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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
23
|
| pubmed:dateCreated |
1994-1-6
|
| pubmed:abstractText |
A convenient synthesis of 5-fluoro-2-thiouracil (11) is based on hydrolytic deamination of 5-fluoro-2-thiocytosine (9). Lewis acid-catalyzed condensation of di-TMS-5-fluoro-2-thiouracil (13) or di-TMS-2-thiouracil (14) with 2-deoxy-3,5-di-O-p-toluyl-D-ribofuranosyl chloride (15) led to mixtures of the beta- and alpha-anomers of 3',5'-toluylated 2'-deoxy-5-fluoro-2-thiouridine (16 and 18) or 2'-deoxy-2-thiouridine (17 and 19), each of which was deblocked with MeOH-NH3 to give the desired free anomeric nucleoside pairs 1, 5 and 3, 7, respectively. These were selectively converted to the corresponding 5'-monophosphates 2, 6 and 4, 8, with the aid of the wheat shoot phosphotransferase system. Conformations of the nucleosides 1, 3, 5, 7 are deduced from 1H NMR spectra, and circular dichroism spectra for nucleotide anomeric pairs 2, 6 and 4, 8 are reported. Whereas beta-2-thio-dUMP (4) was a good substrate (Km approximately 10(-5) M), beta-5-fluoro-2-thio-dUMP (2) proved to be a potent competitive, slow-binding inhibitor (Ki approximately 10(-8) M) of the purified enzymes from Ehrlich ascites carcinoma and L1210 cells. The alpha-anomer 6 was a weak inhibitor, with Ki in the mM range, and its congener 8 hardly interacted with the enzyme. The beta-anomer 1 exhibited antitumor activity in a mouse leukemic cell line L5178Y (IC50 approximately 10(-6) M), hence 40-100-fold weaker than 5-fluoro-dUrd. Its alpha-anomer 5 was 10-fold less active, but exhibited at least 10-fold higher selectivity with respect to the tumor cells than the beta-anomer 1.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Deoxyuracil Nucleotides,
http://linkedlifedata.com/resource/pubmed/chemical/Floxuridine,
http://linkedlifedata.com/resource/pubmed/chemical/Thiouridine,
http://linkedlifedata.com/resource/pubmed/chemical/Thymidylate Synthase
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Nov
|
| pubmed:issn |
0022-2623
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
12
|
| pubmed:volume |
36
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
3611-7
|
| pubmed:dateRevised |
2006-11-15
|
| pubmed:meshHeading |
pubmed-meshheading:8246229-3T3 Cells,
pubmed-meshheading:8246229-Animals,
pubmed-meshheading:8246229-Antineoplastic Agents,
pubmed-meshheading:8246229-Binding, Competitive,
pubmed-meshheading:8246229-Carcinoma, Ehrlich Tumor,
pubmed-meshheading:8246229-Cell Division,
pubmed-meshheading:8246229-Deoxyuracil Nucleotides,
pubmed-meshheading:8246229-Drug Screening Assays, Antitumor,
pubmed-meshheading:8246229-Floxuridine,
pubmed-meshheading:8246229-Kinetics,
pubmed-meshheading:8246229-Leukemia L1210,
pubmed-meshheading:8246229-Mice,
pubmed-meshheading:8246229-Spectrophotometry,
pubmed-meshheading:8246229-Stereoisomerism,
pubmed-meshheading:8246229-Structure-Activity Relationship,
pubmed-meshheading:8246229-Thiouridine,
pubmed-meshheading:8246229-Thymidylate Synthase,
pubmed-meshheading:8246229-Tumor Cells, Cultured
|
| pubmed:year |
1993
|
| pubmed:articleTitle |
2-Thio derivatives of dUrd and 5-fluoro-dUrd and their 5'-monophosphates: synthesis, interaction with tumor thymidylate synthase, and in vitro antitumor activity.
|
| pubmed:affiliation |
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warszawa.
|
| pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, Non-U.S. Gov't
|