Linked Life Data

9668195

Source:http://linkedlifedata.com/resource/pubmed/id/9668195

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
1998-10-27
pubmed:abstractText
Thymidylate synthase (TS), an enzyme that catalyses the conversion of dUMP to dTMP, has been the focus of interest as a target in cancer chemotherapy for more than two decades. Over the last 10 years much research has been devoted to the design and development of nonpolyglutamatable inhibitors of TS as antitumour agents, mainly to over-come resistance due to unfavourable expression of folylpolyglutamate synthetase (FPGS). Lipophilic inhibitors of the enzyme were expected not to depend on the reduced folate carrier transporter (RFC) for cellular uptake, thus avoiding resistance due to an impaired RFC. Compounds of this type can be classified in three groups: A: nonclassical lipophilic inhibitors of TS, mainly folate-based analogues lacking the glutamate side chain; B: folate-based analogues in which the glutamate side chain has been modified in such a way that polyglutamation is precluded; and C: nonpolyglutamatable glutamate-containing inhibitors of TS. Compounds of group A included 5- or 6-substituted quinazolin-4-ones, benzo[flquinazolines, imidazotetrahydroquinoline- and benz[cd]indole-based inhibitors. The second group is mainly related to a series of g-linked dipeptide derivatives of ICIl98583, or analogues of this inhibitor where the glutamate residue was replaced with a range of a-amino acids. The third group is concerned with some 7-substituted derivatives of ICI198583 and the pyrrolo[3, 2-d]pyrimidine-based inhibitor 175. A large number of structurally diverse nonpolyglutamatable inhibitors of TS were synthesised some of which were potent inhibitors of the enzyme (human or E. coli) and in vitro cell growth. Three compounds, i.e. 49 (AG 337), 83 (AG 331), 123 (ZD9331) have reached the stage of clinical evaluation.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0929-8673
pubmed:author
pubmed:issnType
Print
pubmed:volume
5
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
265-88
pubmed:dateRevised
2007-2-12
pubmed:meshHeading
pubmed:year
1998
pubmed:articleTitle
Nonpolyglutamatable antifolates as inhibitors of thymidylate synthase (TS) and potential antitumour agents.
pubmed:affiliation
CRC Centre for Cancer Therapeutics at The Institute of Cancer Research, CRC Laboratory, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, U.S. Gov't, P.H.S., Review