Synthesis and biological evaluation of purine derivatives incorporating metal chelating ligands as HIV integrase inhibitors.
Identifieur interne : 001F69 ( PubMed/Checkpoint ); précédent : 001F68; suivant : 001F70Synthesis and biological evaluation of purine derivatives incorporating metal chelating ligands as HIV integrase inhibitors.
Auteurs : Xingnan Li [États-Unis] ; Robert VinceSource :
- Bioorganic & medicinal chemistry [ 0968-0896 ] ; 2006.
Descripteurs français
- KwdFr :
- Acides picoliniques (), Amides (), Catalyse, Chélateurs (), Cétoacides (), Cétoacides (pharmacologie), Cétoacides (synthèse chimique), Humains, Inhibiteurs de l'intégrase du VIH (pharmacologie), Inhibiteurs de l'intégrase du VIH (synthèse chimique), Intégrase du VIH (métabolisme), Magnésium (), Métaux (), Palladium (), Purines (pharmacologie), Purines (synthèse chimique), Quinoléines (), Relation structure-activité, VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ().
- MESH :
- métabolisme : Intégrase du VIH.
- pharmacologie : Cétoacides, Inhibiteurs de l'intégrase du VIH, Purines.
- synthèse chimique : Cétoacides, Inhibiteurs de l'intégrase du VIH, Purines.
- Acides picoliniques, Amides, Catalyse, Chélateurs, Cétoacides, Humains, Magnésium, Métaux, Palladium, Quinoléines, Relation structure-activité, VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
English descriptors
- KwdEn :
- Amides (chemistry), Catalysis, Chelating Agents (chemistry), HIV Integrase (metabolism), HIV Integrase Inhibitors (chemical synthesis), HIV Integrase Inhibitors (pharmacology), HIV-1 (drug effects), Humans, Keto Acids (chemical synthesis), Keto Acids (chemistry), Keto Acids (pharmacology), Magnesium (chemistry), Metals (chemistry), Palladium (chemistry), Picolinic Acids (chemistry), Purines (chemical synthesis), Purines (pharmacology), Quinolines (chemistry), Structure-Activity Relationship.
- MESH :
- chemical , chemical synthesis : HIV Integrase Inhibitors, Keto Acids, Purines.
- chemical , chemistry : Amides, Chelating Agents, Keto Acids, Magnesium, Metals, Palladium, Picolinic Acids, Quinolines.
- chemical , metabolism : HIV Integrase.
- chemical , pharmacology : HIV Integrase Inhibitors, Keto Acids, Purines.
- drug effects : HIV-1.
- Catalysis, Humans, Structure-Activity Relationship.
Abstract
Because of its essential role in HIV replication and lack of human counterpart, HIV integrase is an attractive target for the development of novel anti-AIDS agents. Among the recently developed integrase inhibitors, only the alpha,gamma-diketo acid (DKA) compounds were biologically validated as potent and selective integrase inhibitors. The general structure of DKAs contains a diketo acid moiety as the Mg(2+) chelating pharmacophore, and an adjacent aryl group to provide selectivity. Numerous structure-activity relationship (SAR) studies on DKAs have been conducted, which generally involved substituting the carboxylate group or the aryl group. Our objective was to investigate the SARs of the DKA molecule by incorporating a purine ring in the aryl moiety and replacing the labile diketo acid moiety with other divalent metal (Me(2+)) chelating ligands. A series of amide substituted purine derivatives were synthesized via palladium-catalyzed amidation reactions, and their biological activities against HIV integrase were evaluated. These purine derivatives showed anti-integrase activity at low micromolar range. The biological results indicated that the type of Me(2+) ligands, two-point ligand picolinamide or three-point ligand 8-hydroxy-quinoline-7-carboxamide, affected inhibitory potency depending on the substitution position of the para-fluorobenzyl group. The C(6)-,C(8)-dipicolinamide substituted purine (32) exhibited the best potency among this series.
DOI: 10.1016/j.bmc.2006.04.011
PubMed: 16753300
Affiliations:
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Drug Design, Academic Health Center, and Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, 55455, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Drug Design, Academic Health Center, and Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, 55455</wicri:regionArea><wicri:noRegion>55455</wicri:noRegion></affiliation></author><author><name sortKey="Vince, Robert" sort="Vince, Robert" uniqKey="Vince R" first="Robert" last="Vince">Robert Vince</name></author></analytic><series><title level="j">Bioorganic & medicinal chemistry</title><idno type="ISSN">0968-0896</idno><imprint><date when="2006" type="published">2006</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amides (chemistry)</term><term>Catalysis</term><term>Chelating Agents (chemistry)</term><term>HIV Integrase (metabolism)</term><term>HIV Integrase Inhibitors (chemical synthesis)</term><term>HIV Integrase Inhibitors (pharmacology)</term><term>HIV-1 (drug effects)</term><term>Humans</term><term>Keto Acids (chemical synthesis)</term><term>Keto Acids (chemistry)</term><term>Keto Acids (pharmacology)</term><term>Magnesium (chemistry)</term><term>Metals (chemistry)</term><term>Palladium (chemistry)</term><term>Picolinic Acids (chemistry)</term><term>Purines (chemical synthesis)</term><term>Purines (pharmacology)</term><term>Quinolines (chemistry)</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Acides picoliniques ()</term><term>Amides ()</term><term>Catalyse</term><term>Chélateurs ()</term><term>Cétoacides ()</term><term>Cétoacides (pharmacologie)</term><term>Cétoacides (synthèse chimique)</term><term>Humains</term><term>Inhibiteurs de l'intégrase du VIH (pharmacologie)</term><term>Inhibiteurs de l'intégrase du VIH (synthèse chimique)</term><term>Intégrase du VIH (métabolisme)</term><term>Magnésium ()</term><term>Métaux ()</term><term>Palladium ()</term><term>Purines (pharmacologie)</term><term>Purines (synthèse chimique)</term><term>Quinoléines ()</term><term>Relation structure-activité</term><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ()</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>HIV Integrase Inhibitors</term><term>Keto Acids</term><term>Purines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Amides</term><term>Chelating Agents</term><term>Keto Acids</term><term>Magnesium</term><term>Metals</term><term>Palladium</term><term>Picolinic Acids</term><term>Quinolines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>HIV Integrase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>HIV Integrase Inhibitors</term><term>Keto Acids</term><term>Purines</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>HIV-1</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Intégrase du VIH</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Cétoacides</term><term>Inhibiteurs de l'intégrase du VIH</term><term>Purines</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Cétoacides</term><term>Inhibiteurs de l'intégrase du VIH</term><term>Purines</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Catalysis</term><term>Humans</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Acides picoliniques</term><term>Amides</term><term>Catalyse</term><term>Chélateurs</term><term>Cétoacides</term><term>Humains</term><term>Magnésium</term><term>Métaux</term><term>Palladium</term><term>Quinoléines</term><term>Relation structure-activité</term><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Because of its essential role in HIV replication and lack of human counterpart, HIV integrase is an attractive target for the development of novel anti-AIDS agents. Among the recently developed integrase inhibitors, only the alpha,gamma-diketo acid (DKA) compounds were biologically validated as potent and selective integrase inhibitors. The general structure of DKAs contains a diketo acid moiety as the Mg(2+) chelating pharmacophore, and an adjacent aryl group to provide selectivity. Numerous structure-activity relationship (SAR) studies on DKAs have been conducted, which generally involved substituting the carboxylate group or the aryl group. Our objective was to investigate the SARs of the DKA molecule by incorporating a purine ring in the aryl moiety and replacing the labile diketo acid moiety with other divalent metal (Me(2+)) chelating ligands. A series of amide substituted purine derivatives were synthesized via palladium-catalyzed amidation reactions, and their biological activities against HIV integrase were evaluated. These purine derivatives showed anti-integrase activity at low micromolar range. The biological results indicated that the type of Me(2+) ligands, two-point ligand picolinamide or three-point ligand 8-hydroxy-quinoline-7-carboxamide, affected inhibitory potency depending on the substitution position of the para-fluorobenzyl group. The C(6)-,C(8)-dipicolinamide substituted purine (32) exhibited the best potency among this series.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16753300</PMID><DateCompleted><Year>2006</Year><Month>10</Month><Day>16</Day></DateCompleted><DateRevised><Year>2019</Year><Month>12</Month><Day>10</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Print">0968-0896</ISSN><JournalIssue CitedMedium="Print"><Volume>14</Volume><Issue>16</Issue><PubDate><Year>2006</Year><Month>Aug</Month><Day>15</Day></PubDate></JournalIssue><Title>Bioorganic & medicinal chemistry</Title><ISOAbbreviation>Bioorg. Med. Chem.</ISOAbbreviation></Journal><ArticleTitle>Synthesis and biological evaluation of purine derivatives incorporating metal chelating ligands as HIV integrase inhibitors.</ArticleTitle><Pagination><MedlinePgn>5742-55</MedlinePgn></Pagination><Abstract><AbstractText>Because of its essential role in HIV replication and lack of human counterpart, HIV integrase is an attractive target for the development of novel anti-AIDS agents. Among the recently developed integrase inhibitors, only the alpha,gamma-diketo acid (DKA) compounds were biologically validated as potent and selective integrase inhibitors. The general structure of DKAs contains a diketo acid moiety as the Mg(2+) chelating pharmacophore, and an adjacent aryl group to provide selectivity. Numerous structure-activity relationship (SAR) studies on DKAs have been conducted, which generally involved substituting the carboxylate group or the aryl group. Our objective was to investigate the SARs of the DKA molecule by incorporating a purine ring in the aryl moiety and replacing the labile diketo acid moiety with other divalent metal (Me(2+)) chelating ligands. A series of amide substituted purine derivatives were synthesized via palladium-catalyzed amidation reactions, and their biological activities against HIV integrase were evaluated. These purine derivatives showed anti-integrase activity at low micromolar range. The biological results indicated that the type of Me(2+) ligands, two-point ligand picolinamide or three-point ligand 8-hydroxy-quinoline-7-carboxamide, affected inhibitory potency depending on the substitution position of the para-fluorobenzyl group. The C(6)-,C(8)-dipicolinamide substituted purine (32) exhibited the best potency among this series.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Li</LastName><ForeName>Xingnan</ForeName><Initials>X</Initials><AffiliationInfo><Affiliation>Center for Drug Design, Academic Health Center, and Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, 55455, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Vince</LastName><ForeName>Robert</ForeName><Initials>R</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D023362">Evaluation Study</PublicationType><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2006</Year><Month>06</Month><Day>05</Day></ArticleDate></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="D000577">Amides</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D002614">Chelating Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D019428">HIV Integrase Inhibitors</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D007651">Keto Acids</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D008670">Metals</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D010848">Picolinic Acids</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011687">Purines</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011804">Quinolines</NameOfSubstance></Chemical><Chemical><RegistryNumber>5TWQ1V240M</RegistryNumber><NameOfSubstance UI="D010165">Palladium</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.7.-</RegistryNumber><NameOfSubstance UI="D019427">HIV Integrase</NameOfSubstance></Chemical><Chemical><RegistryNumber>I3550CCL59</RegistryNumber><NameOfSubstance UI="C003142">picolinamide</NameOfSubstance></Chemical><Chemical><RegistryNumber>I38ZP9992A</RegistryNumber><NameOfSubstance UI="D008274">Magnesium</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000577" MajorTopicYN="N">Amides</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002384" MajorTopicYN="N">Catalysis</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002614" MajorTopicYN="N">Chelating Agents</DescriptorName><QualifierName UI="Q000737" 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MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011804" MajorTopicYN="N">Quinolines</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013329" MajorTopicYN="N">Structure-Activity Relationship</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2006</Year><Month>02</Month><Day>03</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2006</Year><Month>04</Month><Day>03</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2006</Year><Month>04</Month><Day>06</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2006</Year><Month>6</Month><Day>7</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2006</Year><Month>10</Month><Day>17</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2006</Year><Month>6</Month><Day>7</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16753300</ArticleId><ArticleId IdType="pii">S0968-0896(06)00293-8</ArticleId><ArticleId IdType="doi">10.1016/j.bmc.2006.04.011</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>États-Unis</li></country></list><tree><noCountry><name sortKey="Vince, Robert" sort="Vince, Robert" uniqKey="Vince R" first="Robert" last="Vince">Robert Vince</name></noCountry><country name="États-Unis"><noRegion><name sortKey="Li, Xingnan" sort="Li, Xingnan" uniqKey="Li X" first="Xingnan" last="Li">Xingnan Li</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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