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Synthesis and biological evaluation of purine 2'-Fluoro-2'-deoxyriboside ProTides as anti-influenza virus agents

Meneghesso, Silvia, Vanderlinden, Evelien, Brancale, Andrea, Balzarini, Jan, Naesens, Lieve and McGuigan, Christopher 2013. Synthesis and biological evaluation of purine 2'-Fluoro-2'-deoxyriboside ProTides as anti-influenza virus agents. ChemMedChem 8 (3) , pp. 415-425. 10.1002/cmdc.201200562

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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 EC99 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > RM Therapeutics. Pharmacology
R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords: 2′-fluoro-2′-deoxyguanosine; antiviral agents; influenza; nucleosides; ProTides
Publisher: Wiley-Blackwell
ISSN: 1860-7179
Last Modified: 14 Oct 2017 19:43
URI: http://orca-mwe.cf.ac.uk/id/eprint/44094

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