Benzenesulfonamides: A Unique Class of Chemokine Receptor Type 4 Inhibitors
The interaction of CXCR4 with CXCL12 (SDF‐1) plays a critical role in cancer metastasis by facilitating the homing of tumor cells to metastatic sites. Based on our previously published work on CXCR4 antagonists, we have synthesized a series of aryl sulfonamides that inhibit the CXCR4/CXCL12 interact...
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| Veröffentlicht in: | ChemMedChem 2013-04, Vol.8 (4), p.622-632 |
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| creator | Mooring, Suazette Reid Liu, Jin Liang, Zhongxing Ahn, Jeffrey Hong, Samuel Yoon, Younghyoun Snyder, James P. Shim, Hyunsuk |
| description | The interaction of CXCR4 with CXCL12 (SDF‐1) plays a critical role in cancer metastasis by facilitating the homing of tumor cells to metastatic sites. Based on our previously published work on CXCR4 antagonists, we have synthesized a series of aryl sulfonamides that inhibit the CXCR4/CXCL12 interaction. Analogue bioactivities were assessed with binding affinity and Matrigel invasion assays. Computer modeling was employed to evaluate a selection of the new analogues docked into the CXCR4 X‐ray structure and to rationalize discrepancies between the affinity and Matrigel in vitro assays. A lead compound displays nanomolar potency in the binding affinity assay (IC50=8.0 nM) and the Matrigel invasion assay (100 % blockade of invasion at 10 nM). These data demonstrate that benzenesulfonamides are a unique class of CXCR4 inhibitors with high potency.
Running interference: A series of sulfonamide analogues were synthesized by modification of the tunable area around the previously synthesized potent dipyridine 1. Several of these analogues inhibit the CXCR4–CXCL12 interaction, and are suitable leads for the development of anti‐metastasis agents. |
| doi_str_mv | 10.1002/cmdc.201200582 |
| format | Article |
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Running interference: A series of sulfonamide analogues were synthesized by modification of the tunable area around the previously synthesized potent dipyridine 1. Several of these analogues inhibit the CXCR4–CXCL12 interaction, and are suitable leads for the development of anti‐metastasis agents.</description><identifier>ISSN: 1860-7179</identifier><identifier>EISSN: 1860-7187</identifier><identifier>DOI: 10.1002/cmdc.201200582</identifier><identifier>PMID: 23468189</identifier><language>eng</language><publisher>Weinheim: WILEY-VCH Verlag</publisher><subject>Benzenesulfonamides ; Binding Sites ; Cell Line, Tumor ; Chemokine CXCL12 - chemistry ; Chemokine CXCL12 - metabolism ; CXCR4 inhibitors ; Drug Design ; Humans ; inflammation ; metastasis ; Molecular Docking Simulation ; Protein Binding ; Protein Interaction Maps ; Protein Structure, Tertiary ; Pyridines - chemistry ; Receptors, CXCR4 - antagonists & inhibitors ; Receptors, CXCR4 - metabolism ; sulfonamides ; Sulfonamides - chemical synthesis ; Sulfonamides - chemistry ; Sulfonamides - metabolism</subject><ispartof>ChemMedChem, 2013-04, Vol.8 (4), p.622-632</ispartof><rights>Copyright © 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim</rights><rights>Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3232-dc3ea7aa8c1afab028f429d269e5dc9c2abe9e715903684f751518cc62d865083</citedby><cites>FETCH-LOGICAL-c3232-dc3ea7aa8c1afab028f429d269e5dc9c2abe9e715903684f751518cc62d865083</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fcmdc.201200582$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fcmdc.201200582$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,780,784,885,1416,27923,27924,45573,45574</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23468189$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mooring, Suazette Reid</creatorcontrib><creatorcontrib>Liu, Jin</creatorcontrib><creatorcontrib>Liang, Zhongxing</creatorcontrib><creatorcontrib>Ahn, Jeffrey</creatorcontrib><creatorcontrib>Hong, Samuel</creatorcontrib><creatorcontrib>Yoon, Younghyoun</creatorcontrib><creatorcontrib>Snyder, James P.</creatorcontrib><creatorcontrib>Shim, Hyunsuk</creatorcontrib><title>Benzenesulfonamides: A Unique Class of Chemokine Receptor Type 4 Inhibitors</title><title>ChemMedChem</title><addtitle>ChemMedChem</addtitle><description>The interaction of CXCR4 with CXCL12 (SDF‐1) plays a critical role in cancer metastasis by facilitating the homing of tumor cells to metastatic sites. Based on our previously published work on CXCR4 antagonists, we have synthesized a series of aryl sulfonamides that inhibit the CXCR4/CXCL12 interaction. Analogue bioactivities were assessed with binding affinity and Matrigel invasion assays. Computer modeling was employed to evaluate a selection of the new analogues docked into the CXCR4 X‐ray structure and to rationalize discrepancies between the affinity and Matrigel in vitro assays. A lead compound displays nanomolar potency in the binding affinity assay (IC50=8.0 nM) and the Matrigel invasion assay (100 % blockade of invasion at 10 nM). These data demonstrate that benzenesulfonamides are a unique class of CXCR4 inhibitors with high potency.
Running interference: A series of sulfonamide analogues were synthesized by modification of the tunable area around the previously synthesized potent dipyridine 1. Several of these analogues inhibit the CXCR4–CXCL12 interaction, and are suitable leads for the development of anti‐metastasis agents.</description><subject>Benzenesulfonamides</subject><subject>Binding Sites</subject><subject>Cell Line, Tumor</subject><subject>Chemokine CXCL12 - chemistry</subject><subject>Chemokine CXCL12 - metabolism</subject><subject>CXCR4 inhibitors</subject><subject>Drug Design</subject><subject>Humans</subject><subject>inflammation</subject><subject>metastasis</subject><subject>Molecular Docking Simulation</subject><subject>Protein Binding</subject><subject>Protein Interaction Maps</subject><subject>Protein Structure, Tertiary</subject><subject>Pyridines - chemistry</subject><subject>Receptors, CXCR4 - antagonists & inhibitors</subject><subject>Receptors, CXCR4 - metabolism</subject><subject>sulfonamides</subject><subject>Sulfonamides - chemical synthesis</subject><subject>Sulfonamides - chemistry</subject><subject>Sulfonamides - metabolism</subject><issn>1860-7179</issn><issn>1860-7187</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUtP3DAUhS3UCijttssqy24y-JH40UUlSMtLM1SqhnZpeZybjktiT-MZYFix4Y_2l2A0ENFVV76yz_mu7z0IvSd4RDCm-7ar7YhiQjEuJd1Cu0RynAsixauhFmoHvYnxN8ZFIYncRjuUFTxVahdNDsHfgoe4apvgTedqiJ-yg-zCuz8ryKrWxJiFJqvm0IVL5yH7DhYWy9Bn0_UC_t7dF9mpn7uZS1fxLXrdmDbCu6dzD10cfZ1WJ_n42_FpdTDOLaOM5rVlYIQx0hLTmBmmsimoqilXUNZWWWpmoECQUmHGZdGIkpREWstpLXmJJdtDnzfcxWrWQW3BL3vT6kXvOtOvdTBO__vi3Vz_CleaiZJSxRPg4xOgD2nOuNSdixba1ngIq6gJSzsVhCqapKON1PYhxh6aoQ3B-jED_ZiBHjJIhg8vPzfIn5eeBGojuHYtrP-D09XkS_USnm-8Li7hZvCa_lJzkabTP8-PNWfTyfisOtE_2AOzQ6Q0</recordid><startdate>201304</startdate><enddate>201304</enddate><creator>Mooring, Suazette Reid</creator><creator>Liu, Jin</creator><creator>Liang, Zhongxing</creator><creator>Ahn, Jeffrey</creator><creator>Hong, Samuel</creator><creator>Yoon, Younghyoun</creator><creator>Snyder, James P.</creator><creator>Shim, Hyunsuk</creator><general>WILEY-VCH Verlag</general><general>WILEY‐VCH Verlag</general><scope>BSCLL</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><scope>5PM</scope></search><sort><creationdate>201304</creationdate><title>Benzenesulfonamides: A Unique Class of Chemokine Receptor Type 4 Inhibitors</title><author>Mooring, Suazette Reid ; Liu, Jin ; Liang, Zhongxing ; Ahn, Jeffrey ; Hong, Samuel ; Yoon, Younghyoun ; Snyder, James P. ; Shim, Hyunsuk</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3232-dc3ea7aa8c1afab028f429d269e5dc9c2abe9e715903684f751518cc62d865083</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Benzenesulfonamides</topic><topic>Binding Sites</topic><topic>Cell Line, Tumor</topic><topic>Chemokine CXCL12 - chemistry</topic><topic>Chemokine CXCL12 - metabolism</topic><topic>CXCR4 inhibitors</topic><topic>Drug Design</topic><topic>Humans</topic><topic>inflammation</topic><topic>metastasis</topic><topic>Molecular Docking Simulation</topic><topic>Protein Binding</topic><topic>Protein Interaction Maps</topic><topic>Protein Structure, Tertiary</topic><topic>Pyridines - chemistry</topic><topic>Receptors, CXCR4 - antagonists & inhibitors</topic><topic>Receptors, CXCR4 - metabolism</topic><topic>sulfonamides</topic><topic>Sulfonamides - chemical synthesis</topic><topic>Sulfonamides - chemistry</topic><topic>Sulfonamides - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mooring, Suazette Reid</creatorcontrib><creatorcontrib>Liu, Jin</creatorcontrib><creatorcontrib>Liang, Zhongxing</creatorcontrib><creatorcontrib>Ahn, Jeffrey</creatorcontrib><creatorcontrib>Hong, Samuel</creatorcontrib><creatorcontrib>Yoon, Younghyoun</creatorcontrib><creatorcontrib>Snyder, James P.</creatorcontrib><creatorcontrib>Shim, Hyunsuk</creatorcontrib><collection>Istex</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>ChemMedChem</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mooring, Suazette Reid</au><au>Liu, Jin</au><au>Liang, Zhongxing</au><au>Ahn, Jeffrey</au><au>Hong, Samuel</au><au>Yoon, Younghyoun</au><au>Snyder, James P.</au><au>Shim, Hyunsuk</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Benzenesulfonamides: A Unique Class of Chemokine Receptor Type 4 Inhibitors</atitle><jtitle>ChemMedChem</jtitle><addtitle>ChemMedChem</addtitle><date>2013-04</date><risdate>2013</risdate><volume>8</volume><issue>4</issue><spage>622</spage><epage>632</epage><pages>622-632</pages><issn>1860-7179</issn><eissn>1860-7187</eissn><abstract>The interaction of CXCR4 with CXCL12 (SDF‐1) plays a critical role in cancer metastasis by facilitating the homing of tumor cells to metastatic sites. Based on our previously published work on CXCR4 antagonists, we have synthesized a series of aryl sulfonamides that inhibit the CXCR4/CXCL12 interaction. Analogue bioactivities were assessed with binding affinity and Matrigel invasion assays. Computer modeling was employed to evaluate a selection of the new analogues docked into the CXCR4 X‐ray structure and to rationalize discrepancies between the affinity and Matrigel in vitro assays. A lead compound displays nanomolar potency in the binding affinity assay (IC50=8.0 nM) and the Matrigel invasion assay (100 % blockade of invasion at 10 nM). These data demonstrate that benzenesulfonamides are a unique class of CXCR4 inhibitors with high potency.
Running interference: A series of sulfonamide analogues were synthesized by modification of the tunable area around the previously synthesized potent dipyridine 1. Several of these analogues inhibit the CXCR4–CXCL12 interaction, and are suitable leads for the development of anti‐metastasis agents.</abstract><cop>Weinheim</cop><pub>WILEY-VCH Verlag</pub><pmid>23468189</pmid><doi>10.1002/cmdc.201200582</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Benzenesulfonamides Binding Sites Cell Line, Tumor Chemokine CXCL12 - chemistry Chemokine CXCL12 - metabolism CXCR4 inhibitors Drug Design Humans inflammation metastasis Molecular Docking Simulation Protein Binding Protein Interaction Maps Protein Structure, Tertiary Pyridines - chemistry Receptors, CXCR4 - antagonists & inhibitors Receptors, CXCR4 - metabolism sulfonamides Sulfonamides - chemical synthesis Sulfonamides - chemistry Sulfonamides - metabolism |
| title | Benzenesulfonamides: A Unique Class of Chemokine Receptor Type 4 Inhibitors |
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