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 : 002649 ( PubMed/Corpus ); précédent : 002648; suivant : 002650Biologically 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 ; 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.
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
Links to Exploration step
pubmed:9925303Le document en format XML
<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><nlm:affiliation>Exploratory Chemistry Research Lab., Sankyo Co., Ltd, Tokyo, Japan. koizum@shina.sankyo.co.jp</nlm:affiliation></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></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="1998">1998</date><idno type="RBID">pubmed:9925303</idno><idno type="pmid">9925303</idno><idno type="doi">10.1016/s0968-0896(98)80021-7</idno><idno type="wicri:Area/PubMed/Corpus">002649</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">002649</idno></publicationStmt><sourceDesc><biblStruct><analytic><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><nlm:affiliation>Exploratory Chemistry Research Lab., Sankyo Co., Ltd, Tokyo, Japan. koizum@shina.sankyo.co.jp</nlm:affiliation></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="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" 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></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><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">9925303</PMID><DateCompleted><Year>1999</Year><Month>03</Month><Day>31</Day></DateCompleted><DateRevised><Year>2019</Year><Month>08</Month><Day>31</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0968-0896</ISSN><JournalIssue CitedMedium="Print"><Volume>6</Volume><Issue>12</Issue><PubDate><Year>1998</Year><Month>Dec</Month></PubDate></JournalIssue><Title>Bioorganic & medicinal chemistry</Title><ISOAbbreviation>Bioorg. Med. Chem.</ISOAbbreviation></Journal><ArticleTitle>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.</ArticleTitle><Pagination><MedlinePgn>2469-75</MedlinePgn></Pagination><Abstract><AbstractText>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.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Koizumi</LastName><ForeName>M</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Exploratory Chemistry Research Lab., Sankyo Co., Ltd, Tokyo, Japan. koizum@shina.sankyo.co.jp</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Koga</LastName><ForeName>R</ForeName><Initials>R</Initials></Author><Author ValidYN="Y"><LastName>Hotoda</LastName><ForeName>H</ForeName><Initials>H</Initials></Author><Author ValidYN="Y"><LastName>Ohmine</LastName><ForeName>T</ForeName><Initials>T</Initials></Author><Author ValidYN="Y"><LastName>Furukawa</LastName><ForeName>H</ForeName><Initials>H</Initials></Author><Author ValidYN="Y"><LastName>Agatsuma</LastName><ForeName>T</ForeName><Initials>T</Initials></Author><Author ValidYN="Y"><LastName>Nishigaki</LastName><ForeName>T</ForeName><Initials>T</Initials></Author><Author ValidYN="Y"><LastName>Abe</LastName><ForeName>K</ForeName><Initials>K</Initials></Author><Author ValidYN="Y"><LastName>Kosaka</LastName><ForeName>T</ForeName><Initials>T</Initials></Author><Author ValidYN="Y"><LastName>Tsutsumi</LastName><ForeName>S</ForeName><Initials>S</Initials></Author><Author ValidYN="Y"><LastName>Sone</LastName><ForeName>J</ForeName><Initials>J</Initials></Author><Author ValidYN="Y"><LastName>Kaneko</LastName><ForeName>M</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Kimura</LastName><ForeName>S</ForeName><Initials>S</Initials></Author><Author ValidYN="Y"><LastName>Shimada</LastName><ForeName>K</ForeName><Initials>K</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Bioorg Med Chem</MedlineTA><NlmUniqueID>9413298</NlmUniqueID><ISSNLinking>0968-0896</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D019380">Anti-HIV Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D001593">Benzyl Compounds</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D009838">Oligodeoxyribonucleotides</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><CitationSubset>X</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D019380" MajorTopicYN="N">Anti-HIV Agents</DescriptorName><QualifierName UI="Q000097" MajorTopicYN="N">blood</QualifierName><QualifierName UI="Q000138" MajorTopicYN="Y">chemical synthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001483" MajorTopicYN="N">Base Sequence</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D001593" MajorTopicYN="N">Benzyl Compounds</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002470" MajorTopicYN="N">Cell Survival</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002942" MajorTopicYN="N">Circular Dichroism</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015195" MajorTopicYN="N">Drug Design</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004355" MajorTopicYN="N">Drug Stability</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015497" MajorTopicYN="N">HIV-1</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008958" MajorTopicYN="N">Models, Molecular</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015394" MajorTopicYN="N">Molecular Structure</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009690" MajorTopicYN="Y">Nucleic Acid Conformation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009838" MajorTopicYN="N">Oligodeoxyribonucleotides</DescriptorName><QualifierName UI="Q000097" MajorTopicYN="N">blood</QualifierName><QualifierName UI="Q000138" MajorTopicYN="Y">chemical synthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013329" MajorTopicYN="N">Structure-Activity Relationship</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>1999</Year><Month>1</Month><Day>30</Day></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>1999</Year><Month>1</Month><Day>30</Day><Hour>0</Hour><Minute>1</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>1999</Year><Month>1</Month><Day>30</Day><Hour>0</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">9925303</ArticleId><ArticleId IdType="pii">S0968089698800217</ArticleId><ArticleId IdType="doi">10.1016/s0968-0896(98)80021-7</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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