Linked Life Data

8035424

Source:http://linkedlifedata.com/resource/pubmed/id/8035424

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
14
pubmed:dateCreated
1994-8-18
pubmed:abstractText
A series of analogues of the novel hypoxia-selective cytotoxin 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzamide (6) have been prepared and evaluated, in a search for compounds which retain high hypoxic selectivity but have increased potency and/or aqueous solubility. Several analogues with ionizable or dipolar carboxamide side chains showed improved solubility but generally had reduced cytotoxic potency and hypoxic selectivity. Modification of the mustard leaving groups or replacement of the carboxamide moiety provided some compounds with superior potency, but only the mixed chloro/mesylate mustard 20 provided a gain in potency relative to solubility while retaining the hypoxic selectivity of 6. These nitrogen mustards did not show the remarkable activity demonstrated by the related aziridine 7 [CB 1954, 5-(N-aziridinyl)- 2,4-dinitrobenzamide] in Walker 256 adenocarcinoma cells and are not efficient substrates for the DT-diaphorase which activates the latter compound by aerobic nitroreduction in Walker cells. Variations in hypoxic selectivity within the dinitrobenzamide mustards appear not to be due to differences in sensitivity to activation by this enzyme. Walker cells showed intermediate sensitivity to the mono(2-chloroethyl) analogue 26 but not to the related half-mustard 27, suggesting that the inhibition of DT-diaphorase activity is due to steric effects in the 5-position. The preferred compound overall with respect to solubility, potency, and in vitro hypoxic cell selectivity was the (dimethylamino)-ethyl derivative 11. DNA elution studies and comparison of the sensitivity of AA8 and UV4 cells to this compound indicated reductive activation to form a DNA cross-linking agent under hypoxia. Radiobiological studies indicated 11 to be equally active against both aerobic and hypoxic cells in KHT tumors. It is not clear whether this reflects efficient killing of aerobic cells as a result of diffusion of reduced metabolites from hypoxic regions or whether cytotoxicity in tumors is independent of hypoxia.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
8
pubmed:volume
37
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2175-84
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed:year
1994
pubmed:articleTitle
Hypoxia-selective antitumor agents. 9. Structure-activity relationships for hypoxia-selective cytotoxicity among analogues of 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzamide.
pubmed:affiliation
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't