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Anti-AIDS Agents. 42. Synthesis and Anti-HIV Activity of Disubstituted (3‘R,4‘R)-3‘,4‘-Di-O-(S)-camphanoyl-(+)-cis-khellactone Analogues
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 ind...
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| Published in: | Journal of medicinal chemistry 2001-03, Vol.44 (5), p.664-671 |
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| Main Authors: | , , , , |
| Format: | Article |
| Language: | English |
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| cited_by | cdi_FETCH-LOGICAL-a408t-5790fb31bbb75aad31957600e7368aa40bc0407d5db5e8d3cadc90f32337d2313 |
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| cites | cdi_FETCH-LOGICAL-a408t-5790fb31bbb75aad31957600e7368aa40bc0407d5db5e8d3cadc90f32337d2313 |
| container_end_page | 671 |
| container_issue | 5 |
| container_start_page | 664 |
| container_title | Journal of medicinal chemistry |
| container_volume | 44 |
| creator | Xie, Lan Takeuchi, Yasuo Cosentino, L. Mark McPhail, Andrew T Lee, Kuo-Hsiung |
| description | 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. |
| doi_str_mv | 10.1021/jm000070g |
| format | article |
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Synthesis and Anti-HIV Activity of Disubstituted (3‘R,4‘R)-3‘,4‘-Di-O-(S)-camphanoyl-(+)-cis-khellactone Analogues</title><source>American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list)</source><creator>Xie, Lan ; Takeuchi, Yasuo ; Cosentino, L. Mark ; McPhail, Andrew T ; Lee, Kuo-Hsiung</creator><creatorcontrib>Xie, Lan ; Takeuchi, Yasuo ; Cosentino, L. Mark ; McPhail, Andrew T ; Lee, Kuo-Hsiung</creatorcontrib><description>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.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm000070g</identifier><identifier>PMID: 11262077</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Anti-HIV Agents - chemical synthesis ; Anti-HIV Agents - chemistry ; Anti-HIV Agents - pharmacology ; Antibiotics. Antiinfectious agents. 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Mark</creatorcontrib><creatorcontrib>McPhail, Andrew T</creatorcontrib><creatorcontrib>Lee, Kuo-Hsiung</creatorcontrib><title>Anti-AIDS Agents. 42. Synthesis and Anti-HIV Activity of Disubstituted (3‘R,4‘R)-3‘,4‘-Di-O-(S)-camphanoyl-(+)-cis-khellactone Analogues</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>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.</description><subject>Anti-HIV Agents - chemical synthesis</subject><subject>Anti-HIV Agents - chemistry</subject><subject>Anti-HIV Agents - pharmacology</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Biological and medical sciences</subject><subject>Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis</subject><subject>Bridged Bicyclo Compounds, Heterocyclic - chemistry</subject><subject>Bridged Bicyclo Compounds, Heterocyclic - pharmacology</subject><subject>Cell Line</subject><subject>Coumarins - chemical synthesis</subject><subject>Coumarins - chemistry</subject><subject>Coumarins - pharmacology</subject><subject>Crystallography, X-Ray</subject><subject>HIV-1 - drug effects</subject><subject>Humans</subject><subject>Inhibitory Concentration 50</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Structure-Activity Relationship</subject><subject>T-Lymphocytes - cytology</subject><subject>T-Lymphocytes - virology</subject><subject>Virus Replication</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><recordid>eNptkM1uEzEUhS1ERUNhwQsgS6goEXXwz3g8sxw1lKaKVCCFreXxeBKn8xPGHkR2PALLPh9PgqeJwgYvbF_7u-ceHQBeETwlmJL3mxqHJfDqCRgRTjGKEhw9BSOMKUU0puwUPHduExhGKHsGTgkJr1iIEfidNd6ibD5bwmxlGu-mMKJTuNw1fm2cdVA1BXxkruffYKa9_WH9DrYlnFnX585b33tTwDH78-vhy0U07BM0FI93NLPoFo2XE6RVvV2rpt1VaPwulNah-7WpKqV925gwQlXtqjfuBTgpVeXMy8N5Br5efbi7vEaL24_zy2yBVIQTj7hIcZkzkue54EoVjKRcxBgbweJEBSbXOMKi4EXOTVIwrQodOhhlTBSUEXYG3u51t137Pcz1srZOD4Ya0_ZOkoQzztM0gJM9qLvWuc6UctvZWnU7SbAc4pfH-AP7-iDa57Up_pGHvAPw5gAop1VVdqoJSRy5NMjwwRvaU9Z58_P4q7p7GQsmuLz7tJRY0JvP8VUiF4E_3_NKO7lp-y6E6f5j7y-InacR</recordid><startdate>20010301</startdate><enddate>20010301</enddate><creator>Xie, Lan</creator><creator>Takeuchi, Yasuo</creator><creator>Cosentino, L. Mark</creator><creator>McPhail, Andrew T</creator><creator>Lee, Kuo-Hsiung</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7U9</scope><scope>H94</scope></search><sort><creationdate>20010301</creationdate><title>Anti-AIDS Agents. 42. Synthesis and Anti-HIV Activity of Disubstituted (3‘R,4‘R)-3‘,4‘-Di-O-(S)-camphanoyl-(+)-cis-khellactone Analogues</title><author>Xie, Lan ; Takeuchi, Yasuo ; Cosentino, L. Mark ; McPhail, Andrew T ; Lee, Kuo-Hsiung</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a408t-5790fb31bbb75aad31957600e7368aa40bc0407d5db5e8d3cadc90f32337d2313</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Anti-HIV Agents - chemical synthesis</topic><topic>Anti-HIV Agents - chemistry</topic><topic>Anti-HIV Agents - pharmacology</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antiviral agents</topic><topic>Biological and medical sciences</topic><topic>Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis</topic><topic>Bridged Bicyclo Compounds, Heterocyclic - chemistry</topic><topic>Bridged Bicyclo Compounds, Heterocyclic - pharmacology</topic><topic>Cell Line</topic><topic>Coumarins - chemical synthesis</topic><topic>Coumarins - chemistry</topic><topic>Coumarins - pharmacology</topic><topic>Crystallography, X-Ray</topic><topic>HIV-1 - drug effects</topic><topic>Humans</topic><topic>Inhibitory Concentration 50</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Structure-Activity Relationship</topic><topic>T-Lymphocytes - cytology</topic><topic>T-Lymphocytes - virology</topic><topic>Virus Replication</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Xie, Lan</creatorcontrib><creatorcontrib>Takeuchi, Yasuo</creatorcontrib><creatorcontrib>Cosentino, L. 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Synthesis and Anti-HIV Activity of Disubstituted (3‘R,4‘R)-3‘,4‘-Di-O-(S)-camphanoyl-(+)-cis-khellactone Analogues</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2001-03-01</date><risdate>2001</risdate><volume>44</volume><issue>5</issue><spage>664</spage><epage>671</epage><pages>664-671</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><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.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>11262077</pmid><doi>10.1021/jm000070g</doi><tpages>8</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2001-03, Vol.44 (5), p.664-671 |
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| source | American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list) |
| subjects | Anti-HIV Agents - chemical synthesis Anti-HIV Agents - chemistry Anti-HIV Agents - pharmacology Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Biological and medical sciences Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis Bridged Bicyclo Compounds, Heterocyclic - chemistry Bridged Bicyclo Compounds, Heterocyclic - pharmacology Cell Line Coumarins - chemical synthesis Coumarins - chemistry Coumarins - pharmacology Crystallography, X-Ray HIV-1 - drug effects Humans Inhibitory Concentration 50 Medical sciences Pharmacology. Drug treatments Structure-Activity Relationship T-Lymphocytes - cytology T-Lymphocytes - virology Virus Replication |
| title | Anti-AIDS Agents. 42. Synthesis and Anti-HIV Activity of Disubstituted (3‘R,4‘R)-3‘,4‘-Di-O-(S)-camphanoyl-(+)-cis-khellactone Analogues |
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