume
33
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
112-21
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed:year
1990
pubmed:articleTitle
Hypoxia-selective antitumor agents. 3. Relationships between structure and cytotoxicity against cultured tumor cells for substituted N,N-bis(2-chloroethyl)anilines.
pubmed:affiliation
Department of Pathology, University of Auckland School of Medicine, New Zealand.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't