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rdf:type |
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lifeskim:mentions |
umls-concept:C0003392,
umls-concept:C0034289,
umls-concept:C0035647,
umls-concept:C0040085,
umls-concept:C0043309,
umls-concept:C0220781,
umls-concept:C0439858,
umls-concept:C0443177,
umls-concept:C0444626,
umls-concept:C1373048,
umls-concept:C1554184,
umls-concept:C1707689,
umls-concept:C1883254
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pubmed:issue |
15
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pubmed:dateCreated |
2009-9-1
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pubmed:abstractText |
N-{4-[(2-Amino-6-ethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl)thio]benzoyl}-L-glutamic acid 2 and 13 nonclassical analogues 2a-2m were synthesized as potential dual thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibitors and as antitumor agents. The key intermediate in the synthesis was 2-amino-6-ethyl-5-iodothieno[2,3-d]pyrimidin-4(3H)-one, 7, to which various arylthiols were attached at the 5-position. Coupling 8 with L-glutamic acid diethyl ester and saponification afforded 2. X-ray crystal structures of 2 and 1 (the 6-methyl analogue of 2), DHFR, and NADPH showed for the first time that the thieno[2,3-d]pyrimidine ring binds in a "folate" mode. Compound 2 was an excellent dual inhibitor of human TS (IC50 = 54 nM) and human DHFR (IC50 = 19 nM) and afforded nanomolar GI50 values against tumor cells in culture. The 6-ethyl substitution in 2 increases both the potency (by 2-3 orders of magnitude) as well as the spectrum of tumor inhibition in vitro compared to the 6-methyl analogue 1. Some of the nonclassical analogues were potent and selective inhibitors of DHFR from Toxoplasma gondii.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/19719239-10187828,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19719239-11052789,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19719239-12096917,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19719239-13998281,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19719239-1447744,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19719239-15548082,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19719239-15638735,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19719239-16359642,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19719239-16475929,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19719239-17333344,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19719239-17346178,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19719239-1741766,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19719239-18800768,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19719239-18804694,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19719239-1913676,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19719239-1995868,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19719239-2461200,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19719239-3297313,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19719239-410932,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19719239-7680860,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19719239-8459400,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19719239-9010648,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19719239-9548816
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
1520-4804
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
13
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pubmed:volume |
52
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4892-902
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pubmed:dateRevised |
2011-9-26
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pubmed:meshHeading |
pubmed-meshheading:19719239-Animals,
pubmed-meshheading:19719239-Antineoplastic Agents,
pubmed-meshheading:19719239-Cell Line, Tumor,
pubmed-meshheading:19719239-Crystallography, X-Ray,
pubmed-meshheading:19719239-Drug Design,
pubmed-meshheading:19719239-Enzyme Inhibitors,
pubmed-meshheading:19719239-Folic Acid Antagonists,
pubmed-meshheading:19719239-Humans,
pubmed-meshheading:19719239-Pyrimidines,
pubmed-meshheading:19719239-Structure-Activity Relationship,
pubmed-meshheading:19719239-Tetrahydrofolate Dehydrogenase,
pubmed-meshheading:19719239-Thymidylate Synthase,
pubmed-meshheading:19719239-Toxoplasma
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pubmed:year |
2009
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pubmed:articleTitle |
Design, synthesis, and X-ray crystal structure of classical and nonclassical 2-amino-4-oxo-5-substituted-6-ethylthieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors and as potential antitumor agents.
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pubmed:affiliation |
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, USA. gangjee@duq.edu
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pubmed:publicationType |
Journal Article,
Research Support, N.I.H., Extramural
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