tetano
Editor, Senior Moderator
ChemMedChem. 2013 Feb 5. doi: 10.1002/cmdc.201200562. [Epub ahead of print]
Synthesis and Biological Evaluation of Purine 2'-Fluoro-2'-deoxyriboside ProTides as Anti-influenza Virus Agents.
Meneghesso S, Vanderlinden E, Brancale A, Balzarini J, Naesens L, McGuigan C.
Source
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB (UK). meneghessos@cardiff.ac.uk.
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.
Copyright ? 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PMID:
23386468
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/23386468
Synthesis and Biological Evaluation of Purine 2'-Fluoro-2'-deoxyriboside ProTides as Anti-influenza Virus Agents.
Meneghesso S, Vanderlinden E, Brancale A, Balzarini J, Naesens L, McGuigan C.
Source
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB (UK). meneghessos@cardiff.ac.uk.
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.
Copyright ? 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PMID:
23386468
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/23386468