title: Synthesis and biological evaluation of purine 2'-fluoro-2'-deoxyriboside ProTides as anti-influenza virus agents.
abstract: 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 μM. 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.
authors: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, UK. meneghessos@cardiff.ac.uk
authors: Silvia
authors: S
authors: Meneghesso
authors: Evelien
authors: E
authors: Vanderlinden
authors: Andrea
authors: A
authors: Brancale
authors: Jan
authors: J
authors: Balzarini
authors: Lieve
authors: L
authors: Naesens
authors: Christopher
authors: C
authors: McGuigan
mesh_terms: D000243:Adenosine Deaminase / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005461:Fluorine / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D062105:Molecular Docking Simulation; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009975:Orthomyxoviridae / Q000187:drug effects / Q000201:enzymology; D011687:Purines / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D009705:Nucleosides; D011687:Purines; D005461:Fluorine; D012321:DNA-Directed RNA Polymerases; D000243:Adenosine Deaminase; C030985:purine