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Synthesis and Biological Evaluation of Purine 2′‐Fluoro‐2′‐deoxyriboside ProTides as Anti‐influenza Virus Agents
Author(s) -
Meneghesso Silvia,
Vanderlinden Evelien,
Brancale Andrea,
Balzarini Jan,
Naesens Lieve,
McGuigan Christopher
Publication year - 2013
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.201200562
Subject(s) - deoxyguanosine , chemistry , biochemistry , nucleoside , prodrug , influenza a virus , purine , phosphoramidate , stereochemistry , enzyme , guanine , nucleoside analogue , virus , biology , dna , virology , nucleotide , gene
2′‐Fluoro‐2′‐deoxyguanosine has been reported to have potent anti‐influenza virus activity in vitro and in vivo. Herein we describe the synthesis and biological evaluation of 6‐modified 2′‐fluoro‐2′‐deoxyguanosine analogues and their corresponding phosphoramidate ProTides as potential anti‐influenza virus agents. Whereas the parent nucleosides were devoid of antiviral activity in two different cellular assays, the 5′‐ O ‐naphthyl(methoxy‐ L ‐alaninyl) ProTide derivatives of 6‐ O ‐methyl‐2′‐fluoro‐2′‐deoxyguanosine, 6‐ O ‐ethyl‐2′‐fluoro‐2′‐deoxyguanosine, and 2′‐deoxy‐2′‐fluoro‐6‐chloroguanosine, and the 5′‐ O ‐naphthyl(ethoxy‐ L ‐alaninyl) ProTide of 6‐ O ‐ethyl‐2′‐fluoro‐2′‐deoxyguanosine displayed antiviral EC 99 values of ∼12 μ M . The antiviral results are supported by metabolism studies. Rapid conversion into the L ‐alaninyl metabolite and then 6‐modified 2′‐fluoro‐2′‐deoxyguanosine 5′‐monophosphate was observed in enzymatic assays with yeast carboxypeptidase Y or crude cell lysate. Evidence for efficient removal of the 6‐substituent on the guanine part was provided by enzymatic studies with adenosine deaminase, and by molecular modeling of the nucleoside 5′‐monophosphates in the catalytic site of a model of ADAL1, thus indicating the utility of the double prodrug concept.