Linked Life Data

7783125

Source:http://linkedlifedata.com/resource/pubmed/id/7783125

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
11
pubmed:dateCreated
1995-7-18
pubmed:abstractText
A series of analogues of the previously described compound N-[2-(2-methyl-5-nitroimidazol-1H-yl)ethyl]-4-(2-nitroimidazol- 1H-yl)butanamide (4), a novel hypoxic cell cytotoxin and radiosensitizer, have been prepared and evaluated for hypoxia-selective cytotoxicity and hypoxic cell radiosensitization in vitro. The new derivatives were designed to overcome the low aqueous solubility of 4 and its slow kinetics of killing under hypoxia. The nitroheterocycle unit had a significant effect on solubility, with 3-nitrotriazoles being about 6-fold more soluble than the corresponding 2-nitroimidazoles. Analogues with a range of neutral linker chains (polyhydroxy, alkanesulfonamide, and bisamide) showed only slightly improved solubility and were unable to be fully evaluated. However, a series of analogues with cationic amine linkers had adequate aqueous solubility (up to 280 mM). The amine analogues could not be prepared by direct reduction of precursor amides such as 4 and were most conveniently synthesized by aza-Wittig condensation of the appropriate azide and aldehyde components. The amine-linked compounds were more cytotoxic than 4, with the symmetrical bis(2-nitroimidazole) derivatives (13 and 14) up to 9-fold more potent. They showed hypoxic selectivities comparable to that of 4 (ca. 200-fold) but had much more rapid kinetics of killing under hypoxia, resulting in high hypoxic selectivity at early times in culture. The nature of the mechanism of cytotoxicity of these compounds remains unclear but appears not to be DNA cross-linking, with the compounds showing a lack of hypersensitivity toward repair-deficient UV4 cells. The enhanced solubility and hypoxia-selective cytotoxicity (at early times) of 13 compared with 4 represent significant potential advantages.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
26
pubmed:volume
38
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1928-41
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:7783125-Animals, pubmed-meshheading:7783125-Antineoplastic Agents, pubmed-meshheading:7783125-Biotransformation, pubmed-meshheading:7783125-Cell Hypoxia, pubmed-meshheading:7783125-Cell Line, pubmed-meshheading:7783125-Chemistry, Physical, pubmed-meshheading:7783125-Cricetinae, pubmed-meshheading:7783125-Cricetulus, pubmed-meshheading:7783125-Heterocyclic Compounds, pubmed-meshheading:7783125-Humans, pubmed-meshheading:7783125-Mammary Neoplasms, Experimental, pubmed-meshheading:7783125-Melanoma, pubmed-meshheading:7783125-Mice, pubmed-meshheading:7783125-Nitroimidazoles, pubmed-meshheading:7783125-Oxygen, pubmed-meshheading:7783125-Physicochemical Phenomena, pubmed-meshheading:7783125-Radiation-Sensitizing Agents, pubmed-meshheading:7783125-Solubility, pubmed-meshheading:7783125-Structure-Activity Relationship, pubmed-meshheading:7783125-Water
pubmed:year
1995
pubmed:articleTitle
Hypoxia-selective antitumor agents. 10. bis(nitroimidazoles) and related Bis(nitroheterocycles): development of derivatives with higher rates of metabolic activation under hypoxia and improved aqueous solubility.
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