Effect of various pyrimidines possessing the 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl] moiety, able to mimic natural 2'-deoxyribose, on wild-type and mutant hepatitis B virus replication
Identifieur interne : 000485 ( PascalFrancis/Checkpoint ); précédent : 000484; suivant : 000486Effect of various pyrimidines possessing the 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl] moiety, able to mimic natural 2'-deoxyribose, on wild-type and mutant hepatitis B virus replication
Auteurs : Rakesh Kumar [Canada] ; Wassila Semaine [Canada] ; Monika Johar [Canada] ; D. Lome J. Tyrrell [Canada] ; Babita Agrawal [Canada]Source :
- Journal of medicinal chemistry : (Print) [ 0022-2623 ] ; 2006.
Descripteurs français
- Pascal (Inist)
- Relation structure activité, Mutation, Virus hépatite B, Réplication, Antiviral, In vitro, Virus hépatite B canard, Lignée cellulaire, Synthèse chimique, Chlore composé organique, Brome composé organique, Pyrimidine nucléoside, Nucléoside acyclique, Uracile(5-chloro-1-[(2-hydroxy-1-hydroxyméthyléthoxy)méthyl]), Uracile(5-bromo-1-[(2-hydroxy-1-hydroxyméthyléthoxy)méthyl]-6-méthyl).
English descriptors
- KwdEn :
Abstract
Hepatitis B virus (HBV) is the most common cause of chronic liver disease worldwide. Development of drug resistance against clinical anti-HBV drug lamivudine due to long-term use and rebound of viral DNA after cessation of treatment has been a major setback of the current therapy. We have synthesized a series of pyrimidine nucleosides possessing a variety of substituents at the C-5 position, and a 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl] flexible acyclic glycosyl moiety at the N-1 position, that have the ability to mimic the natural 2'-deoxyribosyl moiety. Some of these potential antiviral compounds included variations at both C-5 and C-6 positions of the uracil base. Other variations of the uracil derivatives were the 6-aza congeners. 4-Amino and 4-methoxy pyrimidine derivatives were also made. Compounds in which the base moiety was substituted by 5-chloro- (25), 5-(2-bromovinyl)- (32), or 5-bromo-6-methyl- (37) groups possess significant activity against duck-HBV, wild-type human HBV (2.2.15 cells), and lamivudine-resistant HBV containing single and double mutations. No cytotoxicity was seen in host HepG2 and Vero cells, up to the highest concentration tested. The anti-HBV activity exhibited by compounds 25, 32, and 37 was superior for human HBV and comparable for DHBV to that of the corresponding purine nucleoside, ganciclovir. Further, they were only 10-15-fold less inhibitory against human HBV in 2.2.15 cells than the reference drug, lamivudine. Other compounds in the series were moderately inhibitory against DHBV and wild-type human HBV. The size of the halogen and the electronegativity of the substituents at the 5- and 6-positions are important for antiviral activity toward HBV. These compounds were also evaluated for their antiviral activity for West Nile virus, respiratory syncytial virus, SARS-coronavirus, and hepatitis C virus. They were generally inactive in these antiviral assay systems (at concentrations up to 100 μg/mL). 1-[(2-Hydroxy1-(hydroxymethyl) ethoxy)methyl]-5-fluorocytosine (34) showed some inhibitory activity against hepatitis C virus. Taken together, these data support our previous observations that the 5-substituted pyrimidine nucleosides containing acyclic glycosyl moieties have potential to serve as a new generation of potent, selective, and nontoxic anti-HBV agents for wild-type and lamivudine-resistant mutant HBV.
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Lome J." last="Tyrrell">D. Lome J. Tyrrell</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta</s1><s2>Edmonton, AB, T6G 2H7</s2><s3>CAN</s3><sZ>4 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Edmonton, AB, T6G 2H7</wicri:noRegion></affiliation></author><author><name sortKey="Agrawal, Babita" sort="Agrawal, Babita" uniqKey="Agrawal B" first="Babita" last="Agrawal">Babita Agrawal</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Surgery, University of Alberta</s1><s2>Edmonton, AB, T6G 2H7</s2><s3>CAN</s3><sZ>2 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Edmonton, AB, T6G 2H7</wicri:noRegion></affiliation></author></analytic><series><title level="j" type="main">Journal of medicinal chemistry : (Print)</title><title level="j" type="abbreviated">J. med. chem. : (Print)</title><idno type="ISSN">0022-2623</idno><imprint><date when="2006">2006</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Journal of medicinal chemistry : (Print)</title><title level="j" type="abbreviated">J. med. chem. : (Print)</title><idno type="ISSN">0022-2623</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Acyclic nucleoside</term><term>Antiviral</term><term>Cell line</term><term>Chemical synthesis</term><term>Duck hepatitis B virus</term><term>Hepatitis B virus</term><term>In vitro</term><term>Mutation</term><term>Organic bromine compounds</term><term>Organic chlorine compounds</term><term>Pyrimidine nucleoside</term><term>Replication</term><term>Structure activity relation</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Relation structure activité</term><term>Mutation</term><term>Virus hépatite B</term><term>Réplication</term><term>Antiviral</term><term>In vitro</term><term>Virus hépatite B canard</term><term>Lignée cellulaire</term><term>Synthèse chimique</term><term>Chlore composé organique</term><term>Brome composé organique</term><term>Pyrimidine nucléoside</term><term>Nucléoside acyclique</term><term>Uracile(5-chloro-1-[(2-hydroxy-1-hydroxyméthyléthoxy)méthyl])</term><term>Uracile(5-bromo-1-[(2-hydroxy-1-hydroxyméthyléthoxy)méthyl]-6-méthyl)</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Hepatitis B virus (HBV) is the most common cause of chronic liver disease worldwide. Development of drug resistance against clinical anti-HBV drug lamivudine due to long-term use and rebound of viral DNA after cessation of treatment has been a major setback of the current therapy. We have synthesized a series of pyrimidine nucleosides possessing a variety of substituents at the C-5 position, and a 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl] flexible acyclic glycosyl moiety at the N-1 position, that have the ability to mimic the natural 2'-deoxyribosyl moiety. Some of these potential antiviral compounds included variations at both C-5 and C-6 positions of the uracil base. Other variations of the uracil derivatives were the 6-aza congeners. 4-Amino and 4-methoxy pyrimidine derivatives were also made. Compounds in which the base moiety was substituted by 5-chloro- (25), 5-(2-bromovinyl)- (32), or 5-bromo-6-methyl- (37) groups possess significant activity against duck-HBV, wild-type human HBV (2.2.15 cells), and lamivudine-resistant HBV containing single and double mutations. No cytotoxicity was seen in host HepG2 and Vero cells, up to the highest concentration tested. The anti-HBV activity exhibited by compounds 25, 32, and 37 was superior for human HBV and comparable for DHBV to that of the corresponding purine nucleoside, ganciclovir. Further, they were only 10-15-fold less inhibitory against human HBV in 2.2.15 cells than the reference drug, lamivudine. Other compounds in the series were moderately inhibitory against DHBV and wild-type human HBV. The size of the halogen and the electronegativity of the substituents at the 5- and 6-positions are important for antiviral activity toward HBV. These compounds were also evaluated for their antiviral activity for West Nile virus, respiratory syncytial virus, SARS-coronavirus, and hepatitis C virus. They were generally inactive in these antiviral assay systems (at concentrations up to 100 μg/mL). 1-[(2-Hydroxy1-(hydroxymethyl) ethoxy)methyl]-5-fluorocytosine (34) showed some inhibitory activity against hepatitis C virus. Taken together, these data support our previous observations that the 5-substituted pyrimidine nucleosides containing acyclic glycosyl moieties have potential to serve as a new generation of potent, selective, and nontoxic anti-HBV agents for wild-type and lamivudine-resistant mutant HBV.</div></front></TEI><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0022-2623</s0></fA01><fA02 i1="01"><s0>JMCMAR</s0></fA02><fA03 i2="1"><s0>J. med. chem. : (Print)</s0></fA03><fA05><s2>49</s2></fA05><fA06><s2>12</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>Effect of various pyrimidines possessing the 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl] moiety, able to mimic natural 2'-deoxyribose, on wild-type and mutant hepatitis B virus replication</s1></fA08><fA11 i1="01" i2="1"><s1>KUMAR (Rakesh)</s1></fA11><fA11 i1="02" i2="1"><s1>SEMAINE (Wassila)</s1></fA11><fA11 i1="03" i2="1"><s1>JOHAR (Monika)</s1></fA11><fA11 i1="04" i2="1"><s1>TYRRELL (D. Lome J.)</s1></fA11><fA11 i1="05" i2="1"><s1>AGRAWAL (Babita)</s1></fA11><fA14 i1="01"><s1>Department of Laboratory Medicine and Pathology, 1-41 Medical Sciences Building, University of Alberta</s1><s2>Edmonton, AB, T6G 2H7</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ></fA14><fA14 i1="02"><s1>Department of Surgery, University of Alberta</s1><s2>Edmonton, AB, T6G 2H7</s2><s3>CAN</s3><sZ>2 aut.</sZ><sZ>5 aut.</sZ></fA14><fA14 i1="03"><s1>Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta</s1><s2>Edmonton, AB, T6G 2H7</s2><s3>CAN</s3><sZ>4 aut.</sZ></fA14><fA20><s1>3693-3700</s1></fA20><fA21><s1>2006</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>9165</s2><s5>354000156706810310</s5></fA43><fA44><s0>0000</s0><s1>© 2006 INIST-CNRS. All rights reserved.</s1></fA44><fA47 i1="01" i2="1"><s0>06-0484066</s0></fA47><fA60><s1>P</s1></fA60><fA61><s0>A</s0></fA61><fA64 i1="01" i2="1"><s0>Journal of medicinal chemistry : (Print)</s0></fA64><fA66 i1="01"><s0>USA</s0></fA66><fA99><s0>1 p. ref. et notes</s0></fA99><fC01 i1="01" l="ENG"><s0>Hepatitis B virus (HBV) is the most common cause of chronic liver disease worldwide. Development of drug resistance against clinical anti-HBV drug lamivudine due to long-term use and rebound of viral DNA after cessation of treatment has been a major setback of the current therapy. We have synthesized a series of pyrimidine nucleosides possessing a variety of substituents at the C-5 position, and a 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl] flexible acyclic glycosyl moiety at the N-1 position, that have the ability to mimic the natural 2'-deoxyribosyl moiety. Some of these potential antiviral compounds included variations at both C-5 and C-6 positions of the uracil base. Other variations of the uracil derivatives were the 6-aza congeners. 4-Amino and 4-methoxy pyrimidine derivatives were also made. Compounds in which the base moiety was substituted by 5-chloro- (25), 5-(2-bromovinyl)- (32), or 5-bromo-6-methyl- (37) groups possess significant activity against duck-HBV, wild-type human HBV (2.2.15 cells), and lamivudine-resistant HBV containing single and double mutations. No cytotoxicity was seen in host HepG2 and Vero cells, up to the highest concentration tested. The anti-HBV activity exhibited by compounds 25, 32, and 37 was superior for human HBV and comparable for DHBV to that of the corresponding purine nucleoside, ganciclovir. Further, they were only 10-15-fold less inhibitory against human HBV in 2.2.15 cells than the reference drug, lamivudine. Other compounds in the series were moderately inhibitory against DHBV and wild-type human HBV. The size of the halogen and the electronegativity of the substituents at the 5- and 6-positions are important for antiviral activity toward HBV. These compounds were also evaluated for their antiviral activity for West Nile virus, respiratory syncytial virus, SARS-coronavirus, and hepatitis C virus. They were generally inactive in these antiviral assay systems (at concentrations up to 100 μg/mL). 1-[(2-Hydroxy1-(hydroxymethyl) ethoxy)methyl]-5-fluorocytosine (34) showed some inhibitory activity against hepatitis C virus. Taken together, these data support our previous observations that the 5-substituted pyrimidine nucleosides containing acyclic glycosyl moieties have potential to serve as a new generation of potent, selective, and nontoxic anti-HBV agents for wild-type and lamivudine-resistant mutant HBV.</s0></fC01><fC02 i1="01" i2="X"><s0>002B02S05</s0></fC02><fC03 i1="01" i2="X" l="FRE"><s0>Relation structure activité</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="ENG"><s0>Structure activity relation</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="SPA"><s0>Relación estructura actividad</s0><s5>01</s5></fC03><fC03 i1="02" i2="X" l="FRE"><s0>Mutation</s0><s5>02</s5></fC03><fC03 i1="02" i2="X" l="ENG"><s0>Mutation</s0><s5>02</s5></fC03><fC03 i1="02" i2="X" l="SPA"><s0>Mutación</s0><s5>02</s5></fC03><fC03 i1="03" i2="X" l="FRE"><s0>Virus hépatite B</s0><s2>NW</s2><s5>03</s5></fC03><fC03 i1="03" i2="X" l="ENG"><s0>Hepatitis B virus</s0><s2>NW</s2><s5>03</s5></fC03><fC03 i1="03" i2="X" l="SPA"><s0>Hepatitis 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l="ENG"><s0>Cell line</s0><s5>08</s5></fC03><fC03 i1="08" i2="X" l="SPA"><s0>Línea celular</s0><s5>08</s5></fC03><fC03 i1="09" i2="X" l="FRE"><s0>Synthèse chimique</s0><s5>09</s5></fC03><fC03 i1="09" i2="X" l="ENG"><s0>Chemical synthesis</s0><s5>09</s5></fC03><fC03 i1="09" i2="X" l="SPA"><s0>Síntesis química</s0><s5>09</s5></fC03><fC03 i1="10" i2="3" l="FRE"><s0>Chlore composé organique</s0><s5>10</s5></fC03><fC03 i1="10" i2="3" l="ENG"><s0>Organic chlorine compounds</s0><s5>10</s5></fC03><fC03 i1="11" i2="3" l="FRE"><s0>Brome composé organique</s0><s5>11</s5></fC03><fC03 i1="11" i2="3" l="ENG"><s0>Organic bromine compounds</s0><s5>11</s5></fC03><fC03 i1="12" i2="X" l="FRE"><s0>Pyrimidine nucléoside</s0><s5>12</s5></fC03><fC03 i1="12" i2="X" l="ENG"><s0>Pyrimidine nucleoside</s0><s5>12</s5></fC03><fC03 i1="12" i2="X" l="SPA"><s0>Pirimidina nucleósido</s0><s5>12</s5></fC03><fC03 i1="13" i2="X" l="FRE"><s0>Nucléoside acyclique</s0><s5>13</s5></fC03><fC03 i1="13" i2="X" l="ENG"><s0>Acyclic nucleoside</s0><s5>13</s5></fC03><fC03 i1="13" i2="X" l="SPA"><s0>Nucleósido acíclico</s0><s5>13</s5></fC03><fC03 i1="14" i2="X" l="FRE"><s0>Uracile(5-chloro-1-[(2-hydroxy-1-hydroxyméthyléthoxy)méthyl])</s0><s2>NK</s2><s4>INC</s4><s5>76</s5></fC03><fC03 i1="15" i2="X" l="FRE"><s0>Uracile(5-bromo-1-[(2-hydroxy-1-hydroxyméthyléthoxy)méthyl]-6-méthyl)</s0><s2>NK</s2><s4>INC</s4><s5>77</s5></fC03><fC07 i1="01" i2="X" l="FRE"><s0>Orthohepadnavirus</s0><s2>NW</s2></fC07><fC07 i1="01" i2="X" l="ENG"><s0>Orthohepadnavirus</s0><s2>NW</s2></fC07><fC07 i1="01" i2="X" l="SPA"><s0>Orthohepadnavirus</s0><s2>NW</s2></fC07><fC07 i1="02" i2="X" l="FRE"><s0>Hepadnaviridae</s0><s2>NW</s2></fC07><fC07 i1="02" i2="X" l="ENG"><s0>Hepadnaviridae</s0><s2>NW</s2></fC07><fC07 i1="02" i2="X" l="SPA"><s0>Hepadnaviridae</s0><s2>NW</s2></fC07><fC07 i1="03" i2="X" l="FRE"><s0>Virus</s0><s2>NW</s2></fC07><fC07 i1="03" i2="X" l="ENG"><s0>Virus</s0><s2>NW</s2></fC07><fC07 i1="03" i2="X" l="SPA"><s0>Virus</s0><s2>NW</s2></fC07><fC07 i1="04" i2="X" l="FRE"><s0>Avihepadnavirus</s0><s2>NW</s2></fC07><fC07 i1="04" i2="X" l="ENG"><s0>Avihepadnavirus</s0><s2>NW</s2></fC07><fC07 i1="04" i2="X" l="SPA"><s0>Avihepadnavirus</s0><s2>NW</s2></fC07><fN21><s1>317</s1></fN21></pA></standard></inist><affiliations><list><country><li>Canada</li></country></list><tree><country name="Canada"><noRegion><name sortKey="Kumar, Rakesh" sort="Kumar, Rakesh" uniqKey="Kumar R" first="Rakesh" last="Kumar">Rakesh Kumar</name></noRegion><name sortKey="Agrawal, Babita" sort="Agrawal, Babita" uniqKey="Agrawal B" first="Babita" last="Agrawal">Babita Agrawal</name><name sortKey="Johar, Monika" sort="Johar, Monika" uniqKey="Johar M" first="Monika" last="Johar">Monika Johar</name><name sortKey="Semaine, Wassila" sort="Semaine, Wassila" uniqKey="Semaine W" first="Wassila" last="Semaine">Wassila Semaine</name><name sortKey="Semaine, Wassila" sort="Semaine, Wassila" uniqKey="Semaine W" first="Wassila" last="Semaine">Wassila Semaine</name><name sortKey="Tyrrell, D Lome J" sort="Tyrrell, D Lome J" uniqKey="Tyrrell D" first="D. Lome J." last="Tyrrell">D. Lome J. Tyrrell</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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