Design, synthesis, biological evaluation and molecular docking studies of phenylpropanoid derivatives as potent anti-hepatitis B virus agents.
Identifieur interne : 001335 ( Main/Exploration ); précédent : 001334; suivant : 001336Design, synthesis, biological evaluation and molecular docking studies of phenylpropanoid derivatives as potent anti-hepatitis B virus agents.
Auteurs : Sheng Liu [République populaire de Chine] ; Wanxing Wei [République populaire de Chine] ; Yubin Li [République populaire de Chine] ; Xu Liu [République populaire de Chine] ; Xiaoji Cao [République populaire de Chine] ; Kechan Lei [République populaire de Chine] ; Min Zhou [République populaire de Chine]Source :
- European journal of medicinal chemistry [ 1768-3254 ] ; 2015.
Descripteurs français
- KwdFr :
- Antigènes HLA-A (), Antigènes HLA-A (métabolisme), Antigènes de surface du virus de l'hépatite B (métabolisme), Antigènes e du virus de l'hépatite virale B (métabolisme), Antiviraux (), Antiviraux (métabolisme), Antiviraux (pharmacologie), Antiviraux (synthèse chimique), Cellules HepG2, Conception de médicament, Domaine catalytique, Humains, Phénols (), Phénols (métabolisme), Phénols (pharmacologie), Phénols (synthèse chimique), Relation quantitative structure-activité, Réplication de l'ADN (), Réplication virale (), Simulation de docking moléculaire, Techniques de chimie synthétique, Virus de l'hépatite B (), Virus de l'hépatite B (métabolisme), Virus de l'hépatite B (physiologie).
- MESH :
- métabolisme : Antigènes HLA-A, Antigènes de surface du virus de l'hépatite B, Antigènes e du virus de l'hépatite virale B, Antiviraux, Phénols, Virus de l'hépatite B.
- pharmacologie : Antiviraux, Phénols.
- physiologie : Virus de l'hépatite B.
- synthèse chimique : Antiviraux, Phénols.
- Antigènes HLA-A, Antiviraux, Cellules HepG2, Conception de médicament, Domaine catalytique, Humains, Phénols, Relation quantitative structure-activité, Réplication de l'ADN, Réplication virale, Simulation de docking moléculaire, Techniques de chimie synthétique, Virus de l'hépatite B.
English descriptors
- KwdEn :
- Antiviral Agents (chemical synthesis), Antiviral Agents (chemistry), Antiviral Agents (metabolism), Antiviral Agents (pharmacology), Catalytic Domain, Chemistry Techniques, Synthetic, DNA Replication (drug effects), Drug Design, HLA-A Antigens (chemistry), HLA-A Antigens (metabolism), Hep G2 Cells, Hepatitis B Surface Antigens (metabolism), Hepatitis B e Antigens (metabolism), Hepatitis B virus (drug effects), Hepatitis B virus (metabolism), Hepatitis B virus (physiology), Humans, Molecular Docking Simulation, Phenols (chemical synthesis), Phenols (chemistry), Phenols (metabolism), Phenols (pharmacology), Quantitative Structure-Activity Relationship, Virus Replication (drug effects).
- MESH :
- chemical , chemical synthesis : Antiviral Agents, Phenols.
- chemical , chemistry : Antiviral Agents, HLA-A Antigens, Phenols.
- chemical , metabolism : Antiviral Agents, HLA-A Antigens, Hepatitis B Surface Antigens, Hepatitis B e Antigens, Phenols.
- chemical , pharmacology : Antiviral Agents, Phenols.
- drug effects : DNA Replication, Hepatitis B virus, Virus Replication.
- metabolism : Hepatitis B virus.
- physiology : Hepatitis B virus.
- Catalytic Domain, Chemistry Techniques, Synthetic, Drug Design, Hep G2 Cells, Humans, Molecular Docking Simulation, Quantitative Structure-Activity Relationship.
Abstract
A series of phenylpropanoid derivatives were synthesized, and their anti-hepatitis B virus (HBV) activity was evaluated in HepG 2.2.15 cells. Most of the synthesized derivatives showed effective anti-HBV activity. Of these compounds, compound 4c-1 showed the most potent anti-HBV activity, demonstrating potent inhibitory effect not only on the secretion of HBsAg (IC50 = 14.18 μM, SI = 17.85) and HBeAg (IC50 = 6.20 μM, SI = 40.82) secretion but also HBV DNA replication (IC50 = 23.43 μM, SI = 10.80). The structure-activity relationships (SARs) of phenylpropanoid derivatives had been discussed, which were useful for phenylpropanoid derivatives to be explored and developed as novel anti-HBV agents. Moreover, the docking study of all synthesized compounds inside the HLA-A protein (PDB ID: 3OX8) active site were carried out to explore the molecular interactions and a molecular target for activity of phenylpropanoid derivatives with the protein using a moe-docking technique. This study identified a new class of potent anti-HBV agents.
DOI: 10.1016/j.ejmech.2015.03.056
PubMed: 25847765
Affiliations:
Links toward previous steps (curation, corpus...)
- to stream PubMed, to step Corpus: 000E34
- to stream PubMed, to step Curation: 000E34
- to stream PubMed, to step Checkpoint: 000E33
- to stream Ncbi, to step Merge: 002A58
- to stream Ncbi, to step Curation: 002A58
- to stream Ncbi, to step Checkpoint: 002A58
- to stream Main, to step Merge: 001337
- to stream Main, to step Curation: 001335
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Design, synthesis, biological evaluation and molecular docking studies of phenylpropanoid derivatives as potent anti-hepatitis B virus agents.</title>
<author><name sortKey="Liu, Sheng" sort="Liu, Sheng" uniqKey="Liu S" first="Sheng" last="Liu">Sheng Liu</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry, Guangxi University, Nanning 530004, PR China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Chemistry, Guangxi University, Nanning 530004</wicri:regionArea>
<wicri:noRegion>Nanning 530004</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Wei, Wanxing" sort="Wei, Wanxing" uniqKey="Wei W" first="Wanxing" last="Wei">Wanxing Wei</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry, Guangxi University, Nanning 530004, PR China. Electronic address: wxwei@gxu.edu.cn.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Chemistry, Guangxi University, Nanning 530004</wicri:regionArea>
<wicri:noRegion>Nanning 530004</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Li, Yubin" sort="Li, Yubin" uniqKey="Li Y" first="Yubin" last="Li">Yubin Li</name>
<affiliation wicri:level="1"><nlm:affiliation>School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, PR China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275</wicri:regionArea>
<placeName><settlement type="city">Jiangmen</settlement>
<region type="province">Guangdong</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Liu, Xu" sort="Liu, Xu" uniqKey="Liu X" first="Xu" last="Liu">Xu Liu</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry, Guangxi University, Nanning 530004, PR China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Chemistry, Guangxi University, Nanning 530004</wicri:regionArea>
<wicri:noRegion>Nanning 530004</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Cao, Xiaoji" sort="Cao, Xiaoji" uniqKey="Cao X" first="Xiaoji" last="Cao">Xiaoji Cao</name>
<affiliation wicri:level="1"><nlm:affiliation>Center of Analysis and Testing, Zhejiang University of Industry, Hangzhou 310014, PR China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Center of Analysis and Testing, Zhejiang University of Industry, Hangzhou 310014</wicri:regionArea>
<placeName><settlement type="city">Hangzhou</settlement>
<region type="province">Zhejiang</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lei, Kechan" sort="Lei, Kechan" uniqKey="Lei K" first="Kechan" last="Lei">Kechan Lei</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry, Guangxi University, Nanning 530004, PR China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Chemistry, Guangxi University, Nanning 530004</wicri:regionArea>
<wicri:noRegion>Nanning 530004</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Zhou, Min" sort="Zhou, Min" uniqKey="Zhou M" first="Min" last="Zhou">Min Zhou</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry, Guangxi University, Nanning 530004, PR China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Chemistry, Guangxi University, Nanning 530004</wicri:regionArea>
<wicri:noRegion>Nanning 530004</wicri:noRegion>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PubMed</idno>
<date when="2015">2015</date>
<idno type="RBID">pubmed:25847765</idno>
<idno type="pmid">25847765</idno>
<idno type="doi">10.1016/j.ejmech.2015.03.056</idno>
<idno type="wicri:Area/PubMed/Corpus">000E34</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000E34</idno>
<idno type="wicri:Area/PubMed/Curation">000E34</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000E34</idno>
<idno type="wicri:Area/PubMed/Checkpoint">000E33</idno>
<idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000E33</idno>
<idno type="wicri:Area/Ncbi/Merge">002A58</idno>
<idno type="wicri:Area/Ncbi/Curation">002A58</idno>
<idno type="wicri:Area/Ncbi/Checkpoint">002A58</idno>
<idno type="wicri:Area/Main/Merge">001337</idno>
<idno type="wicri:Area/Main/Curation">001335</idno>
<idno type="wicri:Area/Main/Exploration">001335</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en">Design, synthesis, biological evaluation and molecular docking studies of phenylpropanoid derivatives as potent anti-hepatitis B virus agents.</title>
<author><name sortKey="Liu, Sheng" sort="Liu, Sheng" uniqKey="Liu S" first="Sheng" last="Liu">Sheng Liu</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry, Guangxi University, Nanning 530004, PR China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Chemistry, Guangxi University, Nanning 530004</wicri:regionArea>
<wicri:noRegion>Nanning 530004</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Wei, Wanxing" sort="Wei, Wanxing" uniqKey="Wei W" first="Wanxing" last="Wei">Wanxing Wei</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry, Guangxi University, Nanning 530004, PR China. Electronic address: wxwei@gxu.edu.cn.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Chemistry, Guangxi University, Nanning 530004</wicri:regionArea>
<wicri:noRegion>Nanning 530004</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Li, Yubin" sort="Li, Yubin" uniqKey="Li Y" first="Yubin" last="Li">Yubin Li</name>
<affiliation wicri:level="1"><nlm:affiliation>School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, PR China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275</wicri:regionArea>
<placeName><settlement type="city">Jiangmen</settlement>
<region type="province">Guangdong</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Liu, Xu" sort="Liu, Xu" uniqKey="Liu X" first="Xu" last="Liu">Xu Liu</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry, Guangxi University, Nanning 530004, PR China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Chemistry, Guangxi University, Nanning 530004</wicri:regionArea>
<wicri:noRegion>Nanning 530004</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Cao, Xiaoji" sort="Cao, Xiaoji" uniqKey="Cao X" first="Xiaoji" last="Cao">Xiaoji Cao</name>
<affiliation wicri:level="1"><nlm:affiliation>Center of Analysis and Testing, Zhejiang University of Industry, Hangzhou 310014, PR China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Center of Analysis and Testing, Zhejiang University of Industry, Hangzhou 310014</wicri:regionArea>
<placeName><settlement type="city">Hangzhou</settlement>
<region type="province">Zhejiang</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lei, Kechan" sort="Lei, Kechan" uniqKey="Lei K" first="Kechan" last="Lei">Kechan Lei</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry, Guangxi University, Nanning 530004, PR China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Chemistry, Guangxi University, Nanning 530004</wicri:regionArea>
<wicri:noRegion>Nanning 530004</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Zhou, Min" sort="Zhou, Min" uniqKey="Zhou M" first="Min" last="Zhou">Min Zhou</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry, Guangxi University, Nanning 530004, PR China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Chemistry, Guangxi University, Nanning 530004</wicri:regionArea>
<wicri:noRegion>Nanning 530004</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series><title level="j">European journal of medicinal chemistry</title>
<idno type="eISSN">1768-3254</idno>
<imprint><date when="2015" type="published">2015</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral Agents (chemical synthesis)</term>
<term>Antiviral Agents (chemistry)</term>
<term>Antiviral Agents (metabolism)</term>
<term>Antiviral Agents (pharmacology)</term>
<term>Catalytic Domain</term>
<term>Chemistry Techniques, Synthetic</term>
<term>DNA Replication (drug effects)</term>
<term>Drug Design</term>
<term>HLA-A Antigens (chemistry)</term>
<term>HLA-A Antigens (metabolism)</term>
<term>Hep G2 Cells</term>
<term>Hepatitis B Surface Antigens (metabolism)</term>
<term>Hepatitis B e Antigens (metabolism)</term>
<term>Hepatitis B virus (drug effects)</term>
<term>Hepatitis B virus (metabolism)</term>
<term>Hepatitis B virus (physiology)</term>
<term>Humans</term>
<term>Molecular Docking Simulation</term>
<term>Phenols (chemical synthesis)</term>
<term>Phenols (chemistry)</term>
<term>Phenols (metabolism)</term>
<term>Phenols (pharmacology)</term>
<term>Quantitative Structure-Activity Relationship</term>
<term>Virus Replication (drug effects)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Antigènes HLA-A ()</term>
<term>Antigènes HLA-A (métabolisme)</term>
<term>Antigènes de surface du virus de l'hépatite B (métabolisme)</term>
<term>Antigènes e du virus de l'hépatite virale B (métabolisme)</term>
<term>Antiviraux ()</term>
<term>Antiviraux (métabolisme)</term>
<term>Antiviraux (pharmacologie)</term>
<term>Antiviraux (synthèse chimique)</term>
<term>Cellules HepG2</term>
<term>Conception de médicament</term>
<term>Domaine catalytique</term>
<term>Humains</term>
<term>Phénols ()</term>
<term>Phénols (métabolisme)</term>
<term>Phénols (pharmacologie)</term>
<term>Phénols (synthèse chimique)</term>
<term>Relation quantitative structure-activité</term>
<term>Réplication de l'ADN ()</term>
<term>Réplication virale ()</term>
<term>Simulation de docking moléculaire</term>
<term>Techniques de chimie synthétique</term>
<term>Virus de l'hépatite B ()</term>
<term>Virus de l'hépatite B (métabolisme)</term>
<term>Virus de l'hépatite B (physiologie)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Antiviral Agents</term>
<term>Phenols</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antiviral Agents</term>
<term>HLA-A Antigens</term>
<term>Phenols</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Antiviral Agents</term>
<term>HLA-A Antigens</term>
<term>Hepatitis B Surface Antigens</term>
<term>Hepatitis B e Antigens</term>
<term>Phenols</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term>
<term>Phenols</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>DNA Replication</term>
<term>Hepatitis B virus</term>
<term>Virus Replication</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Hepatitis B virus</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Antigènes HLA-A</term>
<term>Antigènes de surface du virus de l'hépatite B</term>
<term>Antigènes e du virus de l'hépatite virale B</term>
<term>Antiviraux</term>
<term>Phénols</term>
<term>Virus de l'hépatite B</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term>
<term>Phénols</term>
</keywords>
<keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Virus de l'hépatite B</term>
</keywords>
<keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Hepatitis B virus</term>
</keywords>
<keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Antiviraux</term>
<term>Phénols</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Catalytic Domain</term>
<term>Chemistry Techniques, Synthetic</term>
<term>Drug Design</term>
<term>Hep G2 Cells</term>
<term>Humans</term>
<term>Molecular Docking Simulation</term>
<term>Quantitative Structure-Activity Relationship</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Antigènes HLA-A</term>
<term>Antiviraux</term>
<term>Cellules HepG2</term>
<term>Conception de médicament</term>
<term>Domaine catalytique</term>
<term>Humains</term>
<term>Phénols</term>
<term>Relation quantitative structure-activité</term>
<term>Réplication de l'ADN</term>
<term>Réplication virale</term>
<term>Simulation de docking moléculaire</term>
<term>Techniques de chimie synthétique</term>
<term>Virus de l'hépatite B</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">A series of phenylpropanoid derivatives were synthesized, and their anti-hepatitis B virus (HBV) activity was evaluated in HepG 2.2.15 cells. Most of the synthesized derivatives showed effective anti-HBV activity. Of these compounds, compound 4c-1 showed the most potent anti-HBV activity, demonstrating potent inhibitory effect not only on the secretion of HBsAg (IC50 = 14.18 μM, SI = 17.85) and HBeAg (IC50 = 6.20 μM, SI = 40.82) secretion but also HBV DNA replication (IC50 = 23.43 μM, SI = 10.80). The structure-activity relationships (SARs) of phenylpropanoid derivatives had been discussed, which were useful for phenylpropanoid derivatives to be explored and developed as novel anti-HBV agents. Moreover, the docking study of all synthesized compounds inside the HLA-A protein (PDB ID: 3OX8) active site were carried out to explore the molecular interactions and a molecular target for activity of phenylpropanoid derivatives with the protein using a moe-docking technique. This study identified a new class of potent anti-HBV agents. </div>
</front>
</TEI>
<affiliations><list><country><li>République populaire de Chine</li>
</country>
<region><li>Guangdong</li>
<li>Zhejiang</li>
</region>
<settlement><li>Hangzhou</li>
<li>Jiangmen</li>
</settlement>
</list>
<tree><country name="République populaire de Chine"><noRegion><name sortKey="Liu, Sheng" sort="Liu, Sheng" uniqKey="Liu S" first="Sheng" last="Liu">Sheng Liu</name>
</noRegion>
<name sortKey="Cao, Xiaoji" sort="Cao, Xiaoji" uniqKey="Cao X" first="Xiaoji" last="Cao">Xiaoji Cao</name>
<name sortKey="Lei, Kechan" sort="Lei, Kechan" uniqKey="Lei K" first="Kechan" last="Lei">Kechan Lei</name>
<name sortKey="Li, Yubin" sort="Li, Yubin" uniqKey="Li Y" first="Yubin" last="Li">Yubin Li</name>
<name sortKey="Liu, Xu" sort="Liu, Xu" uniqKey="Liu X" first="Xu" last="Liu">Xu Liu</name>
<name sortKey="Wei, Wanxing" sort="Wei, Wanxing" uniqKey="Wei W" first="Wanxing" last="Wei">Wanxing Wei</name>
<name sortKey="Zhou, Min" sort="Zhou, Min" uniqKey="Zhou M" first="Min" last="Zhou">Min Zhou</name>
</country>
</tree>
</affiliations>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/SrasV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 001335 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 001335 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Sante |area= SrasV1 |flux= Main |étape= Exploration |type= RBID |clé= pubmed:25847765 |texte= Design, synthesis, biological evaluation and molecular docking studies of phenylpropanoid derivatives as potent anti-hepatitis B virus agents. }}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i -Sk "pubmed:25847765" \ | HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd \ | NlmPubMed2Wicri -a SrasV1
This area was generated with Dilib version V0.6.33. |