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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
2
|
| pubmed:dateCreated |
1988-9-26
|
| pubmed:abstractText |
Several arabinosyl-, xylosyl-, lyxosyl, 5'-deoxy-, acyclo-, 2,2'-anhydro-, 2,3'-anhydro-2'-deoxy-, 2,5'-anhydro-, 6,5'-cyclo-, and carbocyclic analogues of uridine with various 5-substitutions (fluoro, methyl, bromo, ethyl, benzyl, or benzyloxybenzyl) have been tested and compared with their corresponding ribo- and 2'-deoxyribosides for their potency to inhibit uridine phosphorylase (UrdPase) from both mouse and human livers. The effect of the alpha- and beta-configurations of the glycosidic bond was also tested. Xylo-, lyxo-, 2,3'-anhydro-2'-deoxy-, 6,5'-cyclo-, and carbocyclic uridines did not bind to the enzyme. Ribosides bound better than the corresponding 2'-deoxyribosides, which were better than the 5'-deoxyribosides. 2'-alpha-Deoxyribosides bound to the enzyme, albeit less tightly than the corresponding beta-anomers. The acyclo- and 2,2'-anhydrouridines were all potent inhibitors with the 2,2'-anhydro- derivatives being the most potent. 2,5'-Anhydrouridine bound to UrdPase less effectively than 2,2'-anhydrouridine and acyclouridine. Arabinosyl uracil was at best a very poor inhibitor but binds better if a benzyl group is added at the 5-position of the pyrimidine ring. This binding was enhanced further by adding a 5-benzyloxybenzyl group. A similar enhancement of the binding with increased hydrophobicity at the 5-position of the pyrimidine ring was observed with ribosides, alpha- and beta-anomers of the 2'-deoxyribosides, acyclonucleosides, and 2,2'-anhydronucleosides. The inhibitory potencies of these compounds with UrdPase from human liver roughly parallel those obtained with UrdPase from mouse liver. It is concluded that the presence of a N-glycosidic bond as well as a properly oriented 3'-hydroxyl group are prerequisites for a nucleoside ligand to bind to UrdPase. On the other hand, the presence of a 2'- or 5'-hydroxyl group or an N-glycosidic bond in the beta-configuration enhances but is not essential for binding. Furthermore, the potency of the binding of 2,2'-anhydrouridines (fixed syn-isomers) in contrast to the complete lack of binding of the 6,5'-cyclouridines (fixed anti-isomers) to UrdPase indicates that the binding of ligands to this enzyme is in the syn-conformation around the N-glycosidic bond.
|
| pubmed:grant | |
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical | |
| pubmed:status |
MEDLINE
|
| pubmed:month |
Aug
|
| pubmed:issn |
0026-895X
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:volume |
34
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
104-10
|
| pubmed:dateRevised |
2007-11-14
|
| pubmed:meshHeading |
pubmed-meshheading:3412318-Isomerism,
pubmed-meshheading:3412318-Kinetics,
pubmed-meshheading:3412318-Models, Molecular,
pubmed-meshheading:3412318-Molecular Conformation,
pubmed-meshheading:3412318-Pentoses,
pubmed-meshheading:3412318-Pentosyltransferases,
pubmed-meshheading:3412318-Structure-Activity Relationship,
pubmed-meshheading:3412318-Uridine,
pubmed-meshheading:3412318-Uridine Phosphorylase
|
| pubmed:year |
1988
|
| pubmed:articleTitle |
Effect of the N-glycosidic bond conformation and modifications in the pentose moiety on the binding of nucleoside ligands to uridine phosphorylase.
|
| pubmed:affiliation |
Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912.
|
| pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
|