title: Synthesis of uracil nucleotide analogs with a modified, acyclic ribose moiety as P2Y(2) receptor antagonists.
abstract: A series of new uracil nucleotide analogs (monophosphates, triphosphates, and phosphonates) was synthesized, in which the ribose moiety was replaced by acyclic chains, including branched or linear alkyl or dialkylether linkers. 1-omega-Bromoalkyluracil derivatives (2) were converted to the corresponding alcohols by treatment with sodium hydroxide and subsequently phosphorylated using phosphorus oxychloride followed by hydrolysis to yield the monophosphates, or by coupling with diphosphate to form the triphosphates. Reaction of 2 with triethyl phosphite followed by deprotection with trimethylsilyl bromide led to the omega-phosphonylalkyluracil derivatives. These products could be further phosphorylated by converting them into their imidazolides and subsequent treatment with diphosphate yielding the corresponding UTP analogs. Nucleoside analogs with an oxygen atom in the 2'-position, which are more similar to the natural ribosides, were synthesized from silylated uracil and trimethylsilyl iodide-treated 1,3-dioxolane, or 1,3-dioxane, respectively, and subsequently phosphorylated by standard procedures. The nucleotide analogs were investigated in a functional assay at NG108-15 cells, a neuroblastomaxglioma hybrid cell line which expresses the UTP- and ATP-activated nucleotide receptor subtype P2Y(2). The acyclic nucleotide analogs were generally weaker ligands than UTP, and-in contrast to UTP-they were antagonistic. The most potent compound was diphosphoric 5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pentylphosphonic anhydride (5c) with an IC(50) value of 92microM showing that the replacement of the alpha-phosphate by phosphonate, which leads to enhanced stability, was well tolerated.
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Sauer
authors.forename: Ali
authors.initials: A
authors.lastname: El-Tayeb
authors.forename: Marko
authors.initials: M
authors.lastname: Kaulich
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006822:Hybrid Cells; D051379:Mice; D009711:Nucleotides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058473:Receptors, Purinergic P2Y2; D014498:Uracil / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D009711:Nucleotides; D063065:Organophosphonates; C546386:P2ry2 protein, mouse; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2; D014498:Uracil