Biologically active oligodeoxyribonucleotides. Part 11: The least phosphate-modification of quadruplex-forming hexadeoxyribonucleotide TGGGAG, bearing 3-and 5-end-modification, with anti-HIV-1 activity.
Identifieur interne : 002B56 ( Ncbi/Curation ); précédent : 002B55; suivant : 002B57Biologically active oligodeoxyribonucleotides. Part 11: The least phosphate-modification of quadruplex-forming hexadeoxyribonucleotide TGGGAG, bearing 3-and 5-end-modification, with anti-HIV-1 activity.
Auteurs : M. Koizumi [Japon] ; R. Koga ; H. Hotoda ; T. Ohmine ; H. Furukawa ; T. Agatsuma ; T. Nishigaki ; K. Abe ; T. Kosaka ; S. Tsutsumi ; J. Sone ; M. Kaneko ; S. Kimura ; K. ShimadaSource :
- Bioorganic & medicinal chemistry [ 0968-0896 ] ; 1998.
Descripteurs français
- KwdFr :
- Agents antiVIH (), Agents antiVIH (pharmacologie), Agents antiVIH (sang), Agents antiVIH (synthèse chimique), Composés benzyliques, Conception de médicament, Conformation d'acide nucléique, Dichroïsme circulaire, Humains, Modèles moléculaires, Oligodésoxyribonucléotides (), Oligodésoxyribonucléotides (pharmacologie), Oligodésoxyribonucléotides (sang), Oligodésoxyribonucléotides (synthèse chimique), Relation structure-activité, Stabilité de médicament, Structure moléculaire, Survie cellulaire (), Séquence nucléotidique, VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ().
- MESH :
- pharmacologie : Agents antiVIH, Oligodésoxyribonucléotides.
- sang : Agents antiVIH, Oligodésoxyribonucléotides.
- synthèse chimique : Agents antiVIH, Oligodésoxyribonucléotides.
- Agents antiVIH, Composés benzyliques, Conception de médicament, Conformation d'acide nucléique, Dichroïsme circulaire, Humains, Modèles moléculaires, Oligodésoxyribonucléotides, Relation structure-activité, Stabilité de médicament, Structure moléculaire, Survie cellulaire, Séquence nucléotidique, VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
English descriptors
- KwdEn :
- Anti-HIV Agents (blood), Anti-HIV Agents (chemical synthesis), Anti-HIV Agents (chemistry), Anti-HIV Agents (pharmacology), Base Sequence, Benzyl Compounds, Cell Survival (drug effects), Circular Dichroism, Drug Design, Drug Stability, HIV-1 (drug effects), Humans, Models, Molecular, Molecular Structure, Nucleic Acid Conformation, Oligodeoxyribonucleotides (blood), Oligodeoxyribonucleotides (chemical synthesis), Oligodeoxyribonucleotides (chemistry), Oligodeoxyribonucleotides (pharmacology), Structure-Activity Relationship.
- MESH :
- chemical , blood : Anti-HIV Agents, Oligodeoxyribonucleotides.
- chemical , chemical synthesis : Anti-HIV Agents, Oligodeoxyribonucleotides.
- chemical , chemistry : Anti-HIV Agents, Oligodeoxyribonucleotides.
- chemical , pharmacology : Anti-HIV Agents, Oligodeoxyribonucleotides.
- drug effects : Cell Survival, HIV-1.
- Base Sequence, Benzyl Compounds, Circular Dichroism, Drug Design, Drug Stability, Humans, Models, Molecular, Molecular Structure, Nucleic Acid Conformation, Structure-Activity Relationship.
Abstract
We have found that a hexadeoxyribonucleotide (5'TGGGAG3', R-95288), Koizumi, M. et al. Bioorganic & Medicinal Chemistry, 1997, 5, 2235, bearing a 3,4-dibenzyloxybenzyl (3,4-DBB) group at the 5'-end and a 2-hydroxyethylphosphate at the 3'-end, has high anti-HIV-1 activity and the least cytotoxicity in vitro and in vivo. In order to synthesize more potent hexadeoxyribonucleotides, we substituted phosphodiester (P-O) bonds in the 6-mer with the least phosphorothioate (P-S), phosphoramidate (P-N), or methylphosphonate (P-Me) bonds. When more than two P-N or P-Me bonds were introduced into a 6-mer, the phosphate-modified 6-mers had weak or no anti-HIV- activity, in spite of quadruplex structure formation. However, when P-S bonds were substituted for P-O bonds, anti-HIV-1 activity of their 6-mers did not dramatically decrease, compared with compounds substituted with P-N or P-Me bonds. The results suggest that the formation of a quadruplex structure is not always sufficient for anti-HIV-1 activity of the 6-mer, and that net negative charges derived from P-O or P-S bonds in the quadruplex are important for anti-HIV-1 activity. Moreover, among various phosphate-modified ODNs, we found that the anti-HIV-1 activity of ODN PS7 with only one P-S bond was the same as that of R-95288, both having a high stability in human plasma.
DOI: 10.1016/s0968-0896(98)80021-7
PubMed: 9925303
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Biologically active oligodeoxyribonucleotides. Part 11: The least phosphate-modification of quadruplex-forming hexadeoxyribonucleotide TGGGAG, bearing 3-and 5-end-modification, with anti-HIV-1 activity.</title><author><name sortKey="Koizumi, M" sort="Koizumi, M" uniqKey="Koizumi M" first="M" last="Koizumi">M. Koizumi</name><affiliation wicri:level="3"><nlm:affiliation>Exploratory Chemistry Research Lab., Sankyo Co., Ltd, Tokyo, Japan. koizum@shina.sankyo.co.jp</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Exploratory Chemistry Research Lab., Sankyo Co., Ltd, Tokyo</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author><author><name sortKey="Koga, R" sort="Koga, R" uniqKey="Koga R" first="R" last="Koga">R. Koga</name></author><author><name sortKey="Hotoda, H" sort="Hotoda, H" uniqKey="Hotoda H" first="H" last="Hotoda">H. Hotoda</name></author><author><name sortKey="Ohmine, T" sort="Ohmine, T" uniqKey="Ohmine T" first="T" last="Ohmine">T. Ohmine</name></author><author><name sortKey="Furukawa, H" sort="Furukawa, H" uniqKey="Furukawa H" first="H" last="Furukawa">H. Furukawa</name></author><author><name sortKey="Agatsuma, T" sort="Agatsuma, T" uniqKey="Agatsuma T" first="T" last="Agatsuma">T. Agatsuma</name></author><author><name sortKey="Nishigaki, T" sort="Nishigaki, T" uniqKey="Nishigaki T" first="T" last="Nishigaki">T. Nishigaki</name></author><author><name sortKey="Abe, K" sort="Abe, K" uniqKey="Abe K" first="K" last="Abe">K. Abe</name></author><author><name sortKey="Kosaka, T" sort="Kosaka, T" uniqKey="Kosaka T" first="T" last="Kosaka">T. Kosaka</name></author><author><name sortKey="Tsutsumi, S" sort="Tsutsumi, S" uniqKey="Tsutsumi S" first="S" last="Tsutsumi">S. 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Part 11: The least phosphate-modification of quadruplex-forming hexadeoxyribonucleotide TGGGAG, bearing 3-and 5-end-modification, with anti-HIV-1 activity.</title><author><name sortKey="Koizumi, M" sort="Koizumi, M" uniqKey="Koizumi M" first="M" last="Koizumi">M. Koizumi</name><affiliation wicri:level="3"><nlm:affiliation>Exploratory Chemistry Research Lab., Sankyo Co., Ltd, Tokyo, Japan. koizum@shina.sankyo.co.jp</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Exploratory Chemistry Research Lab., Sankyo Co., Ltd, Tokyo</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author><author><name sortKey="Koga, R" sort="Koga, R" uniqKey="Koga R" first="R" last="Koga">R. Koga</name></author><author><name sortKey="Hotoda, H" sort="Hotoda, H" uniqKey="Hotoda H" first="H" last="Hotoda">H. Hotoda</name></author><author><name sortKey="Ohmine, T" sort="Ohmine, T" uniqKey="Ohmine T" first="T" last="Ohmine">T. Ohmine</name></author><author><name sortKey="Furukawa, H" sort="Furukawa, H" uniqKey="Furukawa H" first="H" last="Furukawa">H. Furukawa</name></author><author><name sortKey="Agatsuma, T" sort="Agatsuma, T" uniqKey="Agatsuma T" first="T" last="Agatsuma">T. Agatsuma</name></author><author><name sortKey="Nishigaki, T" sort="Nishigaki, T" uniqKey="Nishigaki T" first="T" last="Nishigaki">T. Nishigaki</name></author><author><name sortKey="Abe, K" sort="Abe, K" uniqKey="Abe K" first="K" last="Abe">K. Abe</name></author><author><name sortKey="Kosaka, T" sort="Kosaka, T" uniqKey="Kosaka T" first="T" last="Kosaka">T. Kosaka</name></author><author><name sortKey="Tsutsumi, S" sort="Tsutsumi, S" uniqKey="Tsutsumi S" first="S" last="Tsutsumi">S. Tsutsumi</name></author><author><name sortKey="Sone, J" sort="Sone, J" uniqKey="Sone J" first="J" last="Sone">J. Sone</name></author><author><name sortKey="Kaneko, M" sort="Kaneko, M" uniqKey="Kaneko M" first="M" last="Kaneko">M. Kaneko</name></author><author><name sortKey="Kimura, S" sort="Kimura, S" uniqKey="Kimura S" first="S" last="Kimura">S. Kimura</name></author><author><name sortKey="Shimada, K" sort="Shimada, K" uniqKey="Shimada K" first="K" last="Shimada">K. Shimada</name></author></analytic><series><title level="j">Bioorganic & medicinal chemistry</title><idno type="ISSN">0968-0896</idno><imprint><date when="1998" type="published">1998</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Anti-HIV Agents (blood)</term><term>Anti-HIV Agents (chemical synthesis)</term><term>Anti-HIV Agents (chemistry)</term><term>Anti-HIV Agents (pharmacology)</term><term>Base Sequence</term><term>Benzyl Compounds</term><term>Cell Survival (drug effects)</term><term>Circular Dichroism</term><term>Drug Design</term><term>Drug Stability</term><term>HIV-1 (drug effects)</term><term>Humans</term><term>Models, Molecular</term><term>Molecular Structure</term><term>Nucleic Acid Conformation</term><term>Oligodeoxyribonucleotides (blood)</term><term>Oligodeoxyribonucleotides (chemical synthesis)</term><term>Oligodeoxyribonucleotides (chemistry)</term><term>Oligodeoxyribonucleotides (pharmacology)</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Agents antiVIH ()</term><term>Agents antiVIH (pharmacologie)</term><term>Agents antiVIH (sang)</term><term>Agents antiVIH (synthèse chimique)</term><term>Composés benzyliques</term><term>Conception de médicament</term><term>Conformation d'acide nucléique</term><term>Dichroïsme circulaire</term><term>Humains</term><term>Modèles moléculaires</term><term>Oligodésoxyribonucléotides ()</term><term>Oligodésoxyribonucléotides (pharmacologie)</term><term>Oligodésoxyribonucléotides (sang)</term><term>Oligodésoxyribonucléotides (synthèse chimique)</term><term>Relation structure-activité</term><term>Stabilité de médicament</term><term>Structure moléculaire</term><term>Survie cellulaire ()</term><term>Séquence nucléotidique</term><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ()</term></keywords><keywords scheme="MESH" type="chemical" qualifier="blood" xml:lang="en"><term>Anti-HIV Agents</term><term>Oligodeoxyribonucleotides</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Anti-HIV Agents</term><term>Oligodeoxyribonucleotides</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Anti-HIV Agents</term><term>Oligodeoxyribonucleotides</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Anti-HIV Agents</term><term>Oligodeoxyribonucleotides</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>Agents antiVIH</term><term>Oligodésoxyribonucléotides</term></keywords><keywords scheme="MESH" qualifier="sang" xml:lang="fr"><term>Agents antiVIH</term><term>Oligodésoxyribonucléotides</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Agents antiVIH</term><term>Oligodésoxyribonucléotides</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Base Sequence</term><term>Benzyl Compounds</term><term>Circular Dichroism</term><term>Drug Design</term><term>Drug Stability</term><term>Humans</term><term>Models, Molecular</term><term>Molecular Structure</term><term>Nucleic Acid Conformation</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Agents antiVIH</term><term>Composés benzyliques</term><term>Conception de médicament</term><term>Conformation d'acide nucléique</term><term>Dichroïsme circulaire</term><term>Humains</term><term>Modèles moléculaires</term><term>Oligodésoxyribonucléotides</term><term>Relation structure-activité</term><term>Stabilité de médicament</term><term>Structure moléculaire</term><term>Survie cellulaire</term><term>Séquence nucléotidique</term><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">We have found that a hexadeoxyribonucleotide (5'TGGGAG3', R-95288), Koizumi, M. et al. Bioorganic & Medicinal Chemistry, 1997, 5, 2235, bearing a 3,4-dibenzyloxybenzyl (3,4-DBB) group at the 5'-end and a 2-hydroxyethylphosphate at the 3'-end, has high anti-HIV-1 activity and the least cytotoxicity in vitro and in vivo. In order to synthesize more potent hexadeoxyribonucleotides, we substituted phosphodiester (P-O) bonds in the 6-mer with the least phosphorothioate (P-S), phosphoramidate (P-N), or methylphosphonate (P-Me) bonds. When more than two P-N or P-Me bonds were introduced into a 6-mer, the phosphate-modified 6-mers had weak or no anti-HIV- activity, in spite of quadruplex structure formation. However, when P-S bonds were substituted for P-O bonds, anti-HIV-1 activity of their 6-mers did not dramatically decrease, compared with compounds substituted with P-N or P-Me bonds. The results suggest that the formation of a quadruplex structure is not always sufficient for anti-HIV-1 activity of the 6-mer, and that net negative charges derived from P-O or P-S bonds in the quadruplex are important for anti-HIV-1 activity. Moreover, among various phosphate-modified ODNs, we found that the anti-HIV-1 activity of ODN PS7 with only one P-S bond was the same as that of R-95288, both having a high stability in human plasma.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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