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:
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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. 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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)
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