1-(2-Deoxy-2-fluoro-.beta.-D-arabinofuranosyl)-5-ethyluracil. A highly selective antiherpes simplex agent
The protected nucleoside 1-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-beta-D-arabinofuranosyl)-5-ethylura cil (10) was prepared by condensation of 3,5-dibenzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranosyl bromide (9) with 2,4-bis-O-(trimethylsilyl)-5-ethyluracil (8). The ratio in this coupling reaction has be...
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Veröffentlicht in: | Journal of medicinal chemistry 1987-05, Vol.30 (5), p.867-871 |
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creator | Mansuri, Muzammil M Ghazzouli, Ismail Chen, Ming S Howell, Henry G Brodfuehrer, Paul R Benigni, Daniel A Martin, John C |
description | The protected nucleoside 1-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-beta-D-arabinofuranosyl)-5-ethylura cil (10) was prepared by condensation of 3,5-dibenzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranosyl bromide (9) with 2,4-bis-O-(trimethylsilyl)-5-ethyluracil (8). The ratio in this coupling reaction has been raised to 17:1 in favor of the desired beta-anomer. Deprotection by aminolysis gave 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-ethyluracil (FEAU, 1) in 67% isolated yield from the bromo sugar 9. In vitro data show that FEAU has activity against herpes simplex virus types 1 and 2 comparable to that of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-methyluracil (FMAU, 2), 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouracil (FIAU, 3), and acyclovir (ACV, 12). The cellular toxicity of FEAU was found to be much lower than that of the other nucleoside analogues. Biochemical experiments indicate that FEAU has similar affinity toward thymidine kinases encoded by HSV 1 and 2 and a much lower affinity for cellular thymidine kinase than thymidine. The in vivo antiviral effects of FEAU, FMAU, FIAU, and ACV were evaluated against herpes infection in a systemic mouse encephalitis model and a cutaneous guinea pig model. While FEAU showed activity comparable to that of ACV in the systemic infection model, it was superior in the cutaneous herpes infection model. |
doi_str_mv | 10.1021/jm00388a021 |
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A highly selective antiherpes simplex agent</title><source>ACS Publications</source><source>MEDLINE</source><creator>Mansuri, Muzammil M ; Ghazzouli, Ismail ; Chen, Ming S ; Howell, Henry G ; Brodfuehrer, Paul R ; Benigni, Daniel A ; Martin, John C</creator><creatorcontrib>Mansuri, Muzammil M ; Ghazzouli, Ismail ; Chen, Ming S ; Howell, Henry G ; Brodfuehrer, Paul R ; Benigni, Daniel A ; Martin, John C</creatorcontrib><description>The protected nucleoside 1-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-beta-D-arabinofuranosyl)-5-ethylura cil (10) was prepared by condensation of 3,5-dibenzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranosyl bromide (9) with 2,4-bis-O-(trimethylsilyl)-5-ethyluracil (8). The ratio in this coupling reaction has been raised to 17:1 in favor of the desired beta-anomer. Deprotection by aminolysis gave 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-ethyluracil (FEAU, 1) in 67% isolated yield from the bromo sugar 9. In vitro data show that FEAU has activity against herpes simplex virus types 1 and 2 comparable to that of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-methyluracil (FMAU, 2), 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouracil (FIAU, 3), and acyclovir (ACV, 12). The cellular toxicity of FEAU was found to be much lower than that of the other nucleoside analogues. Biochemical experiments indicate that FEAU has similar affinity toward thymidine kinases encoded by HSV 1 and 2 and a much lower affinity for cellular thymidine kinase than thymidine. The in vivo antiviral effects of FEAU, FMAU, FIAU, and ACV were evaluated against herpes infection in a systemic mouse encephalitis model and a cutaneous guinea pig model. While FEAU showed activity comparable to that of ACV in the systemic infection model, it was superior in the cutaneous herpes infection model.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00388a021</identifier><identifier>PMID: 3033244</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Acyclovir - pharmacology ; Acyclovir - therapeutic use ; Animals ; Arabinofuranosyluracil - analogs & derivatives ; Arabinofuranosyluracil - chemical synthesis ; Arabinofuranosyluracil - pharmacology ; Arabinofuranosyluracil - therapeutic use ; Carbohydrates. Nucleosides and nucleotides ; Cell Line ; Chemical Phenomena ; Chemistry ; Encephalitis - drug therapy ; Encephalitis - etiology ; Exact sciences and technology ; Female ; Guinea Pigs ; Herpes Simplex - drug therapy ; Mice ; Nucleosides, nucleotides and oligonucleotides ; Organic chemistry ; Preparations and properties ; Simplexvirus - drug effects ; Skin Diseases - drug therapy ; Skin Diseases - etiology ; Thymidine Kinase - metabolism ; Uridine - analogs & derivatives</subject><ispartof>Journal of medicinal chemistry, 1987-05, Vol.30 (5), p.867-871</ispartof><rights>1987 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a315t-7bd95fd3ceabaca3a6b73fa01269a8c9fb5dce39fc0deb0881b433dcc8b37ae43</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm00388a021$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00388a021$$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=8151355$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/3033244$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mansuri, Muzammil M</creatorcontrib><creatorcontrib>Ghazzouli, Ismail</creatorcontrib><creatorcontrib>Chen, Ming S</creatorcontrib><creatorcontrib>Howell, Henry G</creatorcontrib><creatorcontrib>Brodfuehrer, Paul R</creatorcontrib><creatorcontrib>Benigni, Daniel A</creatorcontrib><creatorcontrib>Martin, John C</creatorcontrib><title>1-(2-Deoxy-2-fluoro-.beta.-D-arabinofuranosyl)-5-ethyluracil. A highly selective antiherpes simplex agent</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The protected nucleoside 1-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-beta-D-arabinofuranosyl)-5-ethylura cil (10) was prepared by condensation of 3,5-dibenzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranosyl bromide (9) with 2,4-bis-O-(trimethylsilyl)-5-ethyluracil (8). The ratio in this coupling reaction has been raised to 17:1 in favor of the desired beta-anomer. Deprotection by aminolysis gave 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-ethyluracil (FEAU, 1) in 67% isolated yield from the bromo sugar 9. In vitro data show that FEAU has activity against herpes simplex virus types 1 and 2 comparable to that of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-methyluracil (FMAU, 2), 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouracil (FIAU, 3), and acyclovir (ACV, 12). The cellular toxicity of FEAU was found to be much lower than that of the other nucleoside analogues. Biochemical experiments indicate that FEAU has similar affinity toward thymidine kinases encoded by HSV 1 and 2 and a much lower affinity for cellular thymidine kinase than thymidine. The in vivo antiviral effects of FEAU, FMAU, FIAU, and ACV were evaluated against herpes infection in a systemic mouse encephalitis model and a cutaneous guinea pig model. While FEAU showed activity comparable to that of ACV in the systemic infection model, it was superior in the cutaneous herpes infection model.</description><subject>Acyclovir - pharmacology</subject><subject>Acyclovir - therapeutic use</subject><subject>Animals</subject><subject>Arabinofuranosyluracil - analogs & derivatives</subject><subject>Arabinofuranosyluracil - chemical synthesis</subject><subject>Arabinofuranosyluracil - pharmacology</subject><subject>Arabinofuranosyluracil - therapeutic use</subject><subject>Carbohydrates. Nucleosides and nucleotides</subject><subject>Cell Line</subject><subject>Chemical Phenomena</subject><subject>Chemistry</subject><subject>Encephalitis - drug therapy</subject><subject>Encephalitis - etiology</subject><subject>Exact sciences and technology</subject><subject>Female</subject><subject>Guinea Pigs</subject><subject>Herpes Simplex - drug therapy</subject><subject>Mice</subject><subject>Nucleosides, nucleotides and oligonucleotides</subject><subject>Organic chemistry</subject><subject>Preparations and properties</subject><subject>Simplexvirus - drug effects</subject><subject>Skin Diseases - drug therapy</subject><subject>Skin Diseases - etiology</subject><subject>Thymidine Kinase - metabolism</subject><subject>Uridine - analogs & derivatives</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1987</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0E1rGzEQBmARWhInzannwB4CSSly9bHyro_BadoEQwN16VGMtKNYjrxrpHXw_vuq2JgeetKg92EYXkI-cjbmTPAvqzVjsq4hzydkxJVgtKxZ-Y6MGBOCiomQZ-Q8pRXLjgt5Sk4lk1KU5Yh4Tm8FvcduN1BBXdh2saNjgz2M6T2FCMa3ndtGaLs0hE9UUeyXQ8gf1odxcVcs_csyDEXCgLb3b1hA2_slxg2mIvn1JuCugBds-w_kvYOQ8PLwXpBfD18Xs-90_uPb4-xuTkFy1dPKNFPlGmkRDFiQMDGVdMC4mEyhtlNnVGNRTp1lDRpW19yUUjbW1kZWgKW8IJ_3e23sUoro9Cb6NcRBc6b_9qX_6Svrq73ebM0am6M9FJTz60MOyUJwuQjr05HVXHGpVGZ0z3zqcXeMIb7qSSUrpRfPPzVfPMx_Pz_NNMv-Zu_BJr3qtrHNlfz3wD8GLY7y</recordid><startdate>19870501</startdate><enddate>19870501</enddate><creator>Mansuri, Muzammil M</creator><creator>Ghazzouli, Ismail</creator><creator>Chen, Ming S</creator><creator>Howell, Henry G</creator><creator>Brodfuehrer, Paul R</creator><creator>Benigni, Daniel A</creator><creator>Martin, John C</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></search><sort><creationdate>19870501</creationdate><title>1-(2-Deoxy-2-fluoro-.beta.-D-arabinofuranosyl)-5-ethyluracil. A highly selective antiherpes simplex agent</title><author>Mansuri, Muzammil M ; Ghazzouli, Ismail ; Chen, Ming S ; Howell, Henry G ; Brodfuehrer, Paul R ; Benigni, Daniel A ; Martin, John C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a315t-7bd95fd3ceabaca3a6b73fa01269a8c9fb5dce39fc0deb0881b433dcc8b37ae43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1987</creationdate><topic>Acyclovir - pharmacology</topic><topic>Acyclovir - therapeutic use</topic><topic>Animals</topic><topic>Arabinofuranosyluracil - analogs & derivatives</topic><topic>Arabinofuranosyluracil - chemical synthesis</topic><topic>Arabinofuranosyluracil - pharmacology</topic><topic>Arabinofuranosyluracil - therapeutic use</topic><topic>Carbohydrates. Nucleosides and nucleotides</topic><topic>Cell Line</topic><topic>Chemical Phenomena</topic><topic>Chemistry</topic><topic>Encephalitis - drug therapy</topic><topic>Encephalitis - etiology</topic><topic>Exact sciences and technology</topic><topic>Female</topic><topic>Guinea Pigs</topic><topic>Herpes Simplex - drug therapy</topic><topic>Mice</topic><topic>Nucleosides, nucleotides and oligonucleotides</topic><topic>Organic chemistry</topic><topic>Preparations and properties</topic><topic>Simplexvirus - drug effects</topic><topic>Skin Diseases - drug therapy</topic><topic>Skin Diseases - etiology</topic><topic>Thymidine Kinase - metabolism</topic><topic>Uridine - analogs & derivatives</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mansuri, Muzammil M</creatorcontrib><creatorcontrib>Ghazzouli, Ismail</creatorcontrib><creatorcontrib>Chen, Ming S</creatorcontrib><creatorcontrib>Howell, Henry G</creatorcontrib><creatorcontrib>Brodfuehrer, Paul R</creatorcontrib><creatorcontrib>Benigni, Daniel A</creatorcontrib><creatorcontrib>Martin, John C</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><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mansuri, Muzammil M</au><au>Ghazzouli, Ismail</au><au>Chen, Ming S</au><au>Howell, Henry G</au><au>Brodfuehrer, Paul R</au><au>Benigni, Daniel A</au><au>Martin, John C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>1-(2-Deoxy-2-fluoro-.beta.-D-arabinofuranosyl)-5-ethyluracil. A highly selective antiherpes simplex agent</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1987-05-01</date><risdate>1987</risdate><volume>30</volume><issue>5</issue><spage>867</spage><epage>871</epage><pages>867-871</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>The protected nucleoside 1-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-beta-D-arabinofuranosyl)-5-ethylura cil (10) was prepared by condensation of 3,5-dibenzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranosyl bromide (9) with 2,4-bis-O-(trimethylsilyl)-5-ethyluracil (8). The ratio in this coupling reaction has been raised to 17:1 in favor of the desired beta-anomer. Deprotection by aminolysis gave 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-ethyluracil (FEAU, 1) in 67% isolated yield from the bromo sugar 9. In vitro data show that FEAU has activity against herpes simplex virus types 1 and 2 comparable to that of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-methyluracil (FMAU, 2), 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouracil (FIAU, 3), and acyclovir (ACV, 12). The cellular toxicity of FEAU was found to be much lower than that of the other nucleoside analogues. Biochemical experiments indicate that FEAU has similar affinity toward thymidine kinases encoded by HSV 1 and 2 and a much lower affinity for cellular thymidine kinase than thymidine. The in vivo antiviral effects of FEAU, FMAU, FIAU, and ACV were evaluated against herpes infection in a systemic mouse encephalitis model and a cutaneous guinea pig model. While FEAU showed activity comparable to that of ACV in the systemic infection model, it was superior in the cutaneous herpes infection model.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>3033244</pmid><doi>10.1021/jm00388a021</doi><tpages>5</tpages></addata></record> |
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subjects | Acyclovir - pharmacology Acyclovir - therapeutic use Animals Arabinofuranosyluracil - analogs & derivatives Arabinofuranosyluracil - chemical synthesis Arabinofuranosyluracil - pharmacology Arabinofuranosyluracil - therapeutic use Carbohydrates. Nucleosides and nucleotides Cell Line Chemical Phenomena Chemistry Encephalitis - drug therapy Encephalitis - etiology Exact sciences and technology Female Guinea Pigs Herpes Simplex - drug therapy Mice Nucleosides, nucleotides and oligonucleotides Organic chemistry Preparations and properties Simplexvirus - drug effects Skin Diseases - drug therapy Skin Diseases - etiology Thymidine Kinase - metabolism Uridine - analogs & derivatives |
title | 1-(2-Deoxy-2-fluoro-.beta.-D-arabinofuranosyl)-5-ethyluracil. A highly selective antiherpes simplex agent |
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