Structure-Based Design and Synthesis of 2-Benzylidene-benzofuran-3-ones as Flavopiridol Mimics
Novel 2-benzylidene-benzofuran-3-ones were designed and synthesized to mimic flavopiridol, a well-established inhibitor of cyclin-dependent kinases (CDKs) which is currently undergoing clinical evaluation. The underlying design concepts as well as the synthesis and structure−activity relationships (...
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| Veröffentlicht in: | Journal of medicinal chemistry 2002-04, Vol.45 (9), p.1741-1747 |
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| container_issue | 9 |
| container_start_page | 1741 |
| container_title | Journal of medicinal chemistry |
| container_volume | 45 |
| creator | Schoepfer, Joseph Fretz, Heinz Chaudhuri, Bhabatosh Muller, Lionel Seeber, Egge Meijer, Laurent Lozach, Olivier Vangrevelinghe, Eric Furet, Pascal |
| description | Novel 2-benzylidene-benzofuran-3-ones were designed and synthesized to mimic flavopiridol, a well-established inhibitor of cyclin-dependent kinases (CDKs) which is currently undergoing clinical evaluation. The underlying design concepts as well as the synthesis and structure−activity relationships (CDKs 1, 2, and 4 enzyme assays) of these mimics are described. Inhibitors of CDKs 1 and 2 that are more potent and selective than flavopiridol were obtained. |
| doi_str_mv | 10.1021/jm0108348 |
| format | Article |
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The underlying design concepts as well as the synthesis and structure−activity relationships (CDKs 1, 2, and 4 enzyme assays) of these mimics are described. Inhibitors of CDKs 1 and 2 that are more potent and selective than flavopiridol were obtained.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm0108348</identifier><identifier>PMID: 11960485</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Antineoplastic agents ; Benzylidene Compounds - chemical synthesis ; Benzylidene Compounds - chemistry ; Biological and medical sciences ; CDC2 Protein Kinase - antagonists & inhibitors ; CDC2 Protein Kinase - chemistry ; CDC2-CDC28 Kinases ; Cyclin-Dependent Kinase 2 ; Cyclin-Dependent Kinase 4 ; Cyclin-Dependent Kinases - antagonists & inhibitors ; Cyclin-Dependent Kinases - chemistry ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Flavonoids - chemistry ; Furans - chemical synthesis ; Furans - chemistry ; General aspects ; Medical sciences ; Models, Molecular ; Molecular Mimicry ; Pharmacology. Drug treatments ; Piperidines - chemistry ; Protein-Serine-Threonine Kinases - antagonists & inhibitors ; Protein-Serine-Threonine Kinases - chemistry ; Proto-Oncogene Proteins ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2002-04, Vol.45 (9), p.1741-1747</ispartof><rights>Copyright © 2002 American Chemical Society</rights><rights>2002 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a445t-1848e606258b1c78496135401632a6fbe79cdd76f8ca58f32e8c83cc0b8c5aae3</citedby><cites>FETCH-LOGICAL-a445t-1848e606258b1c78496135401632a6fbe79cdd76f8ca58f32e8c83cc0b8c5aae3</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/jm0108348$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm0108348$$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&idt=13634609$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11960485$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Schoepfer, Joseph</creatorcontrib><creatorcontrib>Fretz, Heinz</creatorcontrib><creatorcontrib>Chaudhuri, Bhabatosh</creatorcontrib><creatorcontrib>Muller, Lionel</creatorcontrib><creatorcontrib>Seeber, Egge</creatorcontrib><creatorcontrib>Meijer, Laurent</creatorcontrib><creatorcontrib>Lozach, Olivier</creatorcontrib><creatorcontrib>Vangrevelinghe, Eric</creatorcontrib><creatorcontrib>Furet, Pascal</creatorcontrib><title>Structure-Based Design and Synthesis of 2-Benzylidene-benzofuran-3-ones as Flavopiridol Mimics</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Novel 2-benzylidene-benzofuran-3-ones were designed and synthesized to mimic flavopiridol, a well-established inhibitor of cyclin-dependent kinases (CDKs) which is currently undergoing clinical evaluation. The underlying design concepts as well as the synthesis and structure−activity relationships (CDKs 1, 2, and 4 enzyme assays) of these mimics are described. Inhibitors of CDKs 1 and 2 that are more potent and selective than flavopiridol were obtained.</description><subject>Antineoplastic agents</subject><subject>Benzylidene Compounds - chemical synthesis</subject><subject>Benzylidene Compounds - chemistry</subject><subject>Biological and medical sciences</subject><subject>CDC2 Protein Kinase - antagonists & inhibitors</subject><subject>CDC2 Protein Kinase - chemistry</subject><subject>CDC2-CDC28 Kinases</subject><subject>Cyclin-Dependent Kinase 2</subject><subject>Cyclin-Dependent Kinase 4</subject><subject>Cyclin-Dependent Kinases - antagonists & inhibitors</subject><subject>Cyclin-Dependent Kinases - chemistry</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Flavonoids - chemistry</subject><subject>Furans - chemical synthesis</subject><subject>Furans - chemistry</subject><subject>General aspects</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Molecular Mimicry</subject><subject>Pharmacology. Drug treatments</subject><subject>Piperidines - chemistry</subject><subject>Protein-Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein-Serine-Threonine Kinases - chemistry</subject><subject>Proto-Oncogene Proteins</subject><subject>Structure-Activity Relationship</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>eNptkE1vEzEQhi1ERUPhwB9Ae6FSD279tV7nSEoDqEUgEjhieb2z4LBrB88uIvx6tkrUXDjNjObRO6OHkBecXXIm-NWmZ5wZqcwjMuOlYFQZph6TGWNCUKGFPCVPETeMMcmFfEJOOZ9rpkw5I99WQx79MGagC4fQFG8Aw_dYuNgUq10cfkwjFqktBF1A_LvrQgMRaD31qR2zi1TSFAELh8Wyc7_TNuTQpK74EPrg8Rk5aV2H8PxQz8iX5c36-h29-_j2_fXrO-qUKgfKjTKgmRalqbmvjJprLkvFuJbC6baGau6bptKt8a40rRRgvJHes9r40jmQZ-R8n7vN6dcIONg-oIeucxHSiLbimisu5hN4sQd9TogZWrvNoXd5Zzmz9zLtg8yJfXkIHesemiN5sDcBrw6AQ--6dtLhAx45qaXS7P4o3XMBB_jzsHf5p9WVrEq7_rSyXz8v17eL5cKqY67zaDdpzHFy958H_wGwi5ZW</recordid><startdate>20020425</startdate><enddate>20020425</enddate><creator>Schoepfer, Joseph</creator><creator>Fretz, Heinz</creator><creator>Chaudhuri, Bhabatosh</creator><creator>Muller, Lionel</creator><creator>Seeber, Egge</creator><creator>Meijer, Laurent</creator><creator>Lozach, Olivier</creator><creator>Vangrevelinghe, Eric</creator><creator>Furet, Pascal</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>20020425</creationdate><title>Structure-Based Design and Synthesis of 2-Benzylidene-benzofuran-3-ones as Flavopiridol Mimics</title><author>Schoepfer, Joseph ; Fretz, Heinz ; Chaudhuri, Bhabatosh ; Muller, Lionel ; Seeber, Egge ; Meijer, Laurent ; Lozach, Olivier ; Vangrevelinghe, Eric ; Furet, Pascal</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a445t-1848e606258b1c78496135401632a6fbe79cdd76f8ca58f32e8c83cc0b8c5aae3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Antineoplastic agents</topic><topic>Benzylidene Compounds - chemical synthesis</topic><topic>Benzylidene Compounds - chemistry</topic><topic>Biological and medical sciences</topic><topic>CDC2 Protein Kinase - antagonists & inhibitors</topic><topic>CDC2 Protein Kinase - chemistry</topic><topic>CDC2-CDC28 Kinases</topic><topic>Cyclin-Dependent Kinase 2</topic><topic>Cyclin-Dependent Kinase 4</topic><topic>Cyclin-Dependent Kinases - antagonists & inhibitors</topic><topic>Cyclin-Dependent Kinases - chemistry</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Flavonoids - chemistry</topic><topic>Furans - chemical synthesis</topic><topic>Furans - chemistry</topic><topic>General aspects</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Molecular Mimicry</topic><topic>Pharmacology. Drug treatments</topic><topic>Piperidines - chemistry</topic><topic>Protein-Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Protein-Serine-Threonine Kinases - chemistry</topic><topic>Proto-Oncogene Proteins</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schoepfer, Joseph</creatorcontrib><creatorcontrib>Fretz, Heinz</creatorcontrib><creatorcontrib>Chaudhuri, Bhabatosh</creatorcontrib><creatorcontrib>Muller, Lionel</creatorcontrib><creatorcontrib>Seeber, Egge</creatorcontrib><creatorcontrib>Meijer, Laurent</creatorcontrib><creatorcontrib>Lozach, Olivier</creatorcontrib><creatorcontrib>Vangrevelinghe, Eric</creatorcontrib><creatorcontrib>Furet, Pascal</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>Schoepfer, Joseph</au><au>Fretz, Heinz</au><au>Chaudhuri, Bhabatosh</au><au>Muller, Lionel</au><au>Seeber, Egge</au><au>Meijer, Laurent</au><au>Lozach, Olivier</au><au>Vangrevelinghe, Eric</au><au>Furet, Pascal</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure-Based Design and Synthesis of 2-Benzylidene-benzofuran-3-ones as Flavopiridol Mimics</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2002-04-25</date><risdate>2002</risdate><volume>45</volume><issue>9</issue><spage>1741</spage><epage>1747</epage><pages>1741-1747</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Novel 2-benzylidene-benzofuran-3-ones were designed and synthesized to mimic flavopiridol, a well-established inhibitor of cyclin-dependent kinases (CDKs) which is currently undergoing clinical evaluation. The underlying design concepts as well as the synthesis and structure−activity relationships (CDKs 1, 2, and 4 enzyme assays) of these mimics are described. Inhibitors of CDKs 1 and 2 that are more potent and selective than flavopiridol were obtained.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>11960485</pmid><doi>10.1021/jm0108348</doi><tpages>7</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2002-04, Vol.45 (9), p.1741-1747 |
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| source | ACS Publications; MEDLINE |
| subjects | Antineoplastic agents Benzylidene Compounds - chemical synthesis Benzylidene Compounds - chemistry Biological and medical sciences CDC2 Protein Kinase - antagonists & inhibitors CDC2 Protein Kinase - chemistry CDC2-CDC28 Kinases Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinases - antagonists & inhibitors Cyclin-Dependent Kinases - chemistry Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Flavonoids - chemistry Furans - chemical synthesis Furans - chemistry General aspects Medical sciences Models, Molecular Molecular Mimicry Pharmacology. Drug treatments Piperidines - chemistry Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - chemistry Proto-Oncogene Proteins Structure-Activity Relationship |
| title | Structure-Based Design and Synthesis of 2-Benzylidene-benzofuran-3-ones as Flavopiridol Mimics |
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