Sulfated Galactocerebrosides as Potential Antiinflammatory Agents
Native sulfatides, as well as many sulfated glycolipids, have been shown to avidly bind to the selectin receptors. In vivo, native sulfatides significantly block activity in selectin-dependent inflammatory responses. The fact that nonsulfated galactocerebrosides did not inhibit selectin-mediated adh...
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| Veröffentlicht in: | Journal of medicinal chemistry 1997-09, Vol.40 (20), p.3234-3247 |
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| container_title | Journal of medicinal chemistry |
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| creator | Marinier, Anne Martel, Alain Banville, Jacques Bachand, Carol Remillard, Roger Lapointe, Philippe Turmel, Brigitte Menard, Marcel Harte, William E Wright, J. J. Kim Todderud, Gordon Tramposch, Kenneth M Bajorath, Jürgen Hollenbaugh, Diane Aruffo, Alejandro |
| description | Native sulfatides, as well as many sulfated glycolipids, have been shown to avidly bind to the selectin receptors. In vivo, native sulfatides significantly block activity in selectin-dependent inflammatory responses. The fact that nonsulfated galactocerebrosides did not inhibit selectin-mediated adhesion identified a critical role for the anionic sulfate residue. We therefore initiated a program to evaluate the activity of position isomers. This study showed a binding selectivity for the positions 2 and 3 of the sulfate group on the carbohydrate ring as well as enhanced activity for the disulfated analogs. Furthermore, it was discovered that the attachment of lipophilic substituents on the carbohydrate ring was tolerated, consistent with the presence of a lipophilic pocket in the binding cavity. This resulted in compounds with a 6-fold increased potency. |
| doi_str_mv | 10.1021/jm9606960 |
| format | Article |
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J. Kim ; Todderud, Gordon ; Tramposch, Kenneth M ; Bajorath, Jürgen ; Hollenbaugh, Diane ; Aruffo, Alejandro</creator><creatorcontrib>Marinier, Anne ; Martel, Alain ; Banville, Jacques ; Bachand, Carol ; Remillard, Roger ; Lapointe, Philippe ; Turmel, Brigitte ; Menard, Marcel ; Harte, William E ; Wright, J. J. Kim ; Todderud, Gordon ; Tramposch, Kenneth M ; Bajorath, Jürgen ; Hollenbaugh, Diane ; Aruffo, Alejandro</creatorcontrib><description>Native sulfatides, as well as many sulfated glycolipids, have been shown to avidly bind to the selectin receptors. In vivo, native sulfatides significantly block activity in selectin-dependent inflammatory responses. The fact that nonsulfated galactocerebrosides did not inhibit selectin-mediated adhesion identified a critical role for the anionic sulfate residue. We therefore initiated a program to evaluate the activity of position isomers. This study showed a binding selectivity for the positions 2 and 3 of the sulfate group on the carbohydrate ring as well as enhanced activity for the disulfated analogs. Furthermore, it was discovered that the attachment of lipophilic substituents on the carbohydrate ring was tolerated, consistent with the presence of a lipophilic pocket in the binding cavity. This resulted in compounds with a 6-fold increased potency.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm9606960</identifier><identifier>PMID: 9379443</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Anti-Inflammatory Agents - chemistry ; Anti-Inflammatory Agents - pharmacology ; Biological and medical sciences ; Bones, joints and connective tissue. Antiinflammatory agents ; Enzyme-Linked Immunosorbent Assay ; Galactosylceramides - chemistry ; Galactosylceramides - pharmacology ; HL-60 Cells ; Humans ; Isomerism ; Medical sciences ; Models, Chemical ; P-Selectin - metabolism ; Pharmacology. Drug treatments ; Sulfates - chemistry ; Sulfates - pharmacology ; Sulfoglycosphingolipids - pharmacology</subject><ispartof>Journal of medicinal chemistry, 1997-09, Vol.40 (20), p.3234-3247</ispartof><rights>Copyright © 1997 American Chemical Society</rights><rights>1997 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a377t-8d72674d9268cf5ee93c8c2ee9aada2834a2aaa6807e373c58b9fc7089cc0c0a3</citedby><cites>FETCH-LOGICAL-a377t-8d72674d9268cf5ee93c8c2ee9aada2834a2aaa6807e373c58b9fc7089cc0c0a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm9606960$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm9606960$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,781,785,2766,27081,27929,27930,56743,56793</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2833127$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9379443$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Marinier, Anne</creatorcontrib><creatorcontrib>Martel, Alain</creatorcontrib><creatorcontrib>Banville, Jacques</creatorcontrib><creatorcontrib>Bachand, Carol</creatorcontrib><creatorcontrib>Remillard, Roger</creatorcontrib><creatorcontrib>Lapointe, Philippe</creatorcontrib><creatorcontrib>Turmel, Brigitte</creatorcontrib><creatorcontrib>Menard, Marcel</creatorcontrib><creatorcontrib>Harte, William E</creatorcontrib><creatorcontrib>Wright, J. J. Kim</creatorcontrib><creatorcontrib>Todderud, Gordon</creatorcontrib><creatorcontrib>Tramposch, Kenneth M</creatorcontrib><creatorcontrib>Bajorath, Jürgen</creatorcontrib><creatorcontrib>Hollenbaugh, Diane</creatorcontrib><creatorcontrib>Aruffo, Alejandro</creatorcontrib><title>Sulfated Galactocerebrosides as Potential Antiinflammatory Agents</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Native sulfatides, as well as many sulfated glycolipids, have been shown to avidly bind to the selectin receptors. In vivo, native sulfatides significantly block activity in selectin-dependent inflammatory responses. The fact that nonsulfated galactocerebrosides did not inhibit selectin-mediated adhesion identified a critical role for the anionic sulfate residue. We therefore initiated a program to evaluate the activity of position isomers. This study showed a binding selectivity for the positions 2 and 3 of the sulfate group on the carbohydrate ring as well as enhanced activity for the disulfated analogs. Furthermore, it was discovered that the attachment of lipophilic substituents on the carbohydrate ring was tolerated, consistent with the presence of a lipophilic pocket in the binding cavity. This resulted in compounds with a 6-fold increased potency.</description><subject>Animals</subject><subject>Anti-Inflammatory Agents - chemistry</subject><subject>Anti-Inflammatory Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Bones, joints and connective tissue. Antiinflammatory agents</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Galactosylceramides - chemistry</subject><subject>Galactosylceramides - pharmacology</subject><subject>HL-60 Cells</subject><subject>Humans</subject><subject>Isomerism</subject><subject>Medical sciences</subject><subject>Models, Chemical</subject><subject>P-Selectin - metabolism</subject><subject>Pharmacology. Drug treatments</subject><subject>Sulfates - chemistry</subject><subject>Sulfates - pharmacology</subject><subject>Sulfoglycosphingolipids - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1997</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkMtOwzAQRS0EglJY8AFIWQASi4BjJ7G9jAqURyUqWthaU8dBKXkU25Ho32OUqCsWo7u4R6OZg9BZhG8iTKLbdS1SnPrZQ6MoITiMOY730QhjQkKSEnqEjq1dY4xpROghOhSUiTimI5QtuqoAp_NgChUo1ypt9Mq0tsy1DcAG89bpxpVQBZmPsikqqGtwrdkG2adv7Ak6KKCy-nTIMXp_uF9OHsPZ6_Rpks1CoIy5kOeMpCzOBUm5KhKtBVVcEZ8AORBOYyAAkHLMNGVUJXwlCsUwF0phhYGO0VW_d2Pa705bJ-vSKl1V0Oi2s5IJyhMuuAeve1D5N6zRhdyYsgazlRGWf7rkTpdnz4el3arW-Y4c_Pj-YujBKqgKA40q7Q7zZ3uhzGNhj5XW6Z9dDeZLpoyyRC7nC0lf3j4Wd8tnOfX8Zc-DsnLddqbx5v457xejdo0p</recordid><startdate>19970926</startdate><enddate>19970926</enddate><creator>Marinier, Anne</creator><creator>Martel, Alain</creator><creator>Banville, Jacques</creator><creator>Bachand, Carol</creator><creator>Remillard, Roger</creator><creator>Lapointe, Philippe</creator><creator>Turmel, Brigitte</creator><creator>Menard, Marcel</creator><creator>Harte, William E</creator><creator>Wright, J. J. Kim</creator><creator>Todderud, Gordon</creator><creator>Tramposch, Kenneth M</creator><creator>Bajorath, Jürgen</creator><creator>Hollenbaugh, Diane</creator><creator>Aruffo, Alejandro</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><scope>7X8</scope></search><sort><creationdate>19970926</creationdate><title>Sulfated Galactocerebrosides as Potential Antiinflammatory Agents</title><author>Marinier, Anne ; Martel, Alain ; Banville, Jacques ; Bachand, Carol ; Remillard, Roger ; Lapointe, Philippe ; Turmel, Brigitte ; Menard, Marcel ; Harte, William E ; Wright, J. J. Kim ; Todderud, Gordon ; Tramposch, Kenneth M ; Bajorath, Jürgen ; Hollenbaugh, Diane ; Aruffo, Alejandro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a377t-8d72674d9268cf5ee93c8c2ee9aada2834a2aaa6807e373c58b9fc7089cc0c0a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1997</creationdate><topic>Animals</topic><topic>Anti-Inflammatory Agents - chemistry</topic><topic>Anti-Inflammatory Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Bones, joints and connective tissue. Antiinflammatory agents</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>Galactosylceramides - chemistry</topic><topic>Galactosylceramides - pharmacology</topic><topic>HL-60 Cells</topic><topic>Humans</topic><topic>Isomerism</topic><topic>Medical sciences</topic><topic>Models, Chemical</topic><topic>P-Selectin - metabolism</topic><topic>Pharmacology. Drug treatments</topic><topic>Sulfates - chemistry</topic><topic>Sulfates - pharmacology</topic><topic>Sulfoglycosphingolipids - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Marinier, Anne</creatorcontrib><creatorcontrib>Martel, Alain</creatorcontrib><creatorcontrib>Banville, Jacques</creatorcontrib><creatorcontrib>Bachand, Carol</creatorcontrib><creatorcontrib>Remillard, Roger</creatorcontrib><creatorcontrib>Lapointe, Philippe</creatorcontrib><creatorcontrib>Turmel, Brigitte</creatorcontrib><creatorcontrib>Menard, Marcel</creatorcontrib><creatorcontrib>Harte, William E</creatorcontrib><creatorcontrib>Wright, J. J. Kim</creatorcontrib><creatorcontrib>Todderud, Gordon</creatorcontrib><creatorcontrib>Tramposch, Kenneth M</creatorcontrib><creatorcontrib>Bajorath, Jürgen</creatorcontrib><creatorcontrib>Hollenbaugh, Diane</creatorcontrib><creatorcontrib>Aruffo, Alejandro</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><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Marinier, Anne</au><au>Martel, Alain</au><au>Banville, Jacques</au><au>Bachand, Carol</au><au>Remillard, Roger</au><au>Lapointe, Philippe</au><au>Turmel, Brigitte</au><au>Menard, Marcel</au><au>Harte, William E</au><au>Wright, J. J. Kim</au><au>Todderud, Gordon</au><au>Tramposch, Kenneth M</au><au>Bajorath, Jürgen</au><au>Hollenbaugh, Diane</au><au>Aruffo, Alejandro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sulfated Galactocerebrosides as Potential Antiinflammatory Agents</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1997-09-26</date><risdate>1997</risdate><volume>40</volume><issue>20</issue><spage>3234</spage><epage>3247</epage><pages>3234-3247</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Native sulfatides, as well as many sulfated glycolipids, have been shown to avidly bind to the selectin receptors. In vivo, native sulfatides significantly block activity in selectin-dependent inflammatory responses. The fact that nonsulfated galactocerebrosides did not inhibit selectin-mediated adhesion identified a critical role for the anionic sulfate residue. 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| ispartof | Journal of medicinal chemistry, 1997-09, Vol.40 (20), p.3234-3247 |
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| subjects | Animals Anti-Inflammatory Agents - chemistry Anti-Inflammatory Agents - pharmacology Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Enzyme-Linked Immunosorbent Assay Galactosylceramides - chemistry Galactosylceramides - pharmacology HL-60 Cells Humans Isomerism Medical sciences Models, Chemical P-Selectin - metabolism Pharmacology. Drug treatments Sulfates - chemistry Sulfates - pharmacology Sulfoglycosphingolipids - pharmacology |
| title | Sulfated Galactocerebrosides as Potential Antiinflammatory Agents |
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