Design, synthesis and biological evaluation of phosphorodiamidate prodrugs of antiviral and anticancer nucleosides
Identifieur interne : 000756 ( Pmc/Corpus ); précédent : 000755; suivant : 000757Design, synthesis and biological evaluation of phosphorodiamidate prodrugs of antiviral and anticancer nucleosides
Auteurs : Christopher Mcguigan ; Claire Bourdin ; Marco Derudas ; Nadège Hamon ; Karen Hinsinger ; Sahar Kandil ; Karolina Madela ; Silvia Meneghesso ; Fabrizio Pertusati ; Michaela Serpi ; Magdalena Slusarczyk ; Stanley Chamberlain ; Alexander Kolykhalov ; John Vernachio ; Christophe Vanpouille ; Andrea Introini ; Leonid Margolis ; Jan BalzariniSource :
- European journal of medicinal chemistry [ 0223-5234 ] ; 2013.
Abstract
We herein report the application of the phosphorodiamidate phosphate prodrug approach to a series of thirteen nucleoside analogs with antiviral or anticancer activity. Twenty-five symmetrical phosphorodiamidates were synthesized, bearing esterified
Url:
DOI: 10.1016/j.ejmech.2013.09.047
PubMed: 24177359
PubMed Central: 4358806
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of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK</nlm:aff></affiliation></author><author><name sortKey="Hamon, Nadege" sort="Hamon, Nadege" uniqKey="Hamon N" first="Nadège" last="Hamon">Nadège Hamon</name><affiliation><nlm:aff id="A1"> School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK</nlm:aff></affiliation></author><author><name sortKey="Hinsinger, Karen" sort="Hinsinger, Karen" uniqKey="Hinsinger K" first="Karen" last="Hinsinger">Karen Hinsinger</name><affiliation><nlm:aff id="A1"> School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK</nlm:aff></affiliation></author><author><name sortKey="Kandil, Sahar" sort="Kandil, Sahar" uniqKey="Kandil S" first="Sahar" last="Kandil">Sahar Kandil</name><affiliation><nlm:aff id="A1"> School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK</nlm:aff></affiliation></author><author><name sortKey="Madela, Karolina" sort="Madela, Karolina" uniqKey="Madela K" first="Karolina" last="Madela">Karolina Madela</name><affiliation><nlm:aff id="A1"> School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK</nlm:aff></affiliation></author><author><name sortKey="Meneghesso, Silvia" sort="Meneghesso, Silvia" uniqKey="Meneghesso S" first="Silvia" last="Meneghesso">Silvia Meneghesso</name><affiliation><nlm:aff id="A1"> School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK</nlm:aff></affiliation></author><author><name sortKey="Pertusati, Fabrizio" sort="Pertusati, Fabrizio" uniqKey="Pertusati F" first="Fabrizio" last="Pertusati">Fabrizio Pertusati</name><affiliation><nlm:aff id="A1"> School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK</nlm:aff></affiliation></author><author><name sortKey="Serpi, Michaela" sort="Serpi, Michaela" uniqKey="Serpi M" first="Michaela" last="Serpi">Michaela Serpi</name><affiliation><nlm:aff id="A1"> School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK</nlm:aff></affiliation></author><author><name sortKey="Slusarczyk, Magdalena" sort="Slusarczyk, Magdalena" uniqKey="Slusarczyk M" first="Magdalena" last="Slusarczyk">Magdalena Slusarczyk</name><affiliation><nlm:aff id="A1"> School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK</nlm:aff></affiliation></author><author><name sortKey="Chamberlain, Stanley" sort="Chamberlain, Stanley" uniqKey="Chamberlain S" first="Stanley" last="Chamberlain">Stanley Chamberlain</name><affiliation><nlm:aff id="A2"> Inhibitex Inc., 9005 Westside Parkway, Alpharetta, GA 30004, USA</nlm:aff></affiliation></author><author><name sortKey="Kolykhalov, Alexander" sort="Kolykhalov, Alexander" uniqKey="Kolykhalov A" first="Alexander" last="Kolykhalov">Alexander Kolykhalov</name><affiliation><nlm:aff id="A2"> Inhibitex Inc., 9005 Westside Parkway, Alpharetta, GA 30004, USA</nlm:aff></affiliation></author><author><name sortKey="Vernachio, John" sort="Vernachio, John" uniqKey="Vernachio J" first="John" last="Vernachio">John Vernachio</name><affiliation><nlm:aff id="A2"> Inhibitex Inc., 9005 Westside Parkway, Alpharetta, GA 30004, USA</nlm:aff></affiliation></author><author><name sortKey="Vanpouille, Christophe" sort="Vanpouille, Christophe" uniqKey="Vanpouille C" first="Christophe" last="Vanpouille">Christophe Vanpouille</name><affiliation><nlm:aff id="A3"> Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Introini, Andrea" sort="Introini, Andrea" uniqKey="Introini A" first="Andrea" last="Introini">Andrea Introini</name><affiliation><nlm:aff id="A3"> Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Margolis, Leonid" sort="Margolis, Leonid" uniqKey="Margolis L" first="Leonid" last="Margolis">Leonid Margolis</name><affiliation><nlm:aff id="A3"> Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Balzarini, Jan" sort="Balzarini, Jan" uniqKey="Balzarini J" first="Jan" last="Balzarini">Jan Balzarini</name><affiliation><nlm:aff id="A4"> Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24177359</idno><idno type="pmc">4358806</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358806</idno><idno type="RBID">PMC:4358806</idno><idno type="doi">10.1016/j.ejmech.2013.09.047</idno><date when="2013">2013</date><idno type="wicri:Area/Pmc/Corpus">000756</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000756</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Design, synthesis and biological evaluation of phosphorodiamidate prodrugs of antiviral and anticancer nucleosides</title><author><name sortKey="Mcguigan, Christopher" sort="Mcguigan, Christopher" uniqKey="Mcguigan C" first="Christopher" last="Mcguigan">Christopher Mcguigan</name><affiliation><nlm:aff id="A1"> School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK</nlm:aff></affiliation></author><author><name sortKey="Bourdin, Claire" sort="Bourdin, Claire" uniqKey="Bourdin C" first="Claire" last="Bourdin">Claire Bourdin</name><affiliation><nlm:aff id="A1"> School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK</nlm:aff></affiliation></author><author><name sortKey="Derudas, Marco" sort="Derudas, Marco" uniqKey="Derudas M" first="Marco" last="Derudas">Marco Derudas</name><affiliation><nlm:aff id="A1"> School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK</nlm:aff></affiliation></author><author><name sortKey="Hamon, Nadege" sort="Hamon, Nadege" uniqKey="Hamon N" first="Nadège" last="Hamon">Nadège Hamon</name><affiliation><nlm:aff id="A1"> School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK</nlm:aff></affiliation></author><author><name sortKey="Hinsinger, Karen" sort="Hinsinger, Karen" uniqKey="Hinsinger K" first="Karen" last="Hinsinger">Karen Hinsinger</name><affiliation><nlm:aff id="A1"> School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK</nlm:aff></affiliation></author><author><name sortKey="Kandil, Sahar" sort="Kandil, Sahar" uniqKey="Kandil S" first="Sahar" last="Kandil">Sahar Kandil</name><affiliation><nlm:aff id="A1"> School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK</nlm:aff></affiliation></author><author><name sortKey="Madela, Karolina" sort="Madela, Karolina" uniqKey="Madela K" first="Karolina" last="Madela">Karolina Madela</name><affiliation><nlm:aff id="A1"> School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK</nlm:aff></affiliation></author><author><name sortKey="Meneghesso, Silvia" sort="Meneghesso, Silvia" uniqKey="Meneghesso S" first="Silvia" last="Meneghesso">Silvia Meneghesso</name><affiliation><nlm:aff id="A1"> School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK</nlm:aff></affiliation></author><author><name sortKey="Pertusati, Fabrizio" sort="Pertusati, Fabrizio" uniqKey="Pertusati F" first="Fabrizio" last="Pertusati">Fabrizio Pertusati</name><affiliation><nlm:aff id="A1"> School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK</nlm:aff></affiliation></author><author><name sortKey="Serpi, Michaela" sort="Serpi, Michaela" uniqKey="Serpi M" first="Michaela" last="Serpi">Michaela Serpi</name><affiliation><nlm:aff id="A1"> School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK</nlm:aff></affiliation></author><author><name sortKey="Slusarczyk, Magdalena" sort="Slusarczyk, Magdalena" uniqKey="Slusarczyk M" first="Magdalena" last="Slusarczyk">Magdalena Slusarczyk</name><affiliation><nlm:aff id="A1"> School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK</nlm:aff></affiliation></author><author><name sortKey="Chamberlain, Stanley" sort="Chamberlain, Stanley" uniqKey="Chamberlain S" first="Stanley" last="Chamberlain">Stanley Chamberlain</name><affiliation><nlm:aff id="A2"> Inhibitex Inc., 9005 Westside Parkway, Alpharetta, GA 30004, USA</nlm:aff></affiliation></author><author><name sortKey="Kolykhalov, Alexander" sort="Kolykhalov, Alexander" uniqKey="Kolykhalov A" first="Alexander" last="Kolykhalov">Alexander Kolykhalov</name><affiliation><nlm:aff id="A2"> Inhibitex Inc., 9005 Westside Parkway, Alpharetta, GA 30004, USA</nlm:aff></affiliation></author><author><name sortKey="Vernachio, John" sort="Vernachio, John" uniqKey="Vernachio J" first="John" last="Vernachio">John Vernachio</name><affiliation><nlm:aff id="A2"> Inhibitex Inc., 9005 Westside Parkway, Alpharetta, GA 30004, USA</nlm:aff></affiliation></author><author><name sortKey="Vanpouille, Christophe" sort="Vanpouille, Christophe" uniqKey="Vanpouille C" first="Christophe" last="Vanpouille">Christophe Vanpouille</name><affiliation><nlm:aff id="A3"> Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Introini, Andrea" sort="Introini, Andrea" uniqKey="Introini A" first="Andrea" last="Introini">Andrea Introini</name><affiliation><nlm:aff id="A3"> Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Margolis, Leonid" sort="Margolis, Leonid" uniqKey="Margolis L" first="Leonid" last="Margolis">Leonid Margolis</name><affiliation><nlm:aff id="A3"> Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA</nlm:aff></affiliation></author><author><name sortKey="Balzarini, Jan" sort="Balzarini, Jan" uniqKey="Balzarini J" first="Jan" last="Balzarini">Jan Balzarini</name><affiliation><nlm:aff id="A4"> Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium</nlm:aff></affiliation></author></analytic><series><title level="j">European journal of medicinal chemistry</title><idno type="ISSN">0223-5234</idno><idno type="eISSN">1768-3254</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P1">We herein report the application of the phosphorodiamidate phosphate prodrug approach to a series of thirteen nucleoside analogs with antiviral or anticancer activity. Twenty-five symmetrical phosphorodiamidates were synthesized, bearing esterified <sc>l</sc>-Alanine (and in one case <sc>d</sc>-alanine) in the prodrug moiety, each as single stereoisomer. The presence of an achiral phosphorus represents a potential advantage over the phosphoramidate ProTide approach, where diastereoisomeric mixtures are routinely obtained, and different biological profiles may be expected from the diastereoisomers. Optimization of the synthetic pathway allowed us to identify two general methods depending on the particular nucleoside analogs. All the compounds were biologically evaluated in antiviral and anticancer assays and several showed improvement of activity compared to their parent nucleosides, as in the case of ddA, d4T, abacavir and acyclovir against HIV-1 and/or HIV-2. The biological results were supported by metabolism studies with carboxypeptidase Y monitored by <sup>31</sup>P NMR to investigate their bioactivation. This work further validates the phosphorodiamidate approach as a monophosphate prodrug motif with broad application in the antiviral and anticancer fields.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">0420510</journal-id><journal-id journal-id-type="pubmed-jr-id">21651</journal-id><journal-id journal-id-type="nlm-ta">Eur J Med Chem</journal-id><journal-id journal-id-type="iso-abbrev">Eur J Med Chem</journal-id><journal-title-group><journal-title>European journal of medicinal chemistry</journal-title></journal-title-group><issn pub-type="ppub">0223-5234</issn><issn pub-type="epub">1768-3254</issn></journal-meta><article-meta><article-id pub-id-type="pmid">24177359</article-id><article-id pub-id-type="pmc">4358806</article-id><article-id pub-id-type="doi">10.1016/j.ejmech.2013.09.047</article-id><article-id pub-id-type="manuscript">NIHMS625599</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Design, synthesis and biological evaluation of phosphorodiamidate prodrugs of antiviral and anticancer nucleosides</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>McGuigan</surname><given-names>Christopher</given-names></name><xref ref-type="aff" rid="A1">a</xref><xref ref-type="corresp" rid="CR1">*</xref></contrib><contrib contrib-type="author"><name><surname>Bourdin</surname><given-names>Claire</given-names></name><xref ref-type="aff" rid="A1">a</xref></contrib><contrib contrib-type="author"><name><surname>Derudas</surname><given-names>Marco</given-names></name><xref ref-type="aff" rid="A1">a</xref></contrib><contrib contrib-type="author"><name><surname>Hamon</surname><given-names>Nadège</given-names></name><xref ref-type="aff" rid="A1">a</xref></contrib><contrib contrib-type="author"><name><surname>Hinsinger</surname><given-names>Karen</given-names></name><xref ref-type="aff" rid="A1">a</xref></contrib><contrib contrib-type="author"><name><surname>Kandil</surname><given-names>Sahar</given-names></name><xref ref-type="aff" rid="A1">a</xref></contrib><contrib contrib-type="author"><name><surname>Madela</surname><given-names>Karolina</given-names></name><xref ref-type="aff" rid="A1">a</xref></contrib><contrib contrib-type="author"><name><surname>Meneghesso</surname><given-names>Silvia</given-names></name><xref ref-type="aff" rid="A1">a</xref></contrib><contrib contrib-type="author"><name><surname>Pertusati</surname><given-names>Fabrizio</given-names></name><xref ref-type="aff" rid="A1">a</xref></contrib><contrib contrib-type="author"><name><surname>Serpi</surname><given-names>Michaela</given-names></name><xref ref-type="aff" rid="A1">a</xref></contrib><contrib contrib-type="author"><name><surname>Slusarczyk</surname><given-names>Magdalena</given-names></name><xref ref-type="aff" rid="A1">a</xref></contrib><contrib contrib-type="author"><name><surname>Chamberlain</surname><given-names>Stanley</given-names></name><xref ref-type="aff" rid="A2">b</xref></contrib><contrib contrib-type="author"><name><surname>Kolykhalov</surname><given-names>Alexander</given-names></name><xref ref-type="aff" rid="A2">b</xref></contrib><contrib contrib-type="author"><name><surname>Vernachio</surname><given-names>John</given-names></name><xref ref-type="aff" rid="A2">b</xref></contrib><contrib contrib-type="author"><name><surname>Vanpouille</surname><given-names>Christophe</given-names></name><xref ref-type="aff" rid="A3">c</xref></contrib><contrib contrib-type="author"><name><surname>Introini</surname><given-names>Andrea</given-names></name><xref ref-type="aff" rid="A3">c</xref></contrib><contrib contrib-type="author"><name><surname>Margolis</surname><given-names>Leonid</given-names></name><xref ref-type="aff" rid="A3">c</xref></contrib><contrib contrib-type="author"><name><surname>Balzarini</surname><given-names>Jan</given-names></name><xref ref-type="aff" rid="A4">d</xref></contrib></contrib-group><aff id="A1"><label>a</label> School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK</aff><aff id="A2"><label>b</label> Inhibitex Inc., 9005 Westside Parkway, Alpharetta, GA 30004, USA</aff><aff id="A3"><label>c</label> Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA</aff><aff id="A4"><label>d</label> Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium</aff><author-notes><corresp id="CR1"><label>*</label> Corresponding author. Tel./fax: +44 02920874537. <email>mcguigan/cardiff.ac.uk</email>, <email>mcguigan/cf.ac.uk</email> (C. McGuigan).</corresp></author-notes><pub-date pub-type="nihms-submitted"><day>4</day><month>9</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>09</day><month>10</month><year>2013</year></pub-date><pub-date pub-type="ppub"><year>2013</year></pub-date><pub-date pub-type="pmc-release"><day>13</day><month>3</month><year>2015</year></pub-date><volume>70</volume><fpage>326</fpage><lpage>340</lpage><pmc-comment>elocation-id from pubmed: 10.1016/j.ejmech.2013.09.047</pmc-comment>
<permissions><copyright-statement>© 2013 Elsevier Masson SAS. All rights reserved</copyright-statement><copyright-year>2013</copyright-year></permissions><abstract><p id="P1">We herein report the application of the phosphorodiamidate phosphate prodrug approach to a series of thirteen nucleoside analogs with antiviral or anticancer activity. Twenty-five symmetrical phosphorodiamidates were synthesized, bearing esterified <sc>l</sc>-Alanine (and in one case <sc>d</sc>-alanine) in the prodrug moiety, each as single stereoisomer. The presence of an achiral phosphorus represents a potential advantage over the phosphoramidate ProTide approach, where diastereoisomeric mixtures are routinely obtained, and different biological profiles may be expected from the diastereoisomers. Optimization of the synthetic pathway allowed us to identify two general methods depending on the particular nucleoside analogs. All the compounds were biologically evaluated in antiviral and anticancer assays and several showed improvement of activity compared to their parent nucleosides, as in the case of ddA, d4T, abacavir and acyclovir against HIV-1 and/or HIV-2. The biological results were supported by metabolism studies with carboxypeptidase Y monitored by <sup>31</sup>P NMR to investigate their bioactivation. This work further validates the phosphorodiamidate approach as a monophosphate prodrug motif with broad application in the antiviral and anticancer fields.</p></abstract><kwd-group><kwd>Nucleoside analogs</kwd><kwd>Antiviral</kwd><kwd>Anticancer</kwd><kwd>Phosphorodiamidates</kwd><kwd>Prodrugs</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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