Evaluation of 2′-α-fluorine modified nucleoside phosphonates as potential inhibitors of HCV polymerase
Ribonucleoside phosphonate analogues containing 2′-α-fluoro modifications were synthesized and their potency evaluated against HCV RNA polymerase. Ribonucleoside phosphonate analogues containing 2′-α-fluoro modifications were synthesized and their potency evaluated against HCV RNA polymerase. The di...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2013-06, Vol.23 (11), p.3354-3357 |
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| container_issue | 11 |
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| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 23 |
| creator | Parrish, Jay P. Lee, Sharon K. Boojamra, Constantine G. Hui, Hon Babusis, Darius Brown, Brandon Shih, I-hung Feng, Joy Y. Ray, Adrian S. Mackman, Richard L. |
| description | Ribonucleoside phosphonate analogues containing 2′-α-fluoro modifications were synthesized and their potency evaluated against HCV RNA polymerase.
Ribonucleoside phosphonate analogues containing 2′-α-fluoro modifications were synthesized and their potency evaluated against HCV RNA polymerase. The diphosphophosphonate (triphosphate equivalent) adenine and cytidine analogues displayed potent inhibition of the HCV polymerase in the range of 1.9–2.1μM, but only modest cell-based activity in the HCV replicon. Pro-drugs of the parent nucleoside phosphonates improved the cell-based activity. |
| doi_str_mv | 10.1016/j.bmcl.2013.03.095 |
| format | Article |
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Ribonucleoside phosphonate analogues containing 2′-α-fluoro modifications were synthesized and their potency evaluated against HCV RNA polymerase. The diphosphophosphonate (triphosphate equivalent) adenine and cytidine analogues displayed potent inhibition of the HCV polymerase in the range of 1.9–2.1μM, but only modest cell-based activity in the HCV replicon. Pro-drugs of the parent nucleoside phosphonates improved the cell-based activity.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2013.03.095</identifier><identifier>PMID: 23639543</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>adenine ; Antiviral Agents - chemical synthesis ; Antiviral Agents - chemistry ; Antiviral Agents - pharmacology ; Cell Line ; chemistry ; cytidine ; DNA-directed RNA polymerase ; DNA-Directed RNA Polymerases - antagonists & inhibitors ; DNA-Directed RNA Polymerases - metabolism ; Drug Evaluation, Preclinical ; Fluorine - chemistry ; HCV ; HCV NS5b polymerase ; Hepacivirus - enzymology ; Hepatitis C ; Humans ; NS5b ; Nucleosides ; Organophosphonates - chemical synthesis ; Organophosphonates - chemistry ; Organophosphonates - pharmacology ; phosphonates ; Polymerase ; replicon ; Ribonucleosides - chemistry ; Virus Replication - drug effects</subject><ispartof>Bioorganic & medicinal chemistry letters, 2013-06, Vol.23 (11), p.3354-3357</ispartof><rights>2013 Elsevier Ltd</rights><rights>Copyright © 2013 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c380t-91e673f89bfb8c11480f12f6f992d802d5f1a918b23be621e56e560e9819fc873</citedby><cites>FETCH-LOGICAL-c380t-91e673f89bfb8c11480f12f6f992d802d5f1a918b23be621e56e560e9819fc873</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2013.03.095$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,781,785,3551,27929,27930,46000</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23639543$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Parrish, Jay P.</creatorcontrib><creatorcontrib>Lee, Sharon K.</creatorcontrib><creatorcontrib>Boojamra, Constantine G.</creatorcontrib><creatorcontrib>Hui, Hon</creatorcontrib><creatorcontrib>Babusis, Darius</creatorcontrib><creatorcontrib>Brown, Brandon</creatorcontrib><creatorcontrib>Shih, I-hung</creatorcontrib><creatorcontrib>Feng, Joy Y.</creatorcontrib><creatorcontrib>Ray, Adrian S.</creatorcontrib><creatorcontrib>Mackman, Richard L.</creatorcontrib><title>Evaluation of 2′-α-fluorine modified nucleoside phosphonates as potential inhibitors of HCV polymerase</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Ribonucleoside phosphonate analogues containing 2′-α-fluoro modifications were synthesized and their potency evaluated against HCV RNA polymerase.
Ribonucleoside phosphonate analogues containing 2′-α-fluoro modifications were synthesized and their potency evaluated against HCV RNA polymerase. The diphosphophosphonate (triphosphate equivalent) adenine and cytidine analogues displayed potent inhibition of the HCV polymerase in the range of 1.9–2.1μM, but only modest cell-based activity in the HCV replicon. Pro-drugs of the parent nucleoside phosphonates improved the cell-based activity.</description><subject>adenine</subject><subject>Antiviral Agents - chemical synthesis</subject><subject>Antiviral Agents - chemistry</subject><subject>Antiviral Agents - pharmacology</subject><subject>Cell Line</subject><subject>chemistry</subject><subject>cytidine</subject><subject>DNA-directed RNA polymerase</subject><subject>DNA-Directed RNA Polymerases - antagonists & inhibitors</subject><subject>DNA-Directed RNA Polymerases - metabolism</subject><subject>Drug Evaluation, Preclinical</subject><subject>Fluorine - chemistry</subject><subject>HCV</subject><subject>HCV NS5b polymerase</subject><subject>Hepacivirus - enzymology</subject><subject>Hepatitis C</subject><subject>Humans</subject><subject>NS5b</subject><subject>Nucleosides</subject><subject>Organophosphonates - chemical synthesis</subject><subject>Organophosphonates - chemistry</subject><subject>Organophosphonates - pharmacology</subject><subject>phosphonates</subject><subject>Polymerase</subject><subject>replicon</subject><subject>Ribonucleosides - chemistry</subject><subject>Virus Replication - drug effects</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kM1u1DAURi0EokPhBVhAlt1k8PVPakts0KhQpEosoIid5TjX1CMnHuykUne8EjwID8GT4GgKS6TP8sLnftc6hDwHugUK3av9th9d3DIKfEtrtHxANiA60XJB5UOyobqjrdLiywl5UsqeUhBUiMfkhPGOayn4hoSLWxsXO4c0Nck37Pf3n-2vH62PS8phwmZMQ_ABh2ZaXMRUwoDN4SaVeiY7Y2lsaQ5pxmkONjZhugl9mFMua9nl7nN9i3cjZlvwKXnkbSz47P4-JddvLz7tLturD-_e795ctY4rOrcasDvnXune98oBCEU9MN95rdmgKBukB6tB9Yz32DFA2dVQ1Aq0d-qcn5KzY-8hp28LltmMoTiM0U6YlmKASwqSA0BF2RF1OZWS0ZtDDqPNdwaoWRWbvVkVm1WxoTVa1qEX9_1LP-Lwb-Sv0wq8PALeJmO_5lDM9cfaIKt_zqhe974-Elg93AbMpriAk8MhZHSzGVL43w_-APlJmIA</recordid><startdate>20130601</startdate><enddate>20130601</enddate><creator>Parrish, Jay P.</creator><creator>Lee, Sharon K.</creator><creator>Boojamra, Constantine G.</creator><creator>Hui, Hon</creator><creator>Babusis, Darius</creator><creator>Brown, Brandon</creator><creator>Shih, I-hung</creator><creator>Feng, Joy Y.</creator><creator>Ray, Adrian S.</creator><creator>Mackman, Richard L.</creator><general>Elsevier Ltd</general><scope>FBQ</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>7X8</scope></search><sort><creationdate>20130601</creationdate><title>Evaluation of 2′-α-fluorine modified nucleoside phosphonates as potential inhibitors of HCV polymerase</title><author>Parrish, Jay P. ; Lee, Sharon K. ; Boojamra, Constantine G. ; Hui, Hon ; Babusis, Darius ; Brown, Brandon ; Shih, I-hung ; Feng, Joy Y. ; Ray, Adrian S. ; Mackman, Richard L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c380t-91e673f89bfb8c11480f12f6f992d802d5f1a918b23be621e56e560e9819fc873</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>adenine</topic><topic>Antiviral Agents - chemical synthesis</topic><topic>Antiviral Agents - chemistry</topic><topic>Antiviral Agents - pharmacology</topic><topic>Cell Line</topic><topic>chemistry</topic><topic>cytidine</topic><topic>DNA-directed RNA polymerase</topic><topic>DNA-Directed RNA Polymerases - antagonists & inhibitors</topic><topic>DNA-Directed RNA Polymerases - metabolism</topic><topic>Drug Evaluation, Preclinical</topic><topic>Fluorine - chemistry</topic><topic>HCV</topic><topic>HCV NS5b polymerase</topic><topic>Hepacivirus - enzymology</topic><topic>Hepatitis C</topic><topic>Humans</topic><topic>NS5b</topic><topic>Nucleosides</topic><topic>Organophosphonates - chemical synthesis</topic><topic>Organophosphonates - chemistry</topic><topic>Organophosphonates - pharmacology</topic><topic>phosphonates</topic><topic>Polymerase</topic><topic>replicon</topic><topic>Ribonucleosides - chemistry</topic><topic>Virus Replication - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Parrish, Jay P.</creatorcontrib><creatorcontrib>Lee, Sharon K.</creatorcontrib><creatorcontrib>Boojamra, Constantine G.</creatorcontrib><creatorcontrib>Hui, Hon</creatorcontrib><creatorcontrib>Babusis, Darius</creatorcontrib><creatorcontrib>Brown, Brandon</creatorcontrib><creatorcontrib>Shih, I-hung</creatorcontrib><creatorcontrib>Feng, Joy Y.</creatorcontrib><creatorcontrib>Ray, Adrian S.</creatorcontrib><creatorcontrib>Mackman, Richard L.</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Parrish, Jay P.</au><au>Lee, Sharon K.</au><au>Boojamra, Constantine G.</au><au>Hui, Hon</au><au>Babusis, Darius</au><au>Brown, Brandon</au><au>Shih, I-hung</au><au>Feng, Joy Y.</au><au>Ray, Adrian S.</au><au>Mackman, Richard L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Evaluation of 2′-α-fluorine modified nucleoside phosphonates as potential inhibitors of HCV polymerase</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2013-06-01</date><risdate>2013</risdate><volume>23</volume><issue>11</issue><spage>3354</spage><epage>3357</epage><pages>3354-3357</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Ribonucleoside phosphonate analogues containing 2′-α-fluoro modifications were synthesized and their potency evaluated against HCV RNA polymerase.
Ribonucleoside phosphonate analogues containing 2′-α-fluoro modifications were synthesized and their potency evaluated against HCV RNA polymerase. The diphosphophosphonate (triphosphate equivalent) adenine and cytidine analogues displayed potent inhibition of the HCV polymerase in the range of 1.9–2.1μM, but only modest cell-based activity in the HCV replicon. Pro-drugs of the parent nucleoside phosphonates improved the cell-based activity.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>23639543</pmid><doi>10.1016/j.bmcl.2013.03.095</doi><tpages>4</tpages></addata></record> |
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| subjects | adenine Antiviral Agents - chemical synthesis Antiviral Agents - chemistry Antiviral Agents - pharmacology Cell Line chemistry cytidine DNA-directed RNA polymerase DNA-Directed RNA Polymerases - antagonists & inhibitors DNA-Directed RNA Polymerases - metabolism Drug Evaluation, Preclinical Fluorine - chemistry HCV HCV NS5b polymerase Hepacivirus - enzymology Hepatitis C Humans NS5b Nucleosides Organophosphonates - chemical synthesis Organophosphonates - chemistry Organophosphonates - pharmacology phosphonates Polymerase replicon Ribonucleosides - chemistry Virus Replication - drug effects |
| title | Evaluation of 2′-α-fluorine modified nucleoside phosphonates as potential inhibitors of HCV polymerase |
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