Anti-AIDS Agents. 42. Synthesis and Anti-HIV Activity of Disubstituted (3‘R,4‘R)-3‘,4‘-Di-O-(S)-camphanoyl-(+)-cis-khellactone Analogues
Identifieur interne : 006448 ( Main/Exploration ); précédent : 006447; suivant : 006449Anti-AIDS Agents. 42. Synthesis and Anti-HIV Activity of Disubstituted (3‘R,4‘R)-3‘,4‘-Di-O-(S)-camphanoyl-(+)-cis-khellactone Analogues
Auteurs : Lan Xie [États-Unis] ; Yasuo Takeuchi [États-Unis] ; L. Mark Cosentino [États-Unis] ; Andrew T. Mcphail [États-Unis] ; Kuo-Hsiung Lee [États-Unis]Source :
- Journal of Medicinal Chemistry [ 0022-2623 ] ; 2001.
Abstract
A series of disubstituted 3‘,4‘-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogues (1−10) were synthesized and evaluated for inhibition of HIV-1 replication in H9 lymphocytes. 5-Methoxy-4-methyl DCK (8) was the most promising compound with an EC50 value of 7.21 × 10-6 μM and a therapeutic index of >2.08 × 10, which were much better than those of lead compound DCK in the same assay. Another six disubstituted DCK analogues (1−5 and 7) were more potent than AZT but less active than DCK. Conformational analysis suggested that resonance of the coumarin system is an essential structural feature for potent anti-HIV activity. Steric compression of C(4) and C(5) substituents of the coumarin moiety can reduce the overall planarity and thus resonance of the coumarin nucleus, resulting in a decrease or lack of anti-HIV activity.
Url:
DOI: 10.1021/jm000070g
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Mark Cosentino</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Caroline du Nord</region></placeName><wicri:cityArea>Natural Products Laboratory, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599,BBI-Biotech Research Laboratories, Inc., Gaithersburg, Maryland 20877, and Department of Chemistry,Paul M. Gross Chemical Laboratory, Duke University, Durham</wicri:cityArea></affiliation><affiliation></affiliation></author><author><name sortKey="Mcphail, Andrew T" sort="Mcphail, Andrew T" uniqKey="Mcphail A" first="Andrew T." last="Mcphail">Andrew T. 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Chem.</title><idno type="ISSN">0022-2623</idno><idno type="eISSN">1520-4804</idno><imprint><publisher>American Chemical Society</publisher><date type="e-published">2001</date><date type="published">2001</date><biblScope unit="vol">44</biblScope><biblScope unit="issue">5</biblScope><biblScope unit="page" from="664">664</biblScope><biblScope unit="page" to="671">671</biblScope></imprint><idno type="ISSN">0022-2623</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-2623</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">A series of disubstituted 3‘,4‘-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogues (1−10) were synthesized and evaluated for inhibition of HIV-1 replication in H9 lymphocytes. 5-Methoxy-4-methyl DCK (8) was the most promising compound with an EC50 value of 7.21 × 10-6 μM and a therapeutic index of >2.08 × 10, which were much better than those of lead compound DCK in the same assay. Another six disubstituted DCK analogues (1−5 and 7) were more potent than AZT but less active than DCK. Conformational analysis suggested that resonance of the coumarin system is an essential structural feature for potent anti-HIV activity. Steric compression of C(4) and C(5) substituents of the coumarin moiety can reduce the overall planarity and thus resonance of the coumarin nucleus, resulting in a decrease or lack of anti-HIV activity.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Caroline du Nord</li></region></list><tree><country name="États-Unis"><region name="Caroline du Nord"><name sortKey="Xie, Lan" sort="Xie, Lan" uniqKey="Xie L" first="Lan" last="Xie">Lan Xie</name></region><name sortKey="Cosentino, L Mark" sort="Cosentino, L Mark" uniqKey="Cosentino L" first="L. Mark" last="Cosentino">L. Mark Cosentino</name><name sortKey="Lee, Kuo Hsiung" sort="Lee, Kuo Hsiung" uniqKey="Lee K" first="Kuo-Hsiung" last="Lee">Kuo-Hsiung Lee</name><name sortKey="Lee, Kuo Hsiung" sort="Lee, Kuo Hsiung" uniqKey="Lee K" first="Kuo-Hsiung" last="Lee">Kuo-Hsiung Lee</name><name sortKey="Mcphail, Andrew T" sort="Mcphail, Andrew T" uniqKey="Mcphail A" first="Andrew T." last="Mcphail">Andrew T. Mcphail</name><name sortKey="Takeuchi, Yasuo" sort="Takeuchi, Yasuo" uniqKey="Takeuchi Y" first="Yasuo" last="Takeuchi">Yasuo Takeuchi</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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