Structure-activity relationships of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine analogues: effect of substitutions at the C-6 phenyl ring and at the C-5 position on anti-HIV-1 activity.
Identifieur interne : 002A17 ( Main/Exploration ); précédent : 002A16; suivant : 002A18Structure-activity relationships of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine analogues: effect of substitutions at the C-6 phenyl ring and at the C-5 position on anti-HIV-1 activity.
Auteurs : H. Tanaka [Japon] ; H. Takashima ; M. Ubasawa ; K. Sekiya ; I. Nitta ; M. Baba ; S. Shigeta ; R T Walker ; E. De Clercq ; T. MiyasakaSource :
- Journal of medicinal chemistry [ 0022-2623 ] ; 1992.
Descripteurs français
- KwdFr :
- Antiviraux (), Antiviraux (pharmacologie), Antiviraux (synthèse chimique), Effet cytopathogène viral (), Lignée cellulaire, Relation structure-activité, Réplication virale (), Survie cellulaire (), Thymine (), Thymine (analogues et dérivés), Thymine (pharmacologie), Thymine (synthèse chimique), VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (), VIH-2 (Virus de l'Immunodéficience Humaine de type 2) ().
- MESH :
- analogues et dérivés : Thymine.
- pharmacologie : Antiviraux, Thymine.
- synthèse chimique : Antiviraux, Thymine.
- Antiviraux, Effet cytopathogène viral, Lignée cellulaire, Relation structure-activité, Réplication virale, Survie cellulaire, Thymine, VIH-1 (Virus de l'Immunodéficience Humaine de type 1), VIH-2 (Virus de l'Immunodéficience Humaine de type 2).
English descriptors
- KwdEn :
- Antiviral Agents (chemical synthesis), Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Cell Line, Cell Survival (drug effects), Cytopathogenic Effect, Viral (drug effects), HIV-1 (drug effects), HIV-2 (drug effects), Structure-Activity Relationship, Thymine (analogs & derivatives), Thymine (chemical synthesis), Thymine (chemistry), Thymine (pharmacology), Virus Replication (drug effects).
- MESH :
- chemical , analogs & derivatives : Thymine.
- chemical , chemical synthesis : Antiviral Agents, Thymine.
- chemical , chemistry : Antiviral Agents, Thymine.
- chemical , pharmacology : Antiviral Agents, Thymine.
- drug effects : Cell Survival, Cytopathogenic Effect, Viral, HIV-1, HIV-2, Virus Replication.
- Cell Line, Structure-Activity Relationship.
Abstract
The effect of substitution on the pyrimidine moiety of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) and 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymine (HEPT-S) on anti-HIV-1 activity was investigated by synthesizing a series of 5-methyl-6-(arylthio) and 5-substituted-6-(phenylthio) derivatives. Preparation of the 5-methyl-6-(arylthio) derivatives was carried out based on either LDA lithiation of 1-[[2-(tert-butyldimethylsiloxy)ethoxy]methyl]thymine (3) and 1-[[2-(tert-butyldimethylsiloxy)ethoxy]methyl]-2-thiothymine (4) followed by reaction with diaryl disulfides or an addition-elimination reaction of 1-[[2-(tert-butyldimethylsiloxy)ethoxy]-methyl]-6- (phenylsulfinyl)thymine (31) with aromatic thiols. Preparation of the 5-substituted-6-(phenylthio) derivatives was carried out based on either C-5 lithiation of the 1-[[2-(tert-butyldimethylsiloxy)ethoxy]methyl]-6-(phenylthio)uraci l (41) with LTMP or the LDA lithiation of 5-alkyl-1-[[2-(tert-butyldimethylsiloxy)ethoxy]methyl]-2-thiouraci l derivatives 45-47. Substitution at the meta position of the C-6-(phenylthio) ring by the methyl group improved the original anti-HIV-1 activity of HEPT, and introduction of two m-methyl groups to the phenylthio ring further potentiated the activity [EC50: 6-[(3,5-dimethylphenyl)thio]-1-[(2-hydroxyethoxy)methyl]thymine (28), 0.26 microM; 6-[(3,5-dimethylphenyl)thio]-1-[(2-hydroxyethoxy)methyl]-2-thiothymin e (30), 0.22 microM]. When the 5-methyl group was replaced by an ethyl or an isopropyl group, the anti-HIV-1 activity of HEPT was also improved remarkably [EC50: 5-ethyl-1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiouracil (48), 0.11 microM; 5-isopropyl-1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)-2-thiouracil (50), 0.059 microM; 5-ethyl-1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiouracil (54), 0.12 microM; 5-isopropyl-1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiouracil (56), 0.063 microM]. 6-[(3,5-Dimethylphenyl)thio]-5-ethyl-1-[(2-hydroxyethoxy)methyl]thymine derivatives 51 and 57 and 6-[(3,5-dimethylphenyl)thio]-5-isopropyl-1-[(2- hydroxyethoxy)methyl]thymine derivatives 52 and 58 inhibited the replication of HIV-1 in the nanomolar concentration range.
PubMed: 1732552
Affiliations:
Links toward previous steps (curation, corpus...)
- to stream PubMed, to step Corpus: 000260
- to stream PubMed, to step Curation: 000260
- to stream PubMed, to step Checkpoint: 000260
- to stream Ncbi, to step Merge: 000106
- to stream Ncbi, to step Curation: 000106
- to stream Ncbi, to step Checkpoint: 000106
- to stream Main, to step Merge: 003019
- to stream Main, to step Curation: 002A17
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Structure-activity relationships of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine analogues: effect of substitutions at the C-6 phenyl ring and at the C-5 position on anti-HIV-1 activity.</title>
<author><name sortKey="Tanaka, H" sort="Tanaka, H" uniqKey="Tanaka H" first="H" last="Tanaka">H. Tanaka</name>
<affiliation wicri:level="3"><nlm:affiliation>School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.</nlm:affiliation>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>School of Pharmaceutical Sciences, Showa University, Tokyo</wicri:regionArea>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Takashima, H" sort="Takashima, H" uniqKey="Takashima H" first="H" last="Takashima">H. Takashima</name>
</author>
<author><name sortKey="Ubasawa, M" sort="Ubasawa, M" uniqKey="Ubasawa M" first="M" last="Ubasawa">M. Ubasawa</name>
</author>
<author><name sortKey="Sekiya, K" sort="Sekiya, K" uniqKey="Sekiya K" first="K" last="Sekiya">K. Sekiya</name>
</author>
<author><name sortKey="Nitta, I" sort="Nitta, I" uniqKey="Nitta I" first="I" last="Nitta">I. Nitta</name>
</author>
<author><name sortKey="Baba, M" sort="Baba, M" uniqKey="Baba M" first="M" last="Baba">M. Baba</name>
</author>
<author><name sortKey="Shigeta, S" sort="Shigeta, S" uniqKey="Shigeta S" first="S" last="Shigeta">S. Shigeta</name>
</author>
<author><name sortKey="Walker, R T" sort="Walker, R T" uniqKey="Walker R" first="R T" last="Walker">R T Walker</name>
</author>
<author><name sortKey="De Clercq, E" sort="De Clercq, E" uniqKey="De Clercq E" first="E" last="De Clercq">E. De Clercq</name>
</author>
<author><name sortKey="Miyasaka, T" sort="Miyasaka, T" uniqKey="Miyasaka T" first="T" last="Miyasaka">T. Miyasaka</name>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PubMed</idno>
<date when="1992">1992</date>
<idno type="RBID">pubmed:1732552</idno>
<idno type="pmid">1732552</idno>
<idno type="wicri:Area/PubMed/Corpus">000260</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000260</idno>
<idno type="wicri:Area/PubMed/Curation">000260</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000260</idno>
<idno type="wicri:Area/PubMed/Checkpoint">000260</idno>
<idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000260</idno>
<idno type="wicri:Area/Ncbi/Merge">000106</idno>
<idno type="wicri:Area/Ncbi/Curation">000106</idno>
<idno type="wicri:Area/Ncbi/Checkpoint">000106</idno>
<idno type="wicri:doubleKey">0022-2623:1992:Tanaka H:structure:activity:relationships</idno>
<idno type="wicri:Area/Main/Merge">003019</idno>
<idno type="wicri:Area/Main/Curation">002A17</idno>
<idno type="wicri:Area/Main/Exploration">002A17</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en">Structure-activity relationships of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine analogues: effect of substitutions at the C-6 phenyl ring and at the C-5 position on anti-HIV-1 activity.</title>
<author><name sortKey="Tanaka, H" sort="Tanaka, H" uniqKey="Tanaka H" first="H" last="Tanaka">H. Tanaka</name>
<affiliation wicri:level="3"><nlm:affiliation>School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.</nlm:affiliation>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>School of Pharmaceutical Sciences, Showa University, Tokyo</wicri:regionArea>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Takashima, H" sort="Takashima, H" uniqKey="Takashima H" first="H" last="Takashima">H. Takashima</name>
</author>
<author><name sortKey="Ubasawa, M" sort="Ubasawa, M" uniqKey="Ubasawa M" first="M" last="Ubasawa">M. Ubasawa</name>
</author>
<author><name sortKey="Sekiya, K" sort="Sekiya, K" uniqKey="Sekiya K" first="K" last="Sekiya">K. Sekiya</name>
</author>
<author><name sortKey="Nitta, I" sort="Nitta, I" uniqKey="Nitta I" first="I" last="Nitta">I. Nitta</name>
</author>
<author><name sortKey="Baba, M" sort="Baba, M" uniqKey="Baba M" first="M" last="Baba">M. Baba</name>
</author>
<author><name sortKey="Shigeta, S" sort="Shigeta, S" uniqKey="Shigeta S" first="S" last="Shigeta">S. Shigeta</name>
</author>
<author><name sortKey="Walker, R T" sort="Walker, R T" uniqKey="Walker R" first="R T" last="Walker">R T Walker</name>
</author>
<author><name sortKey="De Clercq, E" sort="De Clercq, E" uniqKey="De Clercq E" first="E" last="De Clercq">E. De Clercq</name>
</author>
<author><name sortKey="Miyasaka, T" sort="Miyasaka, T" uniqKey="Miyasaka T" first="T" last="Miyasaka">T. Miyasaka</name>
</author>
</analytic>
<series><title level="j">Journal of medicinal chemistry</title>
<idno type="ISSN">0022-2623</idno>
<imprint><date when="1992" type="published">1992</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 (pharmacology)</term>
<term>Cell Line</term>
<term>Cell Survival (drug effects)</term>
<term>Cytopathogenic Effect, Viral (drug effects)</term>
<term>HIV-1 (drug effects)</term>
<term>HIV-2 (drug effects)</term>
<term>Structure-Activity Relationship</term>
<term>Thymine (analogs & derivatives)</term>
<term>Thymine (chemical synthesis)</term>
<term>Thymine (chemistry)</term>
<term>Thymine (pharmacology)</term>
<term>Virus Replication (drug effects)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Antiviraux ()</term>
<term>Antiviraux (pharmacologie)</term>
<term>Antiviraux (synthèse chimique)</term>
<term>Effet cytopathogène viral ()</term>
<term>Lignée cellulaire</term>
<term>Relation structure-activité</term>
<term>Réplication virale ()</term>
<term>Survie cellulaire ()</term>
<term>Thymine ()</term>
<term>Thymine (analogues et dérivés)</term>
<term>Thymine (pharmacologie)</term>
<term>Thymine (synthèse chimique)</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ()</term>
<term>VIH-2 (Virus de l'Immunodéficience Humaine de type 2) ()</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Thymine</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Antiviral Agents</term>
<term>Thymine</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antiviral Agents</term>
<term>Thymine</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term>
<term>Thymine</term>
</keywords>
<keywords scheme="MESH" qualifier="analogues et dérivés" xml:lang="fr"><term>Thymine</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Cell Survival</term>
<term>Cytopathogenic Effect, Viral</term>
<term>HIV-1</term>
<term>HIV-2</term>
<term>Virus Replication</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term>
<term>Thymine</term>
</keywords>
<keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Antiviraux</term>
<term>Thymine</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Cell Line</term>
<term>Structure-Activity Relationship</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Antiviraux</term>
<term>Effet cytopathogène viral</term>
<term>Lignée cellulaire</term>
<term>Relation structure-activité</term>
<term>Réplication virale</term>
<term>Survie cellulaire</term>
<term>Thymine</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term>
<term>VIH-2 (Virus de l'Immunodéficience Humaine de type 2)</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">The effect of substitution on the pyrimidine moiety of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) and 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymine (HEPT-S) on anti-HIV-1 activity was investigated by synthesizing a series of 5-methyl-6-(arylthio) and 5-substituted-6-(phenylthio) derivatives. Preparation of the 5-methyl-6-(arylthio) derivatives was carried out based on either LDA lithiation of 1-[[2-(tert-butyldimethylsiloxy)ethoxy]methyl]thymine (3) and 1-[[2-(tert-butyldimethylsiloxy)ethoxy]methyl]-2-thiothymine (4) followed by reaction with diaryl disulfides or an addition-elimination reaction of 1-[[2-(tert-butyldimethylsiloxy)ethoxy]-methyl]-6- (phenylsulfinyl)thymine (31) with aromatic thiols. Preparation of the 5-substituted-6-(phenylthio) derivatives was carried out based on either C-5 lithiation of the 1-[[2-(tert-butyldimethylsiloxy)ethoxy]methyl]-6-(phenylthio)uraci l (41) with LTMP or the LDA lithiation of 5-alkyl-1-[[2-(tert-butyldimethylsiloxy)ethoxy]methyl]-2-thiouraci l derivatives 45-47. Substitution at the meta position of the C-6-(phenylthio) ring by the methyl group improved the original anti-HIV-1 activity of HEPT, and introduction of two m-methyl groups to the phenylthio ring further potentiated the activity [EC50: 6-[(3,5-dimethylphenyl)thio]-1-[(2-hydroxyethoxy)methyl]thymine (28), 0.26 microM; 6-[(3,5-dimethylphenyl)thio]-1-[(2-hydroxyethoxy)methyl]-2-thiothymin e (30), 0.22 microM]. When the 5-methyl group was replaced by an ethyl or an isopropyl group, the anti-HIV-1 activity of HEPT was also improved remarkably [EC50: 5-ethyl-1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiouracil (48), 0.11 microM; 5-isopropyl-1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)-2-thiouracil (50), 0.059 microM; 5-ethyl-1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiouracil (54), 0.12 microM; 5-isopropyl-1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiouracil (56), 0.063 microM]. 6-[(3,5-Dimethylphenyl)thio]-5-ethyl-1-[(2-hydroxyethoxy)methyl]thymine derivatives 51 and 57 and 6-[(3,5-dimethylphenyl)thio]-5-isopropyl-1-[(2- hydroxyethoxy)methyl]thymine derivatives 52 and 58 inhibited the replication of HIV-1 in the nanomolar concentration range.</div>
</front>
</TEI>
<affiliations><list><country><li>Japon</li>
</country>
<region><li>Région de Kantō</li>
</region>
<settlement><li>Tokyo</li>
</settlement>
</list>
<tree><noCountry><name sortKey="Baba, M" sort="Baba, M" uniqKey="Baba M" first="M" last="Baba">M. Baba</name>
<name sortKey="De Clercq, E" sort="De Clercq, E" uniqKey="De Clercq E" first="E" last="De Clercq">E. De Clercq</name>
<name sortKey="Miyasaka, T" sort="Miyasaka, T" uniqKey="Miyasaka T" first="T" last="Miyasaka">T. Miyasaka</name>
<name sortKey="Nitta, I" sort="Nitta, I" uniqKey="Nitta I" first="I" last="Nitta">I. Nitta</name>
<name sortKey="Sekiya, K" sort="Sekiya, K" uniqKey="Sekiya K" first="K" last="Sekiya">K. Sekiya</name>
<name sortKey="Shigeta, S" sort="Shigeta, S" uniqKey="Shigeta S" first="S" last="Shigeta">S. Shigeta</name>
<name sortKey="Takashima, H" sort="Takashima, H" uniqKey="Takashima H" first="H" last="Takashima">H. Takashima</name>
<name sortKey="Ubasawa, M" sort="Ubasawa, M" uniqKey="Ubasawa M" first="M" last="Ubasawa">M. Ubasawa</name>
<name sortKey="Walker, R T" sort="Walker, R T" uniqKey="Walker R" first="R T" last="Walker">R T Walker</name>
</noCountry>
<country name="Japon"><region name="Région de Kantō"><name sortKey="Tanaka, H" sort="Tanaka, H" uniqKey="Tanaka H" first="H" last="Tanaka">H. Tanaka</name>
</region>
</country>
</tree>
</affiliations>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Lorraine/explor/LrgpV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 002A17 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 002A17 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Wicri/Lorraine |area= LrgpV1 |flux= Main |étape= Exploration |type= RBID |clé= pubmed:1732552 |texte= Structure-activity relationships of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine analogues: effect of substitutions at the C-6 phenyl ring and at the C-5 position on anti-HIV-1 activity. }}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i -Sk "pubmed:1732552" \ | HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd \ | NlmPubMed2Wicri -a LrgpV1
![]() | This area was generated with Dilib version V0.6.32. | ![]() |