Linked Life Data

21366300

Source:http://linkedlifedata.com/resource/pubmed/id/21366300

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2011-3-17
pubmed:abstractText
Membrane transport of nucleosides or nucleobases is mediated by transporters including the equilibrative nucleoside transporters (ENTs), and resistance to antitumor antimetabolite drugs may arise via salvage of exogenous purine or pyrimidine nucleosides or nucleobases by ENT transporters. The therapeutic utility of dipyridamole (3), a potent ENT inhibitor, is compromised by binding to the serum protein ?(1)-acid glycoprotein (AGP). Derivatives and prodrugs of the ENT inhibitor 4,8-bis[(3,4-dimethoxybenzyl)amino]-2,6-bis[(2-hydroxypropyl)amino]pyrimido[5,4-d]pyrimidine (6, NU3108) are described, with improved in vivo pharmacokinetic properties and reduced AGP binding relative to dipyridamole. The mono- and diglycine carbamate derivatives were at least as potent as 6 and showed no reduction in potency by AGP. In a [(3)H]thymidine incorporation assay, employing COR-L23 cells, the diastereoisomers of 6 (IC(50) = 26 nM) exhibited activity comparable with 3 (IC(50) = 15 nM). The monophenyl carbamate and mono-4-methoxyphenyl carbamate exhibited the best ENT-inhibitory activity in the COR-L23 assay (IC(50) = 8 and 4 nM, respectively). All of the new prodrugs were also highly effective at reversing thymidine/hypoxanthine rescue from pemetrexed cytotoxicity in the COR-L23 cell line.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1520-4804
pubmed:author
pubmed:issnType
Electronic
pubmed:day
24
pubmed:volume
54
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1847-59
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
Nucleoside transport inhibitors: structure-activity relationships for pyrimido[5,4-d]pyrimidine derivatives that potentiate pemetrexed cytotoxicity in the presence of ?1-acid glycoprotein.
pubmed:affiliation
Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, U.K.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't