Small-molecule inhibitors of cathepsin L incorporating functionalized ring-fused molecular frameworks
Cathepsin L is a cysteine protease that is upregulated in a variety of malignant tumors and plays a significant role in cancer cell invasion and migration. It is an attractive target for the development of small-molecule inhibitors, which may prove beneficial as treatment agents to limit or arrest c...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2013-05, Vol.23 (9), p.2801-2807 |
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| creator | Song, Jiangli Jones, Lindsay M. Chavarria, Gustavo E. Charlton-Sevcik, Amanda K. Jantz, Adam Johansen, Audra Bayeh, Liela Soeung, Victoria Snyder, Lindsey K. Lade, Shawn D. Chaplin, David J. Trawick, Mary Lynn Pinney, Kevin G. |
| description | Cathepsin L is a cysteine protease that is upregulated in a variety of malignant tumors and plays a significant role in cancer cell invasion and migration. It is an attractive target for the development of small-molecule inhibitors, which may prove beneficial as treatment agents to limit or arrest cancer metastasis. We have previously identified a structurally diverse series of thiosemicarbazone-based inhibitors that incorporate the benzophenone and thiochromanone molecular scaffolds. Herein we report an important extension of this work designed to explore fused aryl–alkyl ring molecular systems that feature nitrogen atom incorporation (dihydroquinoline-based) and carbon atom exclusivity (tetrahydronaphthalene-based). In addition, analogues that contain oxygen (chromanone-based), sulfur (thiochroman-based), sulfoxide, and sulfone functionalization have been prepared in order to further investigate the structure–activity relationship aspects associated with these compounds and their ability to inhibit cathepsins L and B. From this small-library of 30 compounds, five were found to be strongly inhibitory (IC50 10,000nM) as inhibitors of cathepsin B, thus establishing a high degree (>20-fold) of selectivity (cathepsin L vs. cathepsin B) for the most active cathepsin L inhibitors in this series. |
| doi_str_mv | 10.1016/j.bmcl.2012.12.025 |
| format | Article |
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It is an attractive target for the development of small-molecule inhibitors, which may prove beneficial as treatment agents to limit or arrest cancer metastasis. We have previously identified a structurally diverse series of thiosemicarbazone-based inhibitors that incorporate the benzophenone and thiochromanone molecular scaffolds. Herein we report an important extension of this work designed to explore fused aryl–alkyl ring molecular systems that feature nitrogen atom incorporation (dihydroquinoline-based) and carbon atom exclusivity (tetrahydronaphthalene-based). In addition, analogues that contain oxygen (chromanone-based), sulfur (thiochroman-based), sulfoxide, and sulfone functionalization have been prepared in order to further investigate the structure–activity relationship aspects associated with these compounds and their ability to inhibit cathepsins L and B. From this small-library of 30 compounds, five were found to be strongly inhibitory (IC50 <500nM) against cathepsin L with the most active compound (7-bromodihydroquinoline thiosemicarbazone 48) demonstrating an IC50=164nM. All of the compounds evaluated were inactive (IC50 >10,000nM) as inhibitors of cathepsin B, thus establishing a high degree (>20-fold) of selectivity (cathepsin L vs. cathepsin B) for the most active cathepsin L inhibitors in this series.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2012.12.025</identifier><identifier>PMID: 23540644</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>benzophenone ; carbon ; cathepsin B ; Cathepsin B - antagonists & inhibitors ; Cathepsin B - metabolism ; Cathepsin L ; Cathepsin L - antagonists & inhibitors ; Cathepsin L - metabolism ; cell invasion ; Chemical synthesis ; Chromans - chemistry ; Enzyme inhibition ; inhibitory concentration 50 ; metastasis ; neoplasms ; nitrogen ; oxygen ; Protease Inhibitors - chemical synthesis ; Protease Inhibitors - chemistry ; Protease Inhibitors - metabolism ; Protein Binding ; Quinolines - chemistry ; Safrole - analogs & derivatives ; Safrole - chemistry ; Small Molecule Libraries - chemical synthesis ; Small Molecule Libraries - chemistry ; Small Molecule Libraries - metabolism ; Small-molecule inhibitors ; Structure-Activity Relationship ; structure-activity relationships ; Sulfones - chemistry ; sulfur ; Tetrahydronaphthalenes - chemistry</subject><ispartof>Bioorganic & medicinal chemistry letters, 2013-05, Vol.23 (9), p.2801-2807</ispartof><rights>2012 Elsevier Ltd</rights><rights>Copyright © 2012 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c380t-aa1e631dc308b4d07732fbb2384e01e1fc779f50c85be3512cdc074a6ea6808a3</citedby><cites>FETCH-LOGICAL-c380t-aa1e631dc308b4d07732fbb2384e01e1fc779f50c85be3512cdc074a6ea6808a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2012.12.025$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,777,781,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23540644$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Song, Jiangli</creatorcontrib><creatorcontrib>Jones, Lindsay M.</creatorcontrib><creatorcontrib>Chavarria, Gustavo E.</creatorcontrib><creatorcontrib>Charlton-Sevcik, Amanda K.</creatorcontrib><creatorcontrib>Jantz, Adam</creatorcontrib><creatorcontrib>Johansen, Audra</creatorcontrib><creatorcontrib>Bayeh, Liela</creatorcontrib><creatorcontrib>Soeung, Victoria</creatorcontrib><creatorcontrib>Snyder, Lindsey K.</creatorcontrib><creatorcontrib>Lade, Shawn D.</creatorcontrib><creatorcontrib>Chaplin, David J.</creatorcontrib><creatorcontrib>Trawick, Mary Lynn</creatorcontrib><creatorcontrib>Pinney, Kevin G.</creatorcontrib><title>Small-molecule inhibitors of cathepsin L incorporating functionalized ring-fused molecular frameworks</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Cathepsin L is a cysteine protease that is upregulated in a variety of malignant tumors and plays a significant role in cancer cell invasion and migration. It is an attractive target for the development of small-molecule inhibitors, which may prove beneficial as treatment agents to limit or arrest cancer metastasis. We have previously identified a structurally diverse series of thiosemicarbazone-based inhibitors that incorporate the benzophenone and thiochromanone molecular scaffolds. Herein we report an important extension of this work designed to explore fused aryl–alkyl ring molecular systems that feature nitrogen atom incorporation (dihydroquinoline-based) and carbon atom exclusivity (tetrahydronaphthalene-based). In addition, analogues that contain oxygen (chromanone-based), sulfur (thiochroman-based), sulfoxide, and sulfone functionalization have been prepared in order to further investigate the structure–activity relationship aspects associated with these compounds and their ability to inhibit cathepsins L and B. From this small-library of 30 compounds, five were found to be strongly inhibitory (IC50 <500nM) against cathepsin L with the most active compound (7-bromodihydroquinoline thiosemicarbazone 48) demonstrating an IC50=164nM. All of the compounds evaluated were inactive (IC50 >10,000nM) as inhibitors of cathepsin B, thus establishing a high degree (>20-fold) of selectivity (cathepsin L vs. cathepsin B) for the most active cathepsin L inhibitors in this series.</description><subject>benzophenone</subject><subject>carbon</subject><subject>cathepsin B</subject><subject>Cathepsin B - antagonists & inhibitors</subject><subject>Cathepsin B - metabolism</subject><subject>Cathepsin L</subject><subject>Cathepsin L - antagonists & inhibitors</subject><subject>Cathepsin L - metabolism</subject><subject>cell invasion</subject><subject>Chemical synthesis</subject><subject>Chromans - chemistry</subject><subject>Enzyme inhibition</subject><subject>inhibitory concentration 50</subject><subject>metastasis</subject><subject>neoplasms</subject><subject>nitrogen</subject><subject>oxygen</subject><subject>Protease Inhibitors - chemical synthesis</subject><subject>Protease Inhibitors - chemistry</subject><subject>Protease Inhibitors - metabolism</subject><subject>Protein Binding</subject><subject>Quinolines - chemistry</subject><subject>Safrole - analogs & derivatives</subject><subject>Safrole - chemistry</subject><subject>Small Molecule Libraries - chemical synthesis</subject><subject>Small Molecule Libraries - chemistry</subject><subject>Small Molecule Libraries - metabolism</subject><subject>Small-molecule inhibitors</subject><subject>Structure-Activity Relationship</subject><subject>structure-activity relationships</subject><subject>Sulfones - chemistry</subject><subject>sulfur</subject><subject>Tetrahydronaphthalenes - chemistry</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1r3DAQhkVJaDZJ_0APqY-9eDP6sGVDLmFp08JCDkkgNyHLo0Qb2dpKdkvy66tltzkWBmaQnnkZHkI-U1hSoPXlZtkNxi8ZULbMBaz6QBZU1KLkAqojsoC2hrJpxeMJOU1pA0AFCPGRnDBeCaiFWBC8G7T35RA8mtlj4cZn17kpxFQEWxg9PeM2ubFY5x8T4jZEPbnxqbDzaCYXRu3dG_ZFzG-lnVMeD1E6FjbqAf-E-JLOybHVPuGnQz8jD9-_3a9-lOvbm5-r63VpeANTqTXFmtPecGg60YOUnNmuY7wRCBSpNVK2tgLTVB3yijLTG5BC16jrBhrNz8jXfe42hl8zpkkNLhn0Xo8Y5qQoZ1IyWTOZUbZHTQwpRbRqG92g46uioHZ61Ubt9KqdXpUr681LF4f8uRuwf1_55zMDX_aA1UHpp-iSerjLCVV2z2nbskxc7QnMHn47jCoZh6PB3kU0k-qD-98FfwFxyJbc</recordid><startdate>20130501</startdate><enddate>20130501</enddate><creator>Song, Jiangli</creator><creator>Jones, Lindsay M.</creator><creator>Chavarria, Gustavo E.</creator><creator>Charlton-Sevcik, Amanda K.</creator><creator>Jantz, Adam</creator><creator>Johansen, Audra</creator><creator>Bayeh, Liela</creator><creator>Soeung, Victoria</creator><creator>Snyder, Lindsey K.</creator><creator>Lade, Shawn D.</creator><creator>Chaplin, David J.</creator><creator>Trawick, Mary Lynn</creator><creator>Pinney, Kevin G.</creator><general>Elsevier Ltd</general><scope>FBQ</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>20130501</creationdate><title>Small-molecule inhibitors of cathepsin L incorporating functionalized ring-fused molecular frameworks</title><author>Song, Jiangli ; Jones, Lindsay M. ; Chavarria, Gustavo E. ; Charlton-Sevcik, Amanda K. ; Jantz, Adam ; Johansen, Audra ; Bayeh, Liela ; Soeung, Victoria ; Snyder, Lindsey K. ; Lade, Shawn D. ; Chaplin, David J. ; Trawick, Mary Lynn ; Pinney, Kevin G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c380t-aa1e631dc308b4d07732fbb2384e01e1fc779f50c85be3512cdc074a6ea6808a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>benzophenone</topic><topic>carbon</topic><topic>cathepsin B</topic><topic>Cathepsin B - antagonists & inhibitors</topic><topic>Cathepsin B - metabolism</topic><topic>Cathepsin L</topic><topic>Cathepsin L - antagonists & inhibitors</topic><topic>Cathepsin L - metabolism</topic><topic>cell invasion</topic><topic>Chemical synthesis</topic><topic>Chromans - chemistry</topic><topic>Enzyme inhibition</topic><topic>inhibitory concentration 50</topic><topic>metastasis</topic><topic>neoplasms</topic><topic>nitrogen</topic><topic>oxygen</topic><topic>Protease Inhibitors - chemical synthesis</topic><topic>Protease Inhibitors - chemistry</topic><topic>Protease Inhibitors - metabolism</topic><topic>Protein Binding</topic><topic>Quinolines - chemistry</topic><topic>Safrole - analogs & derivatives</topic><topic>Safrole - chemistry</topic><topic>Small Molecule Libraries - chemical synthesis</topic><topic>Small Molecule Libraries - chemistry</topic><topic>Small Molecule Libraries - metabolism</topic><topic>Small-molecule inhibitors</topic><topic>Structure-Activity Relationship</topic><topic>structure-activity relationships</topic><topic>Sulfones - chemistry</topic><topic>sulfur</topic><topic>Tetrahydronaphthalenes - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Song, Jiangli</creatorcontrib><creatorcontrib>Jones, Lindsay M.</creatorcontrib><creatorcontrib>Chavarria, Gustavo E.</creatorcontrib><creatorcontrib>Charlton-Sevcik, Amanda K.</creatorcontrib><creatorcontrib>Jantz, Adam</creatorcontrib><creatorcontrib>Johansen, Audra</creatorcontrib><creatorcontrib>Bayeh, Liela</creatorcontrib><creatorcontrib>Soeung, Victoria</creatorcontrib><creatorcontrib>Snyder, Lindsey K.</creatorcontrib><creatorcontrib>Lade, Shawn D.</creatorcontrib><creatorcontrib>Chaplin, David J.</creatorcontrib><creatorcontrib>Trawick, Mary Lynn</creatorcontrib><creatorcontrib>Pinney, Kevin G.</creatorcontrib><collection>AGRIS</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>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Song, Jiangli</au><au>Jones, Lindsay M.</au><au>Chavarria, Gustavo E.</au><au>Charlton-Sevcik, Amanda K.</au><au>Jantz, Adam</au><au>Johansen, Audra</au><au>Bayeh, Liela</au><au>Soeung, Victoria</au><au>Snyder, Lindsey K.</au><au>Lade, Shawn D.</au><au>Chaplin, David J.</au><au>Trawick, Mary Lynn</au><au>Pinney, Kevin G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Small-molecule inhibitors of cathepsin L incorporating functionalized ring-fused molecular frameworks</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2013-05-01</date><risdate>2013</risdate><volume>23</volume><issue>9</issue><spage>2801</spage><epage>2807</epage><pages>2801-2807</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Cathepsin L is a cysteine protease that is upregulated in a variety of malignant tumors and plays a significant role in cancer cell invasion and migration. It is an attractive target for the development of small-molecule inhibitors, which may prove beneficial as treatment agents to limit or arrest cancer metastasis. We have previously identified a structurally diverse series of thiosemicarbazone-based inhibitors that incorporate the benzophenone and thiochromanone molecular scaffolds. Herein we report an important extension of this work designed to explore fused aryl–alkyl ring molecular systems that feature nitrogen atom incorporation (dihydroquinoline-based) and carbon atom exclusivity (tetrahydronaphthalene-based). In addition, analogues that contain oxygen (chromanone-based), sulfur (thiochroman-based), sulfoxide, and sulfone functionalization have been prepared in order to further investigate the structure–activity relationship aspects associated with these compounds and their ability to inhibit cathepsins L and B. From this small-library of 30 compounds, five were found to be strongly inhibitory (IC50 <500nM) against cathepsin L with the most active compound (7-bromodihydroquinoline thiosemicarbazone 48) demonstrating an IC50=164nM. All of the compounds evaluated were inactive (IC50 >10,000nM) as inhibitors of cathepsin B, thus establishing a high degree (>20-fold) of selectivity (cathepsin L vs. cathepsin B) for the most active cathepsin L inhibitors in this series.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>23540644</pmid><doi>10.1016/j.bmcl.2012.12.025</doi><tpages>7</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2013-05, Vol.23 (9), p.2801-2807 |
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| subjects | benzophenone carbon cathepsin B Cathepsin B - antagonists & inhibitors Cathepsin B - metabolism Cathepsin L Cathepsin L - antagonists & inhibitors Cathepsin L - metabolism cell invasion Chemical synthesis Chromans - chemistry Enzyme inhibition inhibitory concentration 50 metastasis neoplasms nitrogen oxygen Protease Inhibitors - chemical synthesis Protease Inhibitors - chemistry Protease Inhibitors - metabolism Protein Binding Quinolines - chemistry Safrole - analogs & derivatives Safrole - chemistry Small Molecule Libraries - chemical synthesis Small Molecule Libraries - chemistry Small Molecule Libraries - metabolism Small-molecule inhibitors Structure-Activity Relationship structure-activity relationships Sulfones - chemistry sulfur Tetrahydronaphthalenes - chemistry |
| title | Small-molecule inhibitors of cathepsin L incorporating functionalized ring-fused molecular frameworks |
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