Synthesis and Antiviral Activity of Novel Anti-VZV 5-Substituted Uracil Nucleosides with a Cyclopropane Sugar Moiety
A series of 5-substituted uracil nucleoside derivatives with a 1(1‘S,2‘R)-[1‘,2‘-bis(hydroxymethyl)cyclopropyl]methyl group as an acyclosugar moiety were synthesized and evaluated for their anti-herpetic activities. Among the compounds synthesized, (E)-5-halovinyluracil derivatives showed superior a...
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| Veröffentlicht in: | Journal of medicinal chemistry 2000-01, Vol.43 (2), p.278-282 |
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| creator | Onishi, Tomoyuki Mukai, Chika Nakagawa, Ryusuke Sekiyama, Takaaki Aoki, Miho Suzuki, Katsuya Nakazawa, Harumi Ono, Nobukazu Ohmura, Yuko Iwayama, Satoshi Okunishi, Masahiko Tsuji, Takashi |
| description | A series of 5-substituted uracil nucleoside derivatives with a 1(1‘S,2‘R)-[1‘,2‘-bis(hydroxymethyl)cyclopropyl]methyl group as an acyclosugar moiety were synthesized and evaluated for their anti-herpetic activities. Among the compounds synthesized, (E)-5-halovinyluracil derivatives showed superior anti-varicella zoster virus (VZV) activity over acyclovir (ACV) but were less potent than ACV against herpes symplex virus type-1 (HSV-1). IC50 values for the VZV Kawaguchi strain were 0.027 for Br, 0.070 for Cl, and 0.054 μg/mL for I derivatives and 3.4 μg/mL for ACV. The most potent compound, (1‘S,2‘R)-5-[(E)-2-bromoethenyl]-1-[[1‘,2‘-bis(hydroxymethyl)cycloprop-1‘-yl]methyl]-2,4-(1H,3H)-pyrimidinedione (3a), was 40−60-fold more potent than ACV against clinical isolates of VZV. It showed good oral bioavailability in rats (68.5%) and, unlike (E)-5-(2-bromovinyl)-1-β-d-arabinofuranosyluracil (BVaraU), did not result in the release of (E)-5-(2-bromovinyl)uracil (BVU), a potent dihydropyrimidine dehydrogenase inhibitor, in plasma after oral administration. |
| doi_str_mv | 10.1021/jm9904194 |
| format | Article |
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Among the compounds synthesized, (E)-5-halovinyluracil derivatives showed superior anti-varicella zoster virus (VZV) activity over acyclovir (ACV) but were less potent than ACV against herpes symplex virus type-1 (HSV-1). IC50 values for the VZV Kawaguchi strain were 0.027 for Br, 0.070 for Cl, and 0.054 μg/mL for I derivatives and 3.4 μg/mL for ACV. The most potent compound, (1‘S,2‘R)-5-[(E)-2-bromoethenyl]-1-[[1‘,2‘-bis(hydroxymethyl)cycloprop-1‘-yl]methyl]-2,4-(1H,3H)-pyrimidinedione (3a), was 40−60-fold more potent than ACV against clinical isolates of VZV. It showed good oral bioavailability in rats (68.5%) and, unlike (E)-5-(2-bromovinyl)-1-β-d-arabinofuranosyluracil (BVaraU), did not result in the release of (E)-5-(2-bromovinyl)uracil (BVU), a potent dihydropyrimidine dehydrogenase inhibitor, in plasma after oral administration.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm9904194</identifier><identifier>PMID: 10649983</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>acyclovir ; Animals ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Antiviral Agents - chemistry ; Antiviral Agents - pharmacokinetics ; Antiviral Agents - pharmacology ; Biological and medical sciences ; Chromatography, High Pressure Liquid ; Cyclopropanes - chemistry ; Herpesvirus 1, Human - drug effects ; Herpesvirus 3, Human - drug effects ; Magnetic Resonance Spectroscopy ; Male ; Mass Spectrometry ; Medical sciences ; Pharmacology. Drug treatments ; Rats ; Rats, Sprague-Dawley ; Spectrophotometry, Ultraviolet ; Uracil - chemistry ; Uracil - pharmacokinetics ; Uracil - pharmacology ; uracil nucleosides ; Varicella-zoster virus</subject><ispartof>Journal of medicinal chemistry, 2000-01, Vol.43 (2), p.278-282</ispartof><rights>Copyright © 2000 American Chemical Society</rights><rights>2001 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a409t-2eded9c40403e1c5e44422da0b4e9ab77edb6678dce321a0db8160916214693c3</citedby><cites>FETCH-LOGICAL-a409t-2eded9c40403e1c5e44422da0b4e9ab77edb6678dce321a0db8160916214693c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm9904194$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm9904194$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1043382$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10649983$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Onishi, Tomoyuki</creatorcontrib><creatorcontrib>Mukai, Chika</creatorcontrib><creatorcontrib>Nakagawa, Ryusuke</creatorcontrib><creatorcontrib>Sekiyama, Takaaki</creatorcontrib><creatorcontrib>Aoki, Miho</creatorcontrib><creatorcontrib>Suzuki, Katsuya</creatorcontrib><creatorcontrib>Nakazawa, Harumi</creatorcontrib><creatorcontrib>Ono, Nobukazu</creatorcontrib><creatorcontrib>Ohmura, Yuko</creatorcontrib><creatorcontrib>Iwayama, Satoshi</creatorcontrib><creatorcontrib>Okunishi, Masahiko</creatorcontrib><creatorcontrib>Tsuji, Takashi</creatorcontrib><title>Synthesis and Antiviral Activity of Novel Anti-VZV 5-Substituted Uracil Nucleosides with a Cyclopropane Sugar Moiety</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of 5-substituted uracil nucleoside derivatives with a 1(1‘S,2‘R)-[1‘,2‘-bis(hydroxymethyl)cyclopropyl]methyl group as an acyclosugar moiety were synthesized and evaluated for their anti-herpetic activities. Among the compounds synthesized, (E)-5-halovinyluracil derivatives showed superior anti-varicella zoster virus (VZV) activity over acyclovir (ACV) but were less potent than ACV against herpes symplex virus type-1 (HSV-1). IC50 values for the VZV Kawaguchi strain were 0.027 for Br, 0.070 for Cl, and 0.054 μg/mL for I derivatives and 3.4 μg/mL for ACV. The most potent compound, (1‘S,2‘R)-5-[(E)-2-bromoethenyl]-1-[[1‘,2‘-bis(hydroxymethyl)cycloprop-1‘-yl]methyl]-2,4-(1H,3H)-pyrimidinedione (3a), was 40−60-fold more potent than ACV against clinical isolates of VZV. It showed good oral bioavailability in rats (68.5%) and, unlike (E)-5-(2-bromovinyl)-1-β-d-arabinofuranosyluracil (BVaraU), did not result in the release of (E)-5-(2-bromovinyl)uracil (BVU), a potent dihydropyrimidine dehydrogenase inhibitor, in plasma after oral administration.</description><subject>acyclovir</subject><subject>Animals</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Antiviral Agents - chemistry</subject><subject>Antiviral Agents - pharmacokinetics</subject><subject>Antiviral Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Cyclopropanes - chemistry</subject><subject>Herpesvirus 1, Human - drug effects</subject><subject>Herpesvirus 3, Human - drug effects</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Male</subject><subject>Mass Spectrometry</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Spectrophotometry, Ultraviolet</subject><subject>Uracil - chemistry</subject><subject>Uracil - pharmacokinetics</subject><subject>Uracil - pharmacology</subject><subject>uracil nucleosides</subject><subject>Varicella-zoster virus</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0UuP0zAQB3ALgdhSOPAFkA-AxCEwfuThY1XxksoC6m5BXCzHnrIuaVJsZyHfnpRUqz0g4YstzU-jv2cIeczgJQPOXu32SoFkSt4hM5ZzyGQF8i6ZAXCe8YKLM_Igxh0ACMbFfXLGoJBKVWJG0npo0xVGH6lpHV20yV_7YBq6sMdXGmi3pefdNTZ_a9nm24bm2bqvY_KpT-joZTDWN_S8tw120TuM9JdPV9TQ5WCb7hC6g2mRrvvvJtAPncc0PCT3tqaJ-Oh0z8nlm9cXy3fZ6uPb98vFKjMSVMo4OnTKSpAgkNkcpZScOwO1RGXqskRXF0VZOYuCMwOurlgBihWcyUIJK-bk-dR3DPGzx5j03keLTTMG6vqoS6jyknP4L2RlAVyMZ05eTNCGLsaAW30Ifm_CoBno4y70zS5G--TUtK_36G7JafgjeHoCJlrTbINprY-3nBSi4iPLJuZjwt83ZRN-6KIUZa4vPq31aim-fN3AZ338zLPJGxv1rutDO874H_n-ABhrq6g</recordid><startdate>20000127</startdate><enddate>20000127</enddate><creator>Onishi, Tomoyuki</creator><creator>Mukai, Chika</creator><creator>Nakagawa, Ryusuke</creator><creator>Sekiyama, Takaaki</creator><creator>Aoki, Miho</creator><creator>Suzuki, Katsuya</creator><creator>Nakazawa, Harumi</creator><creator>Ono, Nobukazu</creator><creator>Ohmura, Yuko</creator><creator>Iwayama, Satoshi</creator><creator>Okunishi, Masahiko</creator><creator>Tsuji, Takashi</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>7T7</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20000127</creationdate><title>Synthesis and Antiviral Activity of Novel Anti-VZV 5-Substituted Uracil Nucleosides with a Cyclopropane Sugar Moiety</title><author>Onishi, Tomoyuki ; Mukai, Chika ; Nakagawa, Ryusuke ; Sekiyama, Takaaki ; Aoki, Miho ; Suzuki, Katsuya ; Nakazawa, Harumi ; Ono, Nobukazu ; Ohmura, Yuko ; Iwayama, Satoshi ; Okunishi, Masahiko ; Tsuji, Takashi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a409t-2eded9c40403e1c5e44422da0b4e9ab77edb6678dce321a0db8160916214693c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>acyclovir</topic><topic>Animals</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antiviral agents</topic><topic>Antiviral Agents - chemistry</topic><topic>Antiviral Agents - pharmacokinetics</topic><topic>Antiviral Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Cyclopropanes - chemistry</topic><topic>Herpesvirus 1, Human - drug effects</topic><topic>Herpesvirus 3, Human - drug effects</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Male</topic><topic>Mass Spectrometry</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Spectrophotometry, Ultraviolet</topic><topic>Uracil - chemistry</topic><topic>Uracil - pharmacokinetics</topic><topic>Uracil - pharmacology</topic><topic>uracil nucleosides</topic><topic>Varicella-zoster virus</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Onishi, Tomoyuki</creatorcontrib><creatorcontrib>Mukai, Chika</creatorcontrib><creatorcontrib>Nakagawa, Ryusuke</creatorcontrib><creatorcontrib>Sekiyama, Takaaki</creatorcontrib><creatorcontrib>Aoki, Miho</creatorcontrib><creatorcontrib>Suzuki, Katsuya</creatorcontrib><creatorcontrib>Nakazawa, Harumi</creatorcontrib><creatorcontrib>Ono, Nobukazu</creatorcontrib><creatorcontrib>Ohmura, Yuko</creatorcontrib><creatorcontrib>Iwayama, Satoshi</creatorcontrib><creatorcontrib>Okunishi, Masahiko</creatorcontrib><creatorcontrib>Tsuji, Takashi</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Onishi, Tomoyuki</au><au>Mukai, Chika</au><au>Nakagawa, Ryusuke</au><au>Sekiyama, Takaaki</au><au>Aoki, Miho</au><au>Suzuki, Katsuya</au><au>Nakazawa, Harumi</au><au>Ono, Nobukazu</au><au>Ohmura, Yuko</au><au>Iwayama, Satoshi</au><au>Okunishi, Masahiko</au><au>Tsuji, Takashi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and Antiviral Activity of Novel Anti-VZV 5-Substituted Uracil Nucleosides with a Cyclopropane Sugar Moiety</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2000-01-27</date><risdate>2000</risdate><volume>43</volume><issue>2</issue><spage>278</spage><epage>282</epage><pages>278-282</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A series of 5-substituted uracil nucleoside derivatives with a 1(1‘S,2‘R)-[1‘,2‘-bis(hydroxymethyl)cyclopropyl]methyl group as an acyclosugar moiety were synthesized and evaluated for their anti-herpetic activities. Among the compounds synthesized, (E)-5-halovinyluracil derivatives showed superior anti-varicella zoster virus (VZV) activity over acyclovir (ACV) but were less potent than ACV against herpes symplex virus type-1 (HSV-1). IC50 values for the VZV Kawaguchi strain were 0.027 for Br, 0.070 for Cl, and 0.054 μg/mL for I derivatives and 3.4 μg/mL for ACV. The most potent compound, (1‘S,2‘R)-5-[(E)-2-bromoethenyl]-1-[[1‘,2‘-bis(hydroxymethyl)cycloprop-1‘-yl]methyl]-2,4-(1H,3H)-pyrimidinedione (3a), was 40−60-fold more potent than ACV against clinical isolates of VZV. It showed good oral bioavailability in rats (68.5%) and, unlike (E)-5-(2-bromovinyl)-1-β-d-arabinofuranosyluracil (BVaraU), did not result in the release of (E)-5-(2-bromovinyl)uracil (BVU), a potent dihydropyrimidine dehydrogenase inhibitor, in plasma after oral administration.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>10649983</pmid><doi>10.1021/jm9904194</doi><tpages>5</tpages></addata></record> |
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| subjects | acyclovir Animals Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Antiviral Agents - chemistry Antiviral Agents - pharmacokinetics Antiviral Agents - pharmacology Biological and medical sciences Chromatography, High Pressure Liquid Cyclopropanes - chemistry Herpesvirus 1, Human - drug effects Herpesvirus 3, Human - drug effects Magnetic Resonance Spectroscopy Male Mass Spectrometry Medical sciences Pharmacology. Drug treatments Rats Rats, Sprague-Dawley Spectrophotometry, Ultraviolet Uracil - chemistry Uracil - pharmacokinetics Uracil - pharmacology uracil nucleosides Varicella-zoster virus |
| title | Synthesis and Antiviral Activity of Novel Anti-VZV 5-Substituted Uracil Nucleosides with a Cyclopropane Sugar Moiety |
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