CovidV2, Main, Exploration, bibRecord, 001254

Design, synthesis and biological evaluation of phosphorodiamidate prodrugs of antiviral and anticancer nucleosides

Identifieur interne : 001254 ( Main/Exploration ); précédent : 001253; suivant : 001255

Design, synthesis and biological evaluation of phosphorodiamidate prodrugs of antiviral and anticancer nucleosides

Auteurs : Christopher Mcguigan [Royaume-Uni] ; Claire Bourdin [Royaume-Uni] ; Marco Derudas [Royaume-Uni] ; Nadège Hamon [Royaume-Uni] ; Karen Hinsinger [Royaume-Uni] ; Sahar Kandil [Royaume-Uni] ; Karolina Madela [Royaume-Uni] ; Silvia Meneghesso [Royaume-Uni] ; Fabrizio Pertusati [Royaume-Uni] ; Michaela Serpi [Royaume-Uni] ; Magdalena Slusarczyk [Royaume-Uni] ; Stanley Chamberlain [États-Unis] ; Alexander Kolykhalov [États-Unis] ; John Vernachio [États-Unis] ; Christophe Vanpouille [États-Unis] ; Andrea Introini [États-Unis] ; Leonid Margolis [États-Unis] ; Jan Balzarini [Belgique]

Source :

European journal of medicinal chemistry [ 0223-5234 ] ; 2013.

RBID : PMC:4358806

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 l-Alanine (and in one case d-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 ³¹P 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.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358806

DOI: 10.1016/j.ejmech.2013.09.047
PubMed: 24177359
PubMed Central: 4358806

Affiliations:

Le document en format XML

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<author><name sortKey="Madela, Karolina" sort="Madela, Karolina" uniqKey="Madela K" first="Karolina" last="Madela">Karolina Madela</name>
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<author><name sortKey="Serpi, Michaela" sort="Serpi, Michaela" uniqKey="Serpi M" first="Michaela" last="Serpi">Michaela Serpi</name>
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<author><name sortKey="Slusarczyk, Magdalena" sort="Slusarczyk, Magdalena" uniqKey="Slusarczyk M" first="Magdalena" last="Slusarczyk">Magdalena Slusarczyk</name>
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<author><name sortKey="Chamberlain, Stanley" sort="Chamberlain, Stanley" uniqKey="Chamberlain S" first="Stanley" last="Chamberlain">Stanley Chamberlain</name>
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<country xml:lang="fr">États-Unis</country>
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<placeName><region type="state">Géorgie (États-Unis)</region>
</placeName>
</affiliation>
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<author><name sortKey="Kolykhalov, Alexander" sort="Kolykhalov, Alexander" uniqKey="Kolykhalov A" first="Alexander" last="Kolykhalov">Alexander Kolykhalov</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea> Inhibitex Inc., 9005 Westside Parkway, Alpharetta, GA 30004</wicri:regionArea>
<placeName><region type="state">Géorgie (États-Unis)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Vernachio, John" sort="Vernachio, John" uniqKey="Vernachio J" first="John" last="Vernachio">John Vernachio</name>
<affiliation wicri:level="2"><nlm:aff id="A2"> Inhibitex Inc., 9005 Westside Parkway, Alpharetta, GA 30004, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea> Inhibitex Inc., 9005 Westside Parkway, Alpharetta, GA 30004</wicri:regionArea>
<placeName><region type="state">Géorgie (États-Unis)</region>
</placeName>
</affiliation>
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<author><name sortKey="Vanpouille, Christophe" sort="Vanpouille, Christophe" uniqKey="Vanpouille C" first="Christophe" last="Vanpouille">Christophe Vanpouille</name>
<affiliation wicri:level="2"><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>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea> Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
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<author><name sortKey="Introini, Andrea" sort="Introini, Andrea" uniqKey="Introini A" first="Andrea" last="Introini">Andrea Introini</name>
<affiliation wicri:level="2"><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>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea> Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892</wicri:regionArea>
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</placeName>
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</author>
<author><name sortKey="Margolis, Leonid" sort="Margolis, Leonid" uniqKey="Margolis L" first="Leonid" last="Margolis">Leonid Margolis</name>
<affiliation wicri:level="2"><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>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea> Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Balzarini, Jan" sort="Balzarini, Jan" uniqKey="Balzarini J" first="Jan" last="Balzarini">Jan Balzarini</name>
<affiliation wicri:level="1"><nlm:aff id="A4"> Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea> Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven</wicri:regionArea>
<wicri:noRegion>B-3000 Leuven</wicri:noRegion>
</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>
<affiliations><list><country><li>Belgique</li>
<li>Royaume-Uni</li>
<li>États-Unis</li>
</country>
<region><li>Géorgie (États-Unis)</li>
<li>Maryland</li>
</region>
</list>
<tree><country name="Royaume-Uni"><noRegion><name sortKey="Mcguigan, Christopher" sort="Mcguigan, Christopher" uniqKey="Mcguigan C" first="Christopher" last="Mcguigan">Christopher Mcguigan</name>
</noRegion>
<name sortKey="Bourdin, Claire" sort="Bourdin, Claire" uniqKey="Bourdin C" first="Claire" last="Bourdin">Claire Bourdin</name>
<name sortKey="Derudas, Marco" sort="Derudas, Marco" uniqKey="Derudas M" first="Marco" last="Derudas">Marco Derudas</name>
<name sortKey="Hamon, Nadege" sort="Hamon, Nadege" uniqKey="Hamon N" first="Nadège" last="Hamon">Nadège Hamon</name>
<name sortKey="Hinsinger, Karen" sort="Hinsinger, Karen" uniqKey="Hinsinger K" first="Karen" last="Hinsinger">Karen Hinsinger</name>
<name sortKey="Kandil, Sahar" sort="Kandil, Sahar" uniqKey="Kandil S" first="Sahar" last="Kandil">Sahar Kandil</name>
<name sortKey="Madela, Karolina" sort="Madela, Karolina" uniqKey="Madela K" first="Karolina" last="Madela">Karolina Madela</name>
<name sortKey="Meneghesso, Silvia" sort="Meneghesso, Silvia" uniqKey="Meneghesso S" first="Silvia" last="Meneghesso">Silvia Meneghesso</name>
<name sortKey="Pertusati, Fabrizio" sort="Pertusati, Fabrizio" uniqKey="Pertusati F" first="Fabrizio" last="Pertusati">Fabrizio Pertusati</name>
<name sortKey="Serpi, Michaela" sort="Serpi, Michaela" uniqKey="Serpi M" first="Michaela" last="Serpi">Michaela Serpi</name>
<name sortKey="Slusarczyk, Magdalena" sort="Slusarczyk, Magdalena" uniqKey="Slusarczyk M" first="Magdalena" last="Slusarczyk">Magdalena Slusarczyk</name>
</country>
<country name="États-Unis"><region name="Géorgie (États-Unis)"><name sortKey="Chamberlain, Stanley" sort="Chamberlain, Stanley" uniqKey="Chamberlain S" first="Stanley" last="Chamberlain">Stanley Chamberlain</name>
</region>
<name sortKey="Introini, Andrea" sort="Introini, Andrea" uniqKey="Introini A" first="Andrea" last="Introini">Andrea Introini</name>
<name sortKey="Kolykhalov, Alexander" sort="Kolykhalov, Alexander" uniqKey="Kolykhalov A" first="Alexander" last="Kolykhalov">Alexander Kolykhalov</name>
<name sortKey="Margolis, Leonid" sort="Margolis, Leonid" uniqKey="Margolis L" first="Leonid" last="Margolis">Leonid Margolis</name>
<name sortKey="Vanpouille, Christophe" sort="Vanpouille, Christophe" uniqKey="Vanpouille C" first="Christophe" last="Vanpouille">Christophe Vanpouille</name>
<name sortKey="Vernachio, John" sort="Vernachio, John" uniqKey="Vernachio J" first="John" last="Vernachio">John Vernachio</name>
</country>
<country name="Belgique"><noRegion><name sortKey="Balzarini, Jan" sort="Balzarini, Jan" uniqKey="Balzarini J" first="Jan" last="Balzarini">Jan Balzarini</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>

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Design, synthesis and biological evaluation of phosphorodiamidate prodrugs of antiviral and anticancer nucleosides

Design, synthesis and biological evaluation of phosphorodiamidate prodrugs of antiviral and anticancer nucleosides

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