A new class of HIV-1-specific 6-substituted acyclouridine derivatives: synthesis and anti-HIV-1 activity of 5- or 6-substituted analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT).
Identifieur interne : 000164 ( Ncbi/Curation ); précédent : 000163; suivant : 000165A new class of HIV-1-specific 6-substituted acyclouridine derivatives: synthesis and anti-HIV-1 activity of 5- or 6-substituted analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT).
Auteurs : H. Tanaka [Japon] ; M. Baba ; H. Hayakawa ; T. Sakamaki ; T. Miyasaka ; M. Ubasawa ; H. Takashima ; K. Sekiya ; I. Nitta ; S. ShigetaSource :
- Journal of medicinal chemistry [ 0022-2623 ] ; 1991.
Descripteurs français
- KwdFr :
- Antiviraux (synthèse chimique), Humains, Indicateurs et réactifs, Lignée cellulaire, Relation structure-activité, Structure moléculaire, Survie cellulaire (), Thymine (), Thymine (analogues et dérivés), Thymine (pharmacologie), Thymine (synthèse chimique), VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ().
- MESH :
- analogues et dérivés : Thymine.
- pharmacologie : Thymine.
- synthèse chimique : Antiviraux, Thymine.
- Humains, Indicateurs et réactifs, Lignée cellulaire, Relation structure-activité, Structure moléculaire, Survie cellulaire, Thymine, VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
English descriptors
- KwdEn :
- MESH :
- chemical , analogs & derivatives : Thymine.
- chemical , chemical synthesis : Antiviral Agents, Thymine.
- chemical , chemistry : Thymine.
- drug effects : Cell Survival, HIV-1.
- chemical , pharmacology : Thymine.
- Cell Line, Humans, Indicators and Reagents, Molecular Structure, Structure-Activity Relationship.
Abstract
A series of novel acyclouridine derivatives substituted at both the C-5 and C-6 positions were synthesized for the purpose of improving the activity of a recently reported HIV-1-specific lead, 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT). Preparation of C-6 substituted derivatives was carried out based on the following three methods: (1) LDA (lithium diisopropylamide) lithiation of a thymine derivative (4) and subsequent reaction with electrophiles, (2) an addition-elimination reaction of HEPT or its 6-(phenylsulfinyl) derivative (10), or (3) palladium-catalyzed cross-coupling between a 6-iodo derivative (16) and terminal alkynes. Following the methods, 21 C-6 substituted analogues were synthesized. Among these, 6-(cyclohexylthio) (8), 6-phenoxy (13), and 6-benzyl (27) derivatives showed anti-HIV-1 (HTLV-IIIB) activity with EC50 values of 8.2, 85, and 23 microM, respectively. Preparation of C-5 substituted derivatives was based on either LTMP (lithium 2,2,6,6-tetramethylpiperidide) lithiation of 6-(phenylthio)uracil derivative 37 or the above mentioned palladium-catalyzed cross-coupling of a 5-iodo-6-(phenylthio)uracil derivative (38). Following these methods, 11 C-5 substituted analogues were synthesized. Some 5-substituted derivatives (5-I, 44; 5-CH = CPh2, 49; 5-CH = CHPh (Z), 54; and 5-CH = CH2, 55) were more active than HEPT, but their selectivity indices (SI = CC50/EC50) were lower than that of HEPT. Compound 8 was also evaluated against another HIV-1 strain (HTLV-IIIRF) and HIV-2 strains (LAV-2ROD and LAV-2EHO). Only HTLV-IIIRF was as sensitive as HTLV-IIIB.
PubMed: 1992136
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Hayakawa</name></author><author><name sortKey="Sakamaki, T" sort="Sakamaki, T" uniqKey="Sakamaki T" first="T" last="Sakamaki">T. Sakamaki</name></author><author><name sortKey="Miyasaka, T" sort="Miyasaka, T" uniqKey="Miyasaka T" first="T" last="Miyasaka">T. Miyasaka</name></author><author><name sortKey="Ubasawa, M" sort="Ubasawa, M" uniqKey="Ubasawa M" first="M" last="Ubasawa">M. Ubasawa</name></author><author><name sortKey="Takashima, H" sort="Takashima, H" uniqKey="Takashima H" first="H" last="Takashima">H. Takashima</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="Shigeta, S" sort="Shigeta, S" uniqKey="Shigeta S" first="S" last="Shigeta">S. 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Tanaka</name><affiliation wicri:level="3"><nlm:affiliation>School of Pharmaceutical Science, Showa University, Tokyo, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>School of Pharmaceutical Science, Showa University, Tokyo</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author><author><name sortKey="Baba, M" sort="Baba, M" uniqKey="Baba M" first="M" last="Baba">M. Baba</name></author><author><name sortKey="Hayakawa, H" sort="Hayakawa, H" uniqKey="Hayakawa H" first="H" last="Hayakawa">H. Hayakawa</name></author><author><name sortKey="Sakamaki, T" sort="Sakamaki, T" uniqKey="Sakamaki T" first="T" last="Sakamaki">T. Sakamaki</name></author><author><name sortKey="Miyasaka, T" sort="Miyasaka, T" uniqKey="Miyasaka T" first="T" last="Miyasaka">T. Miyasaka</name></author><author><name sortKey="Ubasawa, M" sort="Ubasawa, M" uniqKey="Ubasawa M" first="M" last="Ubasawa">M. Ubasawa</name></author><author><name sortKey="Takashima, H" sort="Takashima, H" uniqKey="Takashima H" first="H" last="Takashima">H. Takashima</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="Shigeta, S" sort="Shigeta, S" uniqKey="Shigeta S" first="S" last="Shigeta">S. Shigeta</name></author></analytic><series><title level="j">Journal of medicinal chemistry</title><idno type="ISSN">0022-2623</idno><imprint><date when="1991" type="published">1991</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral Agents (chemical synthesis)</term><term>Cell Line</term><term>Cell Survival (drug effects)</term><term>HIV-1 (drug effects)</term><term>Humans</term><term>Indicators and Reagents</term><term>Molecular Structure</term><term>Structure-Activity Relationship</term><term>Thymine (analogs & derivatives)</term><term>Thymine (chemical synthesis)</term><term>Thymine (chemistry)</term><term>Thymine (pharmacology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Antiviraux (synthèse chimique)</term><term>Humains</term><term>Indicateurs et réactifs</term><term>Lignée cellulaire</term><term>Relation structure-activité</term><term>Structure moléculaire</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></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>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>HIV-1</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Thymine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><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>Humans</term><term>Indicators and Reagents</term><term>Molecular Structure</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Humains</term><term>Indicateurs et réactifs</term><term>Lignée cellulaire</term><term>Relation structure-activité</term><term>Structure moléculaire</term><term>Survie cellulaire</term><term>Thymine</term><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">A series of novel acyclouridine derivatives substituted at both the C-5 and C-6 positions were synthesized for the purpose of improving the activity of a recently reported HIV-1-specific lead, 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT). Preparation of C-6 substituted derivatives was carried out based on the following three methods: (1) LDA (lithium diisopropylamide) lithiation of a thymine derivative (4) and subsequent reaction with electrophiles, (2) an addition-elimination reaction of HEPT or its 6-(phenylsulfinyl) derivative (10), or (3) palladium-catalyzed cross-coupling between a 6-iodo derivative (16) and terminal alkynes. Following the methods, 21 C-6 substituted analogues were synthesized. Among these, 6-(cyclohexylthio) (8), 6-phenoxy (13), and 6-benzyl (27) derivatives showed anti-HIV-1 (HTLV-IIIB) activity with EC50 values of 8.2, 85, and 23 microM, respectively. Preparation of C-5 substituted derivatives was based on either LTMP (lithium 2,2,6,6-tetramethylpiperidide) lithiation of 6-(phenylthio)uracil derivative 37 or the above mentioned palladium-catalyzed cross-coupling of a 5-iodo-6-(phenylthio)uracil derivative (38). Following these methods, 11 C-5 substituted analogues were synthesized. Some 5-substituted derivatives (5-I, 44; 5-CH = CPh2, 49; 5-CH = CHPh (Z), 54; and 5-CH = CH2, 55) were more active than HEPT, but their selectivity indices (SI = CC50/EC50) were lower than that of HEPT. Compound 8 was also evaluated against another HIV-1 strain (HTLV-IIIRF) and HIV-2 strains (LAV-2ROD and LAV-2EHO). Only HTLV-IIIRF was as sensitive as HTLV-IIIB.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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