Synthesis and antiviral properties of novel 7-heterocyclic substituted 7-deaza-adenine nucleoside inhibitors of Hepatitis C NS5B polymerase
Previous investigations in our laboratories resulted in the discovery of a novel series of potent nucleoside inhibitors of Hepatitis C virus (HCV) NS5B polymerase bearing tetracyclic 7-substituted 7-deaza-adenine nucleobases. The planarity of such modified systems was suggested to play a role in the...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2012-08, Vol.20 (15), p.4801-4811 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | Di Francesco, M. Emilia Avolio, Salvatore Pompei, Marco Pesci, Silvia Monteagudo, Edith Pucci, Vincenzo Giuliano, Claudio Fiore, Fabrizio Rowley, Michael Summa, Vincenzo |
| description | Previous investigations in our laboratories resulted in the discovery of a novel series of potent nucleoside inhibitors of Hepatitis C virus (HCV) NS5B polymerase bearing tetracyclic 7-substituted 7-deaza-adenine nucleobases. The planarity of such modified systems was suggested to play a role in the high inhibitory potency observed. This paper describes how we envisaged to maintain the desired planarity of the modified nucleobase by means of an intra-molecular H-bond, engaging a H-bond donor atom on an appropriately substituted 7-heterocyclic residue with the adjacent amino group of the nucleobase. The success of this strategy is reflected by the identification of several novel potent nucleoside inhibitors of HCV NS5B bearing a 7-heterocyclic substituted 7-deaza-adenine nucleobase. Amongst these, the 1,2,4-oxadiazole analog 11 showed high antiviral potency against HCV replication in replicon cells and efficient conversion to the corresponding NTP in vivo, with high and sustained levels of NTP measured in rat liver following intravenous and oral administration. |
| doi_str_mv | 10.1016/j.bmc.2012.05.067 |
| format | Article |
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Emilia ; Avolio, Salvatore ; Pompei, Marco ; Pesci, Silvia ; Monteagudo, Edith ; Pucci, Vincenzo ; Giuliano, Claudio ; Fiore, Fabrizio ; Rowley, Michael ; Summa, Vincenzo</creator><creatorcontrib>Di Francesco, M. Emilia ; Avolio, Salvatore ; Pompei, Marco ; Pesci, Silvia ; Monteagudo, Edith ; Pucci, Vincenzo ; Giuliano, Claudio ; Fiore, Fabrizio ; Rowley, Michael ; Summa, Vincenzo</creatorcontrib><description>Previous investigations in our laboratories resulted in the discovery of a novel series of potent nucleoside inhibitors of Hepatitis C virus (HCV) NS5B polymerase bearing tetracyclic 7-substituted 7-deaza-adenine nucleobases. The planarity of such modified systems was suggested to play a role in the high inhibitory potency observed. This paper describes how we envisaged to maintain the desired planarity of the modified nucleobase by means of an intra-molecular H-bond, engaging a H-bond donor atom on an appropriately substituted 7-heterocyclic residue with the adjacent amino group of the nucleobase. The success of this strategy is reflected by the identification of several novel potent nucleoside inhibitors of HCV NS5B bearing a 7-heterocyclic substituted 7-deaza-adenine nucleobase. Amongst these, the 1,2,4-oxadiazole analog 11 showed high antiviral potency against HCV replication in replicon cells and efficient conversion to the corresponding NTP in vivo, with high and sustained levels of NTP measured in rat liver following intravenous and oral administration.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2012.05.067</identifier><identifier>PMID: 22770556</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>2′-C-methyl-ribose ; 7-Deaza-adenine ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Antiviral Agents - chemical synthesis ; Antiviral Agents - chemistry ; Antiviral Agents - pharmacology ; antiviral properties ; Biological and medical sciences ; chemistry ; Dose-Response Relationship, Drug ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; HCV polymerase ; Hepacivirus - drug effects ; hepatitis C ; Hepatitis C virus ; intravenous injection ; liver ; Medical sciences ; Microbial Sensitivity Tests ; Molecular Structure ; Nucleoside inhhibitor ; Nucleoside triphosphate ; nucleosides ; Nucleosides - chemical synthesis ; Nucleosides - chemistry ; Nucleosides - pharmacology ; oral administration ; Pharmacology. Drug treatments ; rats ; replicon ; Replicon - drug effects ; Structure-Activity Relationship ; Viral Nonstructural Proteins - antagonists & inhibitors ; Viral Nonstructural Proteins - metabolism ; Virus Replication - drug effects</subject><ispartof>Bioorganic & medicinal chemistry, 2012-08, Vol.20 (15), p.4801-4811</ispartof><rights>2012 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2012 Elsevier Ltd. 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Emilia</creatorcontrib><creatorcontrib>Avolio, Salvatore</creatorcontrib><creatorcontrib>Pompei, Marco</creatorcontrib><creatorcontrib>Pesci, Silvia</creatorcontrib><creatorcontrib>Monteagudo, Edith</creatorcontrib><creatorcontrib>Pucci, Vincenzo</creatorcontrib><creatorcontrib>Giuliano, Claudio</creatorcontrib><creatorcontrib>Fiore, Fabrizio</creatorcontrib><creatorcontrib>Rowley, Michael</creatorcontrib><creatorcontrib>Summa, Vincenzo</creatorcontrib><title>Synthesis and antiviral properties of novel 7-heterocyclic substituted 7-deaza-adenine nucleoside inhibitors of Hepatitis C NS5B polymerase</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>Previous investigations in our laboratories resulted in the discovery of a novel series of potent nucleoside inhibitors of Hepatitis C virus (HCV) NS5B polymerase bearing tetracyclic 7-substituted 7-deaza-adenine nucleobases. The planarity of such modified systems was suggested to play a role in the high inhibitory potency observed. This paper describes how we envisaged to maintain the desired planarity of the modified nucleobase by means of an intra-molecular H-bond, engaging a H-bond donor atom on an appropriately substituted 7-heterocyclic residue with the adjacent amino group of the nucleobase. The success of this strategy is reflected by the identification of several novel potent nucleoside inhibitors of HCV NS5B bearing a 7-heterocyclic substituted 7-deaza-adenine nucleobase. Amongst these, the 1,2,4-oxadiazole analog 11 showed high antiviral potency against HCV replication in replicon cells and efficient conversion to the corresponding NTP in vivo, with high and sustained levels of NTP measured in rat liver following intravenous and oral administration.</description><subject>2′-C-methyl-ribose</subject><subject>7-Deaza-adenine</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Antiviral Agents - chemical synthesis</subject><subject>Antiviral Agents - chemistry</subject><subject>Antiviral Agents - pharmacology</subject><subject>antiviral properties</subject><subject>Biological and medical sciences</subject><subject>chemistry</subject><subject>Dose-Response Relationship, Drug</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>HCV polymerase</subject><subject>Hepacivirus - drug effects</subject><subject>hepatitis C</subject><subject>Hepatitis C virus</subject><subject>intravenous injection</subject><subject>liver</subject><subject>Medical sciences</subject><subject>Microbial Sensitivity Tests</subject><subject>Molecular Structure</subject><subject>Nucleoside inhhibitor</subject><subject>Nucleoside triphosphate</subject><subject>nucleosides</subject><subject>Nucleosides - chemical synthesis</subject><subject>Nucleosides - chemistry</subject><subject>Nucleosides - pharmacology</subject><subject>oral administration</subject><subject>Pharmacology. Drug treatments</subject><subject>rats</subject><subject>replicon</subject><subject>Replicon - drug effects</subject><subject>Structure-Activity Relationship</subject><subject>Viral Nonstructural Proteins - antagonists & inhibitors</subject><subject>Viral Nonstructural Proteins - metabolism</subject><subject>Virus Replication - drug effects</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcGO0zAQhiMEYrsLD8AFckHaS8LYiZ1EnJYKWKQVHMqeLWc8oa6SuNhOpfIKvDReWuDGYeTDfP8_4_mz7AWDkgGTb3ZlP2HJgfESRAmyeZStWC3roqo69jhbQSfbAtpOXmSXIewAgNcde5pdcN40IIRcZT83xzluKdiQ69mkivZgvR7zvXd78tFSyN2Qz-5AY94UW4rkHR5xtJiHpQ_RxiWSSS1D-ocutKHZzpTPC47kgjWU23lrexud_-10S3udRGneOv-8Ee_yvRuPE3kd6Fn2ZNBjoOfn9yq7__D-6_q2uPvy8dP65q5AATIWLTWyBqx43RJSoxkINjR1y2Hg_WCw6wkkIqDo2kFI4Mg1EjYazSA1r6ur7Prkm_74faEQ1WQD0jjqmdwSFBMATVdVvEkoO6HoXQieBrX3dtL-qBiohwzUTqUM1EMGCoRKGSTNy7P90k9k_ir-HD0Br8-ADqjHwesZbfjHSQ41ryBxr07coJ3S33xi7jdpUlqPMahrkYi3J4LSuQ6WvApoaUYy1hNGZZz9z6K_ADybr-o</recordid><startdate>20120801</startdate><enddate>20120801</enddate><creator>Di Francesco, M. Emilia</creator><creator>Avolio, Salvatore</creator><creator>Pompei, Marco</creator><creator>Pesci, Silvia</creator><creator>Monteagudo, Edith</creator><creator>Pucci, Vincenzo</creator><creator>Giuliano, Claudio</creator><creator>Fiore, Fabrizio</creator><creator>Rowley, Michael</creator><creator>Summa, Vincenzo</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>FBQ</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>7QO</scope><scope>7T7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope></search><sort><creationdate>20120801</creationdate><title>Synthesis and antiviral properties of novel 7-heterocyclic substituted 7-deaza-adenine nucleoside inhibitors of Hepatitis C NS5B polymerase</title><author>Di Francesco, M. Emilia ; Avolio, Salvatore ; Pompei, Marco ; Pesci, Silvia ; Monteagudo, Edith ; Pucci, Vincenzo ; Giuliano, Claudio ; Fiore, Fabrizio ; Rowley, Michael ; Summa, Vincenzo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c506t-8e7640c3248ece7a1051f74820f2bfdc9be06cc0c598f5602c2acec7acdf6a243</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>2′-C-methyl-ribose</topic><topic>7-Deaza-adenine</topic><topic>Antibiotics. Antiinfectious agents. 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Drug treatments</topic><topic>rats</topic><topic>replicon</topic><topic>Replicon - drug effects</topic><topic>Structure-Activity Relationship</topic><topic>Viral Nonstructural Proteins - antagonists & inhibitors</topic><topic>Viral Nonstructural Proteins - metabolism</topic><topic>Virus Replication - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Di Francesco, M. Emilia</creatorcontrib><creatorcontrib>Avolio, Salvatore</creatorcontrib><creatorcontrib>Pompei, Marco</creatorcontrib><creatorcontrib>Pesci, Silvia</creatorcontrib><creatorcontrib>Monteagudo, Edith</creatorcontrib><creatorcontrib>Pucci, Vincenzo</creatorcontrib><creatorcontrib>Giuliano, Claudio</creatorcontrib><creatorcontrib>Fiore, Fabrizio</creatorcontrib><creatorcontrib>Rowley, Michael</creatorcontrib><creatorcontrib>Summa, Vincenzo</creatorcontrib><collection>AGRIS</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>Biotechnology Research Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</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><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Di Francesco, M. Emilia</au><au>Avolio, Salvatore</au><au>Pompei, Marco</au><au>Pesci, Silvia</au><au>Monteagudo, Edith</au><au>Pucci, Vincenzo</au><au>Giuliano, Claudio</au><au>Fiore, Fabrizio</au><au>Rowley, Michael</au><au>Summa, Vincenzo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and antiviral properties of novel 7-heterocyclic substituted 7-deaza-adenine nucleoside inhibitors of Hepatitis C NS5B polymerase</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2012-08-01</date><risdate>2012</risdate><volume>20</volume><issue>15</issue><spage>4801</spage><epage>4811</epage><pages>4801-4811</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>Previous investigations in our laboratories resulted in the discovery of a novel series of potent nucleoside inhibitors of Hepatitis C virus (HCV) NS5B polymerase bearing tetracyclic 7-substituted 7-deaza-adenine nucleobases. The planarity of such modified systems was suggested to play a role in the high inhibitory potency observed. This paper describes how we envisaged to maintain the desired planarity of the modified nucleobase by means of an intra-molecular H-bond, engaging a H-bond donor atom on an appropriately substituted 7-heterocyclic residue with the adjacent amino group of the nucleobase. The success of this strategy is reflected by the identification of several novel potent nucleoside inhibitors of HCV NS5B bearing a 7-heterocyclic substituted 7-deaza-adenine nucleobase. Amongst these, the 1,2,4-oxadiazole analog 11 showed high antiviral potency against HCV replication in replicon cells and efficient conversion to the corresponding NTP in vivo, with high and sustained levels of NTP measured in rat liver following intravenous and oral administration.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>22770556</pmid><doi>10.1016/j.bmc.2012.05.067</doi><tpages>11</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Bioorganic & medicinal chemistry, 2012-08, Vol.20 (15), p.4801-4811 |
| issn | 0968-0896 1464-3391 |
| language | eng |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | 2′-C-methyl-ribose 7-Deaza-adenine Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Antiviral Agents - chemical synthesis Antiviral Agents - chemistry Antiviral Agents - pharmacology antiviral properties Biological and medical sciences chemistry Dose-Response Relationship, Drug Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology HCV polymerase Hepacivirus - drug effects hepatitis C Hepatitis C virus intravenous injection liver Medical sciences Microbial Sensitivity Tests Molecular Structure Nucleoside inhhibitor Nucleoside triphosphate nucleosides Nucleosides - chemical synthesis Nucleosides - chemistry Nucleosides - pharmacology oral administration Pharmacology. Drug treatments rats replicon Replicon - drug effects Structure-Activity Relationship Viral Nonstructural Proteins - antagonists & inhibitors Viral Nonstructural Proteins - metabolism Virus Replication - drug effects |
| title | Synthesis and antiviral properties of novel 7-heterocyclic substituted 7-deaza-adenine nucleoside inhibitors of Hepatitis C NS5B polymerase |
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