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
Hauptverfasser: Mansuri, Muzammil M, Ghazzouli, Ismail, Chen, Ming S, Howell, Henry G, Brodfuehrer, Paul R, Benigni, Daniel A, Martin, John C
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container_end_page 871
container_issue 5
container_start_page 867
container_title Journal of medicinal chemistry
container_volume 30
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 &amp; 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 &amp; 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&amp;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 &amp; 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 &amp; 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 &amp; 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 &amp; 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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ispartof Journal of medicinal chemistry, 1987-05, Vol.30 (5), p.867-871
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recordid cdi_crossref_primary_10_1021_jm00388a021
source ACS Publications; MEDLINE
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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