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Synthesis and P2Y? receptor agonist activities of uridine 5'-phosphonate analogues.

ABSTRACT: We explored the influence of modifications of uridine 5'-methylenephosphonate on biological activity at the human P2Y(2) receptor. Key steps in the synthesis of a series of 5-substituted uridine 5'-methylenephosphonates were the reaction of a suitably protected uridine 5'-aldehyde with [(diethoxyphosphinyl)methylidene]triphenylphosphorane, C-5 bromination and a Suzuki-Miyaura coupling. These analogues behaved as selective agonists at the P2Y(2) receptor, with three analogues exhibiting potencies in the submicromolar range. Although maximal activities observed with the phosphonate analogues were much less than observed with UTP, high concentrations of the phosphonates had no effect on the stimulatory effect of UTP. These results suggest that these phosphonates bind to an allosteric site of the P2Y(2) receptor.

SUBMITTER: Van Poecke S

PROVIDER: S-EPMC3303979 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Synthesis and P2Y₂ receptor agonist activities of uridine 5'-phosphonate analogues.

Van Poecke Sara S Barrett Matthew O MO Santhosh Kumar T T Sinnaeve Davy D Martins José C JC Jacobson Kenneth A KA Kendall Harden T T Van Calenbergh Serge S

Bioorganic & medicinal chemistry 20120215 7

We explored the influence of modifications of uridine 5'-methylenephosphonate on biological activity at the human P2Y(2) receptor. Key steps in the synthesis of a series of 5-substituted uridine 5'-methylenephosphonates were the reaction of a suitably protected uridine 5'-aldehyde with [(diethoxyphosphinyl)methylidene]triphenylphosphorane, C-5 bromination and a Suzuki-Miyaura coupling. These analogues behaved as selective agonists at the P2Y(2) receptor, with three analogues exhibiting potencies ...[more]

PMID: 22386981

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