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5′,6′‐Nucleoside Phosphonate Analogues Architecture: Synthesis and Comparative Evaluation towards Metabolic Enzymes
Author(s) -
Gallier Franck,
Alexandre Julie A. C.,
El Amri Chahrazade,
DevilleBonne Dominique,
Peyrottes Suzanne,
Périgaud Christian
Publication year - 2011
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100068
Subject(s) - kinase , phosphonate , nucleoside , chemistry , biochemistry , ribonucleoside , nucleic acid , phosphorylation , ribose , dephosphorylation , enzyme , stereochemistry , combinatorial chemistry , rna , phosphatase , gene
Abstract Nucleoside phosphonates have been designed as stable 5′‐mononucleotide mimics and are nowadays considered a potent class of antiviral agents. Within cells, they must be metabolised to the corresponding diphosphate to exert their biological activity. In this process, the first phosphorylation step, catalysed by nucleoside monophosphate kinases (NMP kinases), has been proposed as a bottleneck. Herein, we report the synthesis of a series of ribonucleoside phosphonate derivatives isosteric to 5′‐mononucleotides, with different degrees of flexibility within the 5′,6′‐CC bond, as well as different polarities, through the introduction of hydroxy groups. The influence of these modifications on the capacity of the compounds to act as substrates for appropriate human NMP kinases, involved in nucleic acids metabolism, has been investigated. Low flexibility, as well as an absence of hydroxy groups within the ribose–phosphorus architecture, is critical for efficient phosphotransfer. Among the series of pyrimidine analogues, one derivative was shown to be phosphorylated by human UMP‐CMP kinase, with rates similar to those of dUMP and even better than dCMP.