CycloSal-BVDUMP Pronucleotides: How to Convert an Antiviral-Inactive Nucleoside Analogue into a Bioactive Compound against EBV
Novel cycloSal-BVDUMP triesters 2-4 5-[(E)-2-bromovinyl]-2'-deoxyuridine (BVDU, 1) have been studied with regard to their potential anti-EBV activity. In addition to the 3'-unmodified cycloSal-BVDUMP triesters 2a-f, the 3'-hydroxyl function has been esterified with different aliphatic...
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| Veröffentlicht in: | Journal of medicinal chemistry 2002-11, Vol.45 (23), p.5157-5172 |
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| container_title | Journal of medicinal chemistry |
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| creator | MEIER, Chris LOMP, Andreas MEERBACH, Astrid WUTZLER, Peter |
| description | Novel cycloSal-BVDUMP triesters 2-4 5-[(E)-2-bromovinyl]-2'-deoxyuridine (BVDU, 1) have been studied with regard to their potential anti-EBV activity. In addition to the 3'-unmodified cycloSal-BVDUMP triesters 2a-f, the 3'-hydroxyl function has been esterified with different aliphatic carboxylic acids (3a-g) and alpha-amino acids having natural and nonnatural Calpha-configuration (4a-m). In addition to the synthesis of these compounds, different physicochemical properties of the new derivatives will be reported, i.e., lipophilicity and hydrolysis behavior. It could be proven that the monophosphate BVDUMP and not 3',5'-cyclic BVDUMP was delivered from most of the compounds by chemical hydrolysis in phosphate buffers at pH 6.8 and 7.3 as well as P3HR-1 cell extracts. Finally, the new compounds were tested for their anti-EBV activity. As a result, the prototype compounds and particularly triesters 2c,d exhibited pronounced anti-EBV activity making these compounds promising candidates for further development. However, the 3'-ester derivatives were devoid of any antiviral activity while the 3'-aminoacyl derivatives showed an antiviral activity dependent upon the amino acid and the Calpha-configuration |
| doi_str_mv | 10.1021/jm0209275 |
| format | Article |
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In addition to the 3'-unmodified cycloSal-BVDUMP triesters 2a-f, the 3'-hydroxyl function has been esterified with different aliphatic carboxylic acids (3a-g) and alpha-amino acids having natural and nonnatural Calpha-configuration (4a-m). In addition to the synthesis of these compounds, different physicochemical properties of the new derivatives will be reported, i.e., lipophilicity and hydrolysis behavior. It could be proven that the monophosphate BVDUMP and not 3',5'-cyclic BVDUMP was delivered from most of the compounds by chemical hydrolysis in phosphate buffers at pH 6.8 and 7.3 as well as P3HR-1 cell extracts. Finally, the new compounds were tested for their anti-EBV activity. As a result, the prototype compounds and particularly triesters 2c,d exhibited pronounced anti-EBV activity making these compounds promising candidates for further development. However, the 3'-ester derivatives were devoid of any antiviral activity while the 3'-aminoacyl derivatives showed an antiviral activity dependent upon the amino acid and the Calpha-configuration</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm0209275</identifier><identifier>PMID: 12408726</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Antiviral Agents - chemical synthesis ; Antiviral Agents - chemistry ; Antiviral Agents - pharmacology ; Biological and medical sciences ; Bromodeoxyuridine - analogs & derivatives ; Bromodeoxyuridine - chemical synthesis ; Bromodeoxyuridine - chemistry ; Bromodeoxyuridine - pharmacology ; Cell Division - drug effects ; Cell Extracts ; Deoxyuracil Nucleotides - chemical synthesis ; Deoxyuracil Nucleotides - chemistry ; Deoxyuracil Nucleotides - pharmacology ; Esters ; Herpesvirus 4, Human - drug effects ; Humans ; Hydrolysis ; Kinetics ; Medical sciences ; Pharmacology. Drug treatments ; Structure-Activity Relationship ; Tumor Cells, Cultured</subject><ispartof>Journal of medicinal chemistry, 2002-11, Vol.45 (23), p.5157-5172</ispartof><rights>2003 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=13998743$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12408726$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>MEIER, Chris</creatorcontrib><creatorcontrib>LOMP, Andreas</creatorcontrib><creatorcontrib>MEERBACH, Astrid</creatorcontrib><creatorcontrib>WUTZLER, Peter</creatorcontrib><title>CycloSal-BVDUMP Pronucleotides: How to Convert an Antiviral-Inactive Nucleoside Analogue into a Bioactive Compound against EBV</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Novel cycloSal-BVDUMP triesters 2-4 5-[(E)-2-bromovinyl]-2'-deoxyuridine (BVDU, 1) have been studied with regard to their potential anti-EBV activity. In addition to the 3'-unmodified cycloSal-BVDUMP triesters 2a-f, the 3'-hydroxyl function has been esterified with different aliphatic carboxylic acids (3a-g) and alpha-amino acids having natural and nonnatural Calpha-configuration (4a-m). In addition to the synthesis of these compounds, different physicochemical properties of the new derivatives will be reported, i.e., lipophilicity and hydrolysis behavior. It could be proven that the monophosphate BVDUMP and not 3',5'-cyclic BVDUMP was delivered from most of the compounds by chemical hydrolysis in phosphate buffers at pH 6.8 and 7.3 as well as P3HR-1 cell extracts. Finally, the new compounds were tested for their anti-EBV activity. As a result, the prototype compounds and particularly triesters 2c,d exhibited pronounced anti-EBV activity making these compounds promising candidates for further development. However, the 3'-ester derivatives were devoid of any antiviral activity while the 3'-aminoacyl derivatives showed an antiviral activity dependent upon the amino acid and the Calpha-configuration</description><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>Biological and medical sciences</subject><subject>Bromodeoxyuridine - analogs & derivatives</subject><subject>Bromodeoxyuridine - chemical synthesis</subject><subject>Bromodeoxyuridine - chemistry</subject><subject>Bromodeoxyuridine - pharmacology</subject><subject>Cell Division - drug effects</subject><subject>Cell Extracts</subject><subject>Deoxyuracil Nucleotides - chemical synthesis</subject><subject>Deoxyuracil Nucleotides - chemistry</subject><subject>Deoxyuracil Nucleotides - pharmacology</subject><subject>Esters</subject><subject>Herpesvirus 4, Human - drug effects</subject><subject>Humans</subject><subject>Hydrolysis</subject><subject>Kinetics</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Structure-Activity Relationship</subject><subject>Tumor Cells, Cultured</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkMtOwzAQRS0EglJY8APIG9gFxo_ECTsaHgXxqAR0GzmJgwyJXeKkwA6W_CZfggUFVjPSPWekuQhtEdgjQMn-QwMUEirCJTQgIYWAx8CX0QCA0oBGlK2hdeceAIARylbRGqEcYkGjAXpPX4va3sg6GE2P7i4neNJa0xe1sp0ulTv4fPvAY_uMO4tTa-aq7bA0-NB0eq5bb50ZWfhd4atvyXnJp7K2973C2nhN4pG2Cyi1zcz2psTyXmrjOnw8mm6glUrWTm0u5hDdnRzfpuPg4vr0LD28CLR_rAtCSiCqIBFAGBe0IIInKoSQRzwXORFREvKyiEUoCCUipyTJk4pzxWUelyyq2BDt_tydtfapV67LGu0KVdfSKNu7zNfBBYDw4PYC7PNGldms1Y1sX7Pf0jywswCkK2RdtdIU2v1zLEliwZnngh9Ou069_OWyfcwiwUSY3U5uMv_HOT8Hnk3ZF1gOiKk</recordid><startdate>20021107</startdate><enddate>20021107</enddate><creator>MEIER, Chris</creator><creator>LOMP, Andreas</creator><creator>MEERBACH, Astrid</creator><creator>WUTZLER, Peter</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>7X8</scope></search><sort><creationdate>20021107</creationdate><title>CycloSal-BVDUMP Pronucleotides: How to Convert an Antiviral-Inactive Nucleoside Analogue into a Bioactive Compound against EBV</title><author>MEIER, Chris ; LOMP, Andreas ; MEERBACH, Astrid ; WUTZLER, Peter</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-i275t-52106f097013472c1749e505464b7b176954dc87571217b219b9f44e4ab8d36f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antiviral agents</topic><topic>Antiviral Agents - chemical synthesis</topic><topic>Antiviral Agents - chemistry</topic><topic>Antiviral Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Bromodeoxyuridine - analogs & derivatives</topic><topic>Bromodeoxyuridine - chemical synthesis</topic><topic>Bromodeoxyuridine - chemistry</topic><topic>Bromodeoxyuridine - pharmacology</topic><topic>Cell Division - drug effects</topic><topic>Cell Extracts</topic><topic>Deoxyuracil Nucleotides - chemical synthesis</topic><topic>Deoxyuracil Nucleotides - chemistry</topic><topic>Deoxyuracil Nucleotides - pharmacology</topic><topic>Esters</topic><topic>Herpesvirus 4, Human - drug effects</topic><topic>Humans</topic><topic>Hydrolysis</topic><topic>Kinetics</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Structure-Activity Relationship</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>MEIER, Chris</creatorcontrib><creatorcontrib>LOMP, Andreas</creatorcontrib><creatorcontrib>MEERBACH, Astrid</creatorcontrib><creatorcontrib>WUTZLER, Peter</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>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>MEIER, Chris</au><au>LOMP, Andreas</au><au>MEERBACH, Astrid</au><au>WUTZLER, Peter</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CycloSal-BVDUMP Pronucleotides: How to Convert an Antiviral-Inactive Nucleoside Analogue into a Bioactive Compound against EBV</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2002-11-07</date><risdate>2002</risdate><volume>45</volume><issue>23</issue><spage>5157</spage><epage>5172</epage><pages>5157-5172</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Novel cycloSal-BVDUMP triesters 2-4 5-[(E)-2-bromovinyl]-2'-deoxyuridine (BVDU, 1) have been studied with regard to their potential anti-EBV activity. In addition to the 3'-unmodified cycloSal-BVDUMP triesters 2a-f, the 3'-hydroxyl function has been esterified with different aliphatic carboxylic acids (3a-g) and alpha-amino acids having natural and nonnatural Calpha-configuration (4a-m). In addition to the synthesis of these compounds, different physicochemical properties of the new derivatives will be reported, i.e., lipophilicity and hydrolysis behavior. It could be proven that the monophosphate BVDUMP and not 3',5'-cyclic BVDUMP was delivered from most of the compounds by chemical hydrolysis in phosphate buffers at pH 6.8 and 7.3 as well as P3HR-1 cell extracts. Finally, the new compounds were tested for their anti-EBV activity. As a result, the prototype compounds and particularly triesters 2c,d exhibited pronounced anti-EBV activity making these compounds promising candidates for further development. However, the 3'-ester derivatives were devoid of any antiviral activity while the 3'-aminoacyl derivatives showed an antiviral activity dependent upon the amino acid and the Calpha-configuration</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>12408726</pmid><doi>10.1021/jm0209275</doi><tpages>16</tpages></addata></record> |
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| subjects | Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Antiviral Agents - chemical synthesis Antiviral Agents - chemistry Antiviral Agents - pharmacology Biological and medical sciences Bromodeoxyuridine - analogs & derivatives Bromodeoxyuridine - chemical synthesis Bromodeoxyuridine - chemistry Bromodeoxyuridine - pharmacology Cell Division - drug effects Cell Extracts Deoxyuracil Nucleotides - chemical synthesis Deoxyuracil Nucleotides - chemistry Deoxyuracil Nucleotides - pharmacology Esters Herpesvirus 4, Human - drug effects Humans Hydrolysis Kinetics Medical sciences Pharmacology. Drug treatments Structure-Activity Relationship Tumor Cells, Cultured |
| title | CycloSal-BVDUMP Pronucleotides: How to Convert an Antiviral-Inactive Nucleoside Analogue into a Bioactive Compound against EBV |
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