title: Effect of the N-glycosidic bond conformation and modifications in the pentose moiety on the binding of nucleoside ligands to uridine phosphorylase.
abstract: 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.
authors.affiliation: Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912.
authors.forename: M H
authors.initials: MH
authors.lastname: el Kouni
authors.forename: F N
authors.initials: FN
authors.lastname: Naguib
authors.forename: S H
authors.initials: SH
authors.lastname: Chu
authors.forename: S M
authors.initials: SM
authors.lastname: Cha
authors.forename: T
authors.initials: T
authors.lastname: Ueda
authors.forename: G
authors.initials: G
authors.lastname: Gosselin
authors.forename: J L
authors.initials: JL
authors.lastname: Imbach
authors.forename: Y F
authors.initials: YF
authors.lastname: Shealy
authors.forename: B A
authors.initials: BA
authors.lastname: Otter
mesh_terms: D007536:Isomerism; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D010429:Pentoses; D010430:Pentosyltransferases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014529:Uridine / Q000031:analogs & derivatives* / Q000378:metabolism; D014543:Uridine Phosphorylase / Q000378:metabolism*
chemical_list: D010429:Pentoses; D010430:Pentosyltransferases; D014543:Uridine Phosphorylase; D014529:Uridine