Linked Life Data

8863812

Source:http://linkedlifedata.com/resource/pubmed/id/8863812

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
21
pubmed:dateCreated
1996-11-25
pubmed:abstractText
Folypolyglutamate synthetase (FPGS) is responsible for the conversion of naturally occurring folates and antifolates to their poly-gama-glutamyl derivatives, which are the forms required for intracellular retention of folates and are also the preferred substrates (cofactors) for most folate-dependent enzymes. Folate and methotrexate analogues 6 and 4, with L-histidine in place of L-glutamate, were designed and synthesized as potential FPGS inhibitors. Target compound 5, the N tau-(carboxymethyl)-L-histidine derivative of 4, was also prepared. Compounds 4 and 5 inhibited the growth of L1210 cells (IC50 values: 0.091 and 0.15 microM, respectively) and were potent inhibitors of L1210 dihydrofolate reductase. No significant inhibition of FPGS by 4, 5, or 6 was observed at the high pH of the standard enzyme assay. This could be the consequence of a lack of protonation of the basic side chains, which is likely to be required for FPGS inhibitory activity. The observed cytotoxicity indicates that partial protonation of the imidazole ring permits cellular uptake of the analogues.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
11
pubmed:volume
39
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4340-4
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
1996
pubmed:articleTitle
Design and synthesis of histidine analogues of folic acid and methotrexate as potential folylpolyglutamate synthetase inhibitors.
pubmed:affiliation
Department of Medicinal Chemistry, School of Pharmacy, State University of New York at Buffalo 14260, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.