Synthesis of enantiomerically pure D- and L-bicyclo[3.1.0]hexenyl carbanucleosides and their antiviral evaluation
Identifieur interne : 001440 ( Main/Exploration ); précédent : 001439; suivant : 001441Synthesis of enantiomerically pure D- and L-bicyclo[3.1.0]hexenyl carbanucleosides and their antiviral evaluation
Auteurs : Ah-Young Park [Corée du Sud] ; WON HEE KIM [Corée du Sud] ; Jin-Ah Kang [Corée du Sud] ; HYE JIN LEE [Corée du Sud] ; Chong-Kyo Lee [Corée du Sud] ; HYUNG RYONG MOON [Corée du Sud]Source :
- Bioorganic & medicinal chemistry [ 0968-0896 ] ; 2011.
Descripteurs français
- Pascal (Inist)
- Synthèse chimique, Stéréoisomère, Antiviral, Virus immunodéficience humaine, Virus à ADN, Oxirane(chlorométhyl), Dérivé de la pyrimidine, Composé éthylénique, Activité biologique, In vitro, Composé bicyclique, Nucléoside, Epoxyde, Pyrimidin-2-one(4-hydroxy-6-[1-hydroxyméthylbicyclo[3.1.0]hex-2-ényl]), Bicyclo[3.1.0]hexène dérivé, Carbanucléoside.
English descriptors
- KwdEn :
Abstract
Based upon the fact that L-nucleosides have been generally known to be less cytotoxic than D-counterparts, L-bicyclo[3.1.0]hexenyl carbanucleoside derivatives with a fixed north conformation were designed and synthesized by employing a novel synthetic strategy starting from (R)-epichlorohydrin in order to search for new anti-HIV agents with high potency and less cytotoxicity. A tandem alkylation, γ-lactonization, a chemoselective reduction of ester in the presence of γ-lactone functional group, a RCM reaction, and a Mitsunobu coupling reaction were used as key reactions. D-Counterpart nucleosides were also prepared according to the same synthetic method. Among the synthesized carbanucleosides, D-thymine nucleoside, D-2 and L-thymine nucleoside, L-2 exhibited excellent anti-HIV-1 and -2 activities, in MT-4 cells, which were higher than those of ddI, an anti-AIDS drug. Whereas D-2 exhibited high cytotoxicity in MT-4 cell lines, L-2 did not show any discernible cytotoxicity in all cell lines tested, reflecting that L-2 may be a good candidate for an anti-AIDS drug. L-2 also showed weak anti-HSV-2 activity without cytotoxicity. However, none of the synthesized nucleosides exhibited antiviral activities against RNA viruses including coxsakie, influenza, corona and polio viruses, maybe due to their 2',3'-dideoxy structure. Potent antiviral effects of D-2 and L-2 indicate that nucleosides belonging to a class of D4Ns can be an excellent candidate for anti-DNA virus agents. This research strongly supports L-nucleosides of a class of D4Ns to be a very promising candidate for antiviral agents due to its low cytotoxicity and a good antiviral activity.
Affiliations:
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Pusan National University</s1><s2>Busan 609-735</s2><s3>KOR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Corée du Sud</country><wicri:noRegion>Busan 609-735</wicri:noRegion></affiliation></author><author><name sortKey="Kang, Jin Ah" sort="Kang, Jin Ah" uniqKey="Kang J" first="Jin-Ah" last="Kang">Jin-Ah Kang</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Laboratory of Medicinal Chemistry, College of Pharmacy and Research Institute for Drug Development, Pusan National University</s1><s2>Busan 609-735</s2><s3>KOR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Corée du Sud</country><wicri:noRegion>Busan 609-735</wicri:noRegion></affiliation></author><author><name sortKey="Hye Jin Lee" sort="Hye Jin Lee" uniqKey="Hye Jin Lee" last="Hye Jin Lee">HYE JIN LEE</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Laboratory of Medicinal Chemistry, College of Pharmacy 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Development, Pusan National University</s1><s2>Busan 609-735</s2><s3>KOR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Corée du Sud</country><wicri:noRegion>Busan 609-735</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">12-0120380</idno><date when="2011">2011</date><idno type="stanalyst">PASCAL 12-0120380 INIST</idno><idno type="RBID">Pascal:12-0120380</idno><idno type="wicri:Area/PascalFrancis/Corpus">000008</idno><idno type="wicri:Area/PascalFrancis/Curation">000051</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">000006</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">000006</idno><idno type="wicri:doubleKey">0968-0896:2011:Park A:synthesis:of:enantiomerically</idno><idno type="wicri:Area/Main/Merge">001442</idno><idno type="wicri:Area/Main/Curation">001440</idno><idno type="wicri:Area/Main/Exploration">001440</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Synthesis of enantiomerically pure D- and L-bicyclo[3.1.0]hexenyl carbanucleosides and their antiviral evaluation</title><author><name sortKey="Park, Ah Young" sort="Park, Ah Young" uniqKey="Park A" first="Ah-Young" last="Park">Ah-Young Park</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Laboratory of Medicinal Chemistry, College of Pharmacy and Research Institute for Drug Development, Pusan National University</s1><s2>Busan 609-735</s2><s3>KOR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Corée du Sud</country><wicri:noRegion>Busan 609-735</wicri:noRegion></affiliation></author><author><name sortKey="Won Hee Kim" sort="Won Hee Kim" uniqKey="Won Hee Kim" last="Won Hee Kim">WON HEE KIM</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Laboratory of Medicinal Chemistry, College of Pharmacy and Research Institute for Drug Development, Pusan National University</s1><s2>Busan 609-735</s2><s3>KOR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Corée du Sud</country><wicri:noRegion>Busan 609-735</wicri:noRegion></affiliation></author><author><name sortKey="Kang, Jin Ah" sort="Kang, Jin Ah" uniqKey="Kang J" first="Jin-Ah" last="Kang">Jin-Ah Kang</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Laboratory of Medicinal Chemistry, College of Pharmacy and Research Institute for Drug Development, Pusan National University</s1><s2>Busan 609-735</s2><s3>KOR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Corée du Sud</country><wicri:noRegion>Busan 609-735</wicri:noRegion></affiliation></author><author><name sortKey="Hye Jin Lee" sort="Hye Jin Lee" uniqKey="Hye Jin Lee" last="Hye Jin Lee">HYE JIN LEE</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Laboratory of Medicinal Chemistry, College of Pharmacy and Research Institute for Drug Development, Pusan National University</s1><s2>Busan 609-735</s2><s3>KOR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Corée du Sud</country><wicri:noRegion>Busan 609-735</wicri:noRegion></affiliation></author><author><name sortKey="Lee, Chong Kyo" sort="Lee, Chong Kyo" uniqKey="Lee C" first="Chong-Kyo" last="Lee">Chong-Kyo Lee</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Pharmacology Research Center, Korea Research Institute of Chemical Technology</s1><s2>Daejon 305-600</s2><s3>KOR</s3><sZ>5 aut.</sZ></inist:fA14><country>Corée du Sud</country><wicri:noRegion>Daejon 305-600</wicri:noRegion></affiliation></author><author><name sortKey="Hyung Ryong Moon" sort="Hyung Ryong Moon" uniqKey="Hyung Ryong Moon" last="Hyung Ryong Moon">HYUNG RYONG MOON</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Laboratory of Medicinal Chemistry, College of Pharmacy and Research Institute for Drug Development, Pusan National University</s1><s2>Busan 609-735</s2><s3>KOR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Corée du Sud</country><wicri:noRegion>Busan 609-735</wicri:noRegion></affiliation></author></analytic><series><title level="j" type="main">Bioorganic & medicinal chemistry</title><title level="j" type="abbreviated">Bioorg. med. chem.</title><idno type="ISSN">0968-0896</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Bioorganic & medicinal chemistry</title><title level="j" type="abbreviated">Bioorg. med. chem.</title><idno type="ISSN">0968-0896</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral</term><term>Bicyclic compound</term><term>Biological activity</term><term>Carbanucleoside</term><term>Chemical synthesis</term><term>DNA virus</term><term>Epichlorhydrin</term><term>Epoxide</term><term>Ethylenic compound</term><term>Human immunodeficiency virus</term><term>In vitro</term><term>Nucleoside</term><term>Pyrimidine derivatives</term><term>Stereoisomer</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Synthèse chimique</term><term>Stéréoisomère</term><term>Antiviral</term><term>Virus immunodéficience humaine</term><term>Virus à ADN</term><term>Oxirane(chlorométhyl)</term><term>Dérivé de la pyrimidine</term><term>Composé éthylénique</term><term>Activité biologique</term><term>In vitro</term><term>Composé bicyclique</term><term>Nucléoside</term><term>Epoxyde</term><term>Pyrimidin-2-one(4-hydroxy-6-[1-hydroxyméthylbicyclo[3.1.0]hex-2-ényl])</term><term>Bicyclo[3.1.0]hexène dérivé</term><term>Carbanucléoside</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Based upon the fact that L-nucleosides have been generally known to be less cytotoxic than D-counterparts, L-bicyclo[3.1.0]hexenyl carbanucleoside derivatives with a fixed north conformation were designed and synthesized by employing a novel synthetic strategy starting from (R)-epichlorohydrin in order to search for new anti-HIV agents with high potency and less cytotoxicity. A tandem alkylation, γ-lactonization, a chemoselective reduction of ester in the presence of γ-lactone functional group, a RCM reaction, and a Mitsunobu coupling reaction were used as key reactions. D-Counterpart nucleosides were also prepared according to the same synthetic method. Among the synthesized carbanucleosides, D-thymine nucleoside, D-2 and <sub>L</sub>-thymine nucleoside, <sub>L</sub>-2 exhibited excellent anti-HIV-1 and -2 activities, in MT-4 cells, which were higher than those of ddI, an anti-AIDS drug. Whereas D-2 exhibited high cytotoxicity in MT-4 cell lines, <sub>L</sub>-2 did not show any discernible cytotoxicity in all cell lines tested, reflecting that <sub>L</sub>-2 may be a good candidate for an anti-AIDS drug. <sub>L</sub>-2 also showed weak anti-HSV-2 activity without cytotoxicity. However, none of the synthesized nucleosides exhibited antiviral activities against RNA viruses including coxsakie, influenza, corona and polio viruses, maybe due to their 2',3'-dideoxy structure. Potent antiviral effects of D-2 and <sub>L</sub>-2 indicate that nucleosides belonging to a class of D4Ns can be an excellent candidate for anti-DNA virus agents. This research strongly supports L-nucleosides of a class of D4Ns to be a very promising candidate for antiviral agents due to its low cytotoxicity and a good antiviral activity.</div></front></TEI><affiliations><list><country><li>Corée du Sud</li></country></list><tree><country name="Corée du Sud"><noRegion><name sortKey="Park, Ah Young" sort="Park, Ah Young" uniqKey="Park A" first="Ah-Young" last="Park">Ah-Young Park</name></noRegion><name sortKey="Hye Jin Lee" sort="Hye Jin Lee" uniqKey="Hye Jin Lee" last="Hye Jin Lee">HYE JIN LEE</name><name sortKey="Hyung Ryong Moon" sort="Hyung Ryong Moon" uniqKey="Hyung Ryong Moon" last="Hyung Ryong Moon">HYUNG RYONG MOON</name><name sortKey="Kang, Jin Ah" sort="Kang, Jin Ah" uniqKey="Kang J" first="Jin-Ah" last="Kang">Jin-Ah Kang</name><name sortKey="Lee, Chong Kyo" sort="Lee, Chong Kyo" uniqKey="Lee C" first="Chong-Kyo" last="Lee">Chong-Kyo Lee</name><name sortKey="Won Hee Kim" sort="Won Hee Kim" uniqKey="Won Hee Kim" last="Won Hee Kim">WON HEE KIM</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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