Discovery of 5-(4-hydroxy-6-methyl-2-oxo-2 H-pyran-3-yl)-7-phenyl-( E)-2,3,6,7-tetrahydro-1,4-thiazepines as a new series of apoptosis inducers using a cell- and caspase-based HTS assay
The discovery and SAR studies of 5-(4-hydroxy-6-methyl-2-oxo-2 H-pyran-3-yl)-7-phenyl-( E)-2,3,6,7-tetrahydro-1,4-thiazepines as a novel series of apoptosis inducers is reported. We report the discovery of 5-(4-hydroxy-6-methyl-2-oxo-2 H-pyran-3-yl)-7-(4-methylphenyl)-( E)-2,3,6,7-tetrahydro-1,4-thi...
Gespeichert in:
| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2007-09, Vol.17 (17), p.4987-4990 |
|---|---|
| Hauptverfasser: | , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 4990 |
|---|---|
| container_issue | 17 |
| container_start_page | 4987 |
| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 17 |
| creator | Drewe, John Kasibhatla, Shailaja Tseng, Ben Shelton, Emma Sperandio, David Yee, Robert M. Litvak, Joane Sendzik, Martin Spencer, Jeffrey R. Cai, Sui Xiong |
| description | The discovery and SAR studies of 5-(4-hydroxy-6-methyl-2-oxo-2
H-pyran-3-yl)-7-phenyl-(
E)-2,3,6,7-tetrahydro-1,4-thiazepines as a novel series of apoptosis inducers is reported.
We report the discovery of 5-(4-hydroxy-6-methyl-2-oxo-2
H-pyran-3-yl)-7-(4-methylphenyl)-(
E)-2,3,6,7-tetrahydro-1,4-thiazepine (
2a) as an inducer of apoptosis using our proprietary cell- and caspase-based HTS assay. Through structure activity relationship (SAR) studies, 5-(4-hydroxy-6-methyl-2-oxo-2
H-pyran-3-yl)-7-(2-methoxy-4-(methylthio)phenyl)-(
E)-2,3,6,7-tetrahydro-1,4-thiazepine (
5d) was identified as a potent apoptosis inducer with an EC
50 value of 0.08
μM in T47D cells, which was >15-fold more potent than screening hit
2a. Compound
5d also was found to be highly active in a growth inhibition assay with a GI
50 value of 0.05
μM in T47D cells and to function as an inhibitor of tubulin polymerization. |
| doi_str_mv | 10.1016/j.bmcl.2007.05.098 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_68135486</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0960894X07006786</els_id><sourcerecordid>68135486</sourcerecordid><originalsourceid>FETCH-LOGICAL-c415t-a2b2dcfa51ffaecb76dac3bff9772a8638fdc61a2f16110bd5b4784691fb1f9f3</originalsourceid><addsrcrecordid>eNqFkdFqFDEUhgdRbK2-gBeSG6WFPWuSyWRmwBup1RUKXljBu5BJTtwss5NpMls7vplvZ9Zd6J1CSAj5zp_D-YriJaNLRpl8u1l2W9MvOaX1klZL2jaPilMmpIBS0OpxcUpbSaFpxfeT4llKG0qZoEI8LU5YXUleSnZa_P7gkwl3GGcSHKngXMB6tjHczyBhi9N67oFDuA_AyQrGOeoBSpj7C6hhXOOQn8_J1QXwRbmQixomnKL-mwBsIWBae_0LRz9gIjovMuBPkjD6fM__6TGMU0g-ET_YncGYyC754UcGDfY9ED1YYnQadULo8mbJ6uZrTkp6fl48cbpP-OJ4nhXfPl7dXK7g-sunz5fvr8EIVk2gecetcbpizmk0XS2tNmXnXFvXXDeybJw1kmnumGSMdrbqRN0I2TLXMde68qx4c8gdY7jdYZrUNo8sd6cHDLukZMPKSuSg_4GsrVhb8jqD_ACaGFKK6NQY_VbHWTGq9mbVRu3Nqr1ZRSuVzeaiV8f0XbdF-1ByVJmB10dAJ6N7l00Znx64pm3Lpikz9-7AYR7anceokvE4GLQ-opmUDf5fffwBCufA0w</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>19519327</pqid></control><display><type>article</type><title>Discovery of 5-(4-hydroxy-6-methyl-2-oxo-2 H-pyran-3-yl)-7-phenyl-( E)-2,3,6,7-tetrahydro-1,4-thiazepines as a new series of apoptosis inducers using a cell- and caspase-based HTS assay</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Drewe, John ; Kasibhatla, Shailaja ; Tseng, Ben ; Shelton, Emma ; Sperandio, David ; Yee, Robert M. ; Litvak, Joane ; Sendzik, Martin ; Spencer, Jeffrey R. ; Cai, Sui Xiong</creator><creatorcontrib>Drewe, John ; Kasibhatla, Shailaja ; Tseng, Ben ; Shelton, Emma ; Sperandio, David ; Yee, Robert M. ; Litvak, Joane ; Sendzik, Martin ; Spencer, Jeffrey R. ; Cai, Sui Xiong</creatorcontrib><description>The discovery and SAR studies of 5-(4-hydroxy-6-methyl-2-oxo-2
H-pyran-3-yl)-7-phenyl-(
E)-2,3,6,7-tetrahydro-1,4-thiazepines as a novel series of apoptosis inducers is reported.
We report the discovery of 5-(4-hydroxy-6-methyl-2-oxo-2
H-pyran-3-yl)-7-(4-methylphenyl)-(
E)-2,3,6,7-tetrahydro-1,4-thiazepine (
2a) as an inducer of apoptosis using our proprietary cell- and caspase-based HTS assay. Through structure activity relationship (SAR) studies, 5-(4-hydroxy-6-methyl-2-oxo-2
H-pyran-3-yl)-7-(2-methoxy-4-(methylthio)phenyl)-(
E)-2,3,6,7-tetrahydro-1,4-thiazepine (
5d) was identified as a potent apoptosis inducer with an EC
50 value of 0.08
μM in T47D cells, which was >15-fold more potent than screening hit
2a. Compound
5d also was found to be highly active in a growth inhibition assay with a GI
50 value of 0.05
μM in T47D cells and to function as an inhibitor of tubulin polymerization.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2007.05.098</identifier><identifier>PMID: 17562361</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>Antineoplastic agents ; Antineoplastic Agents - pharmacology ; Apoptosis ; Apoptosis inducer ; Biological and medical sciences ; Caspases - metabolism ; Cell Line, Tumor ; Cell Proliferation ; Chemistry, Pharmaceutical - methods ; Drug Design ; Drug Screening Assays, Antitumor ; General aspects ; HTS assay ; Humans ; Medical sciences ; Models, Chemical ; Neoplasms - drug therapy ; Pharmacology. Drug treatments ; Structure-Activity Relationship ; Thiazepines - chemistry ; Thiazepines - pharmacology ; Tubulin - chemistry ; Tubulin inhibitor</subject><ispartof>Bioorganic & medicinal chemistry letters, 2007-09, Vol.17 (17), p.4987-4990</ispartof><rights>2007 Elsevier Ltd</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-a2b2dcfa51ffaecb76dac3bff9772a8638fdc61a2f16110bd5b4784691fb1f9f3</citedby><cites>FETCH-LOGICAL-c415t-a2b2dcfa51ffaecb76dac3bff9772a8638fdc61a2f16110bd5b4784691fb1f9f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X07006786$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18993883$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17562361$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Drewe, John</creatorcontrib><creatorcontrib>Kasibhatla, Shailaja</creatorcontrib><creatorcontrib>Tseng, Ben</creatorcontrib><creatorcontrib>Shelton, Emma</creatorcontrib><creatorcontrib>Sperandio, David</creatorcontrib><creatorcontrib>Yee, Robert M.</creatorcontrib><creatorcontrib>Litvak, Joane</creatorcontrib><creatorcontrib>Sendzik, Martin</creatorcontrib><creatorcontrib>Spencer, Jeffrey R.</creatorcontrib><creatorcontrib>Cai, Sui Xiong</creatorcontrib><title>Discovery of 5-(4-hydroxy-6-methyl-2-oxo-2 H-pyran-3-yl)-7-phenyl-( E)-2,3,6,7-tetrahydro-1,4-thiazepines as a new series of apoptosis inducers using a cell- and caspase-based HTS assay</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>The discovery and SAR studies of 5-(4-hydroxy-6-methyl-2-oxo-2
H-pyran-3-yl)-7-phenyl-(
E)-2,3,6,7-tetrahydro-1,4-thiazepines as a novel series of apoptosis inducers is reported.
We report the discovery of 5-(4-hydroxy-6-methyl-2-oxo-2
H-pyran-3-yl)-7-(4-methylphenyl)-(
E)-2,3,6,7-tetrahydro-1,4-thiazepine (
2a) as an inducer of apoptosis using our proprietary cell- and caspase-based HTS assay. Through structure activity relationship (SAR) studies, 5-(4-hydroxy-6-methyl-2-oxo-2
H-pyran-3-yl)-7-(2-methoxy-4-(methylthio)phenyl)-(
E)-2,3,6,7-tetrahydro-1,4-thiazepine (
5d) was identified as a potent apoptosis inducer with an EC
50 value of 0.08
μM in T47D cells, which was >15-fold more potent than screening hit
2a. Compound
5d also was found to be highly active in a growth inhibition assay with a GI
50 value of 0.05
μM in T47D cells and to function as an inhibitor of tubulin polymerization.</description><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis inducer</subject><subject>Biological and medical sciences</subject><subject>Caspases - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Chemistry, Pharmaceutical - methods</subject><subject>Drug Design</subject><subject>Drug Screening Assays, Antitumor</subject><subject>General aspects</subject><subject>HTS assay</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Models, Chemical</subject><subject>Neoplasms - drug therapy</subject><subject>Pharmacology. Drug treatments</subject><subject>Structure-Activity Relationship</subject><subject>Thiazepines - chemistry</subject><subject>Thiazepines - pharmacology</subject><subject>Tubulin - chemistry</subject><subject>Tubulin inhibitor</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkdFqFDEUhgdRbK2-gBeSG6WFPWuSyWRmwBup1RUKXljBu5BJTtwss5NpMls7vplvZ9Zd6J1CSAj5zp_D-YriJaNLRpl8u1l2W9MvOaX1klZL2jaPilMmpIBS0OpxcUpbSaFpxfeT4llKG0qZoEI8LU5YXUleSnZa_P7gkwl3GGcSHKngXMB6tjHczyBhi9N67oFDuA_AyQrGOeoBSpj7C6hhXOOQn8_J1QXwRbmQixomnKL-mwBsIWBae_0LRz9gIjovMuBPkjD6fM__6TGMU0g-ET_YncGYyC754UcGDfY9ED1YYnQadULo8mbJ6uZrTkp6fl48cbpP-OJ4nhXfPl7dXK7g-sunz5fvr8EIVk2gecetcbpizmk0XS2tNmXnXFvXXDeybJw1kmnumGSMdrbqRN0I2TLXMde68qx4c8gdY7jdYZrUNo8sd6cHDLukZMPKSuSg_4GsrVhb8jqD_ACaGFKK6NQY_VbHWTGq9mbVRu3Nqr1ZRSuVzeaiV8f0XbdF-1ByVJmB10dAJ6N7l00Znx64pm3Lpikz9-7AYR7anceokvE4GLQ-opmUDf5fffwBCufA0w</recordid><startdate>20070901</startdate><enddate>20070901</enddate><creator>Drewe, John</creator><creator>Kasibhatla, Shailaja</creator><creator>Tseng, Ben</creator><creator>Shelton, Emma</creator><creator>Sperandio, David</creator><creator>Yee, Robert M.</creator><creator>Litvak, Joane</creator><creator>Sendzik, Martin</creator><creator>Spencer, Jeffrey R.</creator><creator>Cai, Sui Xiong</creator><general>Elsevier Ltd</general><general>Elsevier</general><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>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20070901</creationdate><title>Discovery of 5-(4-hydroxy-6-methyl-2-oxo-2 H-pyran-3-yl)-7-phenyl-( E)-2,3,6,7-tetrahydro-1,4-thiazepines as a new series of apoptosis inducers using a cell- and caspase-based HTS assay</title><author>Drewe, John ; Kasibhatla, Shailaja ; Tseng, Ben ; Shelton, Emma ; Sperandio, David ; Yee, Robert M. ; Litvak, Joane ; Sendzik, Martin ; Spencer, Jeffrey R. ; Cai, Sui Xiong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c415t-a2b2dcfa51ffaecb76dac3bff9772a8638fdc61a2f16110bd5b4784691fb1f9f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis</topic><topic>Apoptosis inducer</topic><topic>Biological and medical sciences</topic><topic>Caspases - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation</topic><topic>Chemistry, Pharmaceutical - methods</topic><topic>Drug Design</topic><topic>Drug Screening Assays, Antitumor</topic><topic>General aspects</topic><topic>HTS assay</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Models, Chemical</topic><topic>Neoplasms - drug therapy</topic><topic>Pharmacology. Drug treatments</topic><topic>Structure-Activity Relationship</topic><topic>Thiazepines - chemistry</topic><topic>Thiazepines - pharmacology</topic><topic>Tubulin - chemistry</topic><topic>Tubulin inhibitor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Drewe, John</creatorcontrib><creatorcontrib>Kasibhatla, Shailaja</creatorcontrib><creatorcontrib>Tseng, Ben</creatorcontrib><creatorcontrib>Shelton, Emma</creatorcontrib><creatorcontrib>Sperandio, David</creatorcontrib><creatorcontrib>Yee, Robert M.</creatorcontrib><creatorcontrib>Litvak, Joane</creatorcontrib><creatorcontrib>Sendzik, Martin</creatorcontrib><creatorcontrib>Spencer, Jeffrey R.</creatorcontrib><creatorcontrib>Cai, Sui Xiong</creatorcontrib><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>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Drewe, John</au><au>Kasibhatla, Shailaja</au><au>Tseng, Ben</au><au>Shelton, Emma</au><au>Sperandio, David</au><au>Yee, Robert M.</au><au>Litvak, Joane</au><au>Sendzik, Martin</au><au>Spencer, Jeffrey R.</au><au>Cai, Sui Xiong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of 5-(4-hydroxy-6-methyl-2-oxo-2 H-pyran-3-yl)-7-phenyl-( E)-2,3,6,7-tetrahydro-1,4-thiazepines as a new series of apoptosis inducers using a cell- and caspase-based HTS assay</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2007-09-01</date><risdate>2007</risdate><volume>17</volume><issue>17</issue><spage>4987</spage><epage>4990</epage><pages>4987-4990</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>The discovery and SAR studies of 5-(4-hydroxy-6-methyl-2-oxo-2
H-pyran-3-yl)-7-phenyl-(
E)-2,3,6,7-tetrahydro-1,4-thiazepines as a novel series of apoptosis inducers is reported.
We report the discovery of 5-(4-hydroxy-6-methyl-2-oxo-2
H-pyran-3-yl)-7-(4-methylphenyl)-(
E)-2,3,6,7-tetrahydro-1,4-thiazepine (
2a) as an inducer of apoptosis using our proprietary cell- and caspase-based HTS assay. Through structure activity relationship (SAR) studies, 5-(4-hydroxy-6-methyl-2-oxo-2
H-pyran-3-yl)-7-(2-methoxy-4-(methylthio)phenyl)-(
E)-2,3,6,7-tetrahydro-1,4-thiazepine (
5d) was identified as a potent apoptosis inducer with an EC
50 value of 0.08
μM in T47D cells, which was >15-fold more potent than screening hit
2a. Compound
5d also was found to be highly active in a growth inhibition assay with a GI
50 value of 0.05
μM in T47D cells and to function as an inhibitor of tubulin polymerization.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>17562361</pmid><doi>10.1016/j.bmcl.2007.05.098</doi><tpages>4</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2007-09, Vol.17 (17), p.4987-4990 |
| issn | 0960-894X 1464-3405 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_68135486 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Antineoplastic agents Antineoplastic Agents - pharmacology Apoptosis Apoptosis inducer Biological and medical sciences Caspases - metabolism Cell Line, Tumor Cell Proliferation Chemistry, Pharmaceutical - methods Drug Design Drug Screening Assays, Antitumor General aspects HTS assay Humans Medical sciences Models, Chemical Neoplasms - drug therapy Pharmacology. Drug treatments Structure-Activity Relationship Thiazepines - chemistry Thiazepines - pharmacology Tubulin - chemistry Tubulin inhibitor |
| title | Discovery of 5-(4-hydroxy-6-methyl-2-oxo-2 H-pyran-3-yl)-7-phenyl-( E)-2,3,6,7-tetrahydro-1,4-thiazepines as a new series of apoptosis inducers using a cell- and caspase-based HTS assay |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-08T08%3A20%3A19IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Discovery%20of%205-(4-hydroxy-6-methyl-2-oxo-2%20H-pyran-3-yl)-7-phenyl-(%20E)-2,3,6,7-tetrahydro-1,4-thiazepines%20as%20a%20new%20series%20of%20apoptosis%20inducers%20using%20a%20cell-%20and%20caspase-based%20HTS%20assay&rft.jtitle=Bioorganic%20&%20medicinal%20chemistry%20letters&rft.au=Drewe,%20John&rft.date=2007-09-01&rft.volume=17&rft.issue=17&rft.spage=4987&rft.epage=4990&rft.pages=4987-4990&rft.issn=0960-894X&rft.eissn=1464-3405&rft_id=info:doi/10.1016/j.bmcl.2007.05.098&rft_dat=%3Cproquest_cross%3E68135486%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=19519327&rft_id=info:pmid/17562361&rft_els_id=S0960894X07006786&rfr_iscdi=true |