Two‐Phase Electrosynthesis of Dihydroxycoumestans: Discovery of a New Scaffold for Topoisomerase I Poison
Coumestan represents a biologically relevant structural motif distributed in a number of natural products, and the rapid construction of related derivatives as well as the characterization of targets would accelerate lead compound discovery in medicinal chemistry. In this work, a general and scalabl...
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| Veröffentlicht in: | Chemistry : a European journal 2024-07, Vol.30 (39), p.e202401400-n/a |
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| creator | Chen, Yue‐Xi Wu, Shanchao Shen, Xiang Xu, Dong‐Fang Wang, Qian Ji, Su‐Hui Zhu, Huajian Wu, Ge Sheng, Chunquan Cai, Yun‐Rui |
| description | Coumestan represents a biologically relevant structural motif distributed in a number of natural products, and the rapid construction of related derivatives as well as the characterization of targets would accelerate lead compound discovery in medicinal chemistry. In this work, a general and scalable approach to 8,9‐dihydroxycoumestans via two‐electrode constant current electrolysis was developed. The application of a two‐phase (aqueous/organic) system plays a crucial role for success, protecting the sensitive o‐benzoquinone intermediates from over‐oxidation. Based on the structurally diverse products, a primary SAR study on coumestan scaffold was completed, and compound 3 r exhibited potent antiproliferative activities and a robust topoisomerase I (Top1) inhibitory activity. Further mechanism studies demonstrates that compound 3 r was a novel Top1 poison, which might open an avenue for the development of Top1‐targeted antitumor agent.
Electrosynthesis of dihydroxycoumestan and its application as topoisomerase I poison. |
| doi_str_mv | 10.1002/chem.202401400 |
| format | Article |
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Electrosynthesis of dihydroxycoumestan and its application as topoisomerase I poison.</description><identifier>ISSN: 0947-6539</identifier><identifier>ISSN: 1521-3765</identifier><identifier>EISSN: 1521-3765</identifier><identifier>DOI: 10.1002/chem.202401400</identifier><identifier>PMID: 38736421</identifier><language>eng</language><publisher>Germany: Wiley Subscription Services, Inc</publisher><subject>Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; antitumor ; Antitumor agents ; Benzoquinone ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Coumarins - chemistry ; Coumarins - pharmacology ; coumestan ; DNA topoisomerase ; DNA Topoisomerases, Type I - chemistry ; DNA Topoisomerases, Type I - metabolism ; Drug Screening Assays, Antitumor ; Electrolysis ; Humans ; Intermediates ; Lead compounds ; Natural products ; o-benzoquinone ; Oxidation ; Oxidation-Reduction ; Poisons ; Scaffolds ; Structural analysis ; Structure-Activity Relationship ; topoisomerase I ; Topoisomerase I Inhibitors - chemical synthesis ; Topoisomerase I Inhibitors - chemistry ; Topoisomerase I Inhibitors - pharmacology ; two-phase electrosynthesis ; Umbelliferones - chemistry ; Umbelliferones - pharmacology</subject><ispartof>Chemistry : a European journal, 2024-07, Vol.30 (39), p.e202401400-n/a</ispartof><rights>2024 Wiley-VCH GmbH</rights><rights>2024 Wiley-VCH GmbH.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c2580-18324b2bbbe4a48c0d6b431e53b9a35d7f22f28c1d610213209712cccb128a753</cites><orcidid>0000-0002-9637-9056</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fchem.202401400$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fchem.202401400$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27903,27904,45553,45554</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38736421$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Yue‐Xi</creatorcontrib><creatorcontrib>Wu, Shanchao</creatorcontrib><creatorcontrib>Shen, Xiang</creatorcontrib><creatorcontrib>Xu, Dong‐Fang</creatorcontrib><creatorcontrib>Wang, Qian</creatorcontrib><creatorcontrib>Ji, Su‐Hui</creatorcontrib><creatorcontrib>Zhu, Huajian</creatorcontrib><creatorcontrib>Wu, Ge</creatorcontrib><creatorcontrib>Sheng, Chunquan</creatorcontrib><creatorcontrib>Cai, Yun‐Rui</creatorcontrib><title>Two‐Phase Electrosynthesis of Dihydroxycoumestans: Discovery of a New Scaffold for Topoisomerase I Poison</title><title>Chemistry : a European journal</title><addtitle>Chemistry</addtitle><description>Coumestan represents a biologically relevant structural motif distributed in a number of natural products, and the rapid construction of related derivatives as well as the characterization of targets would accelerate lead compound discovery in medicinal chemistry. In this work, a general and scalable approach to 8,9‐dihydroxycoumestans via two‐electrode constant current electrolysis was developed. The application of a two‐phase (aqueous/organic) system plays a crucial role for success, protecting the sensitive o‐benzoquinone intermediates from over‐oxidation. Based on the structurally diverse products, a primary SAR study on coumestan scaffold was completed, and compound 3 r exhibited potent antiproliferative activities and a robust topoisomerase I (Top1) inhibitory activity. Further mechanism studies demonstrates that compound 3 r was a novel Top1 poison, which might open an avenue for the development of Top1‐targeted antitumor agent.
Electrosynthesis of dihydroxycoumestan and its application as topoisomerase I poison.</description><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>antitumor</subject><subject>Antitumor agents</subject><subject>Benzoquinone</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Coumarins - chemistry</subject><subject>Coumarins - pharmacology</subject><subject>coumestan</subject><subject>DNA topoisomerase</subject><subject>DNA Topoisomerases, Type I - chemistry</subject><subject>DNA Topoisomerases, Type I - metabolism</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Electrolysis</subject><subject>Humans</subject><subject>Intermediates</subject><subject>Lead compounds</subject><subject>Natural products</subject><subject>o-benzoquinone</subject><subject>Oxidation</subject><subject>Oxidation-Reduction</subject><subject>Poisons</subject><subject>Scaffolds</subject><subject>Structural analysis</subject><subject>Structure-Activity Relationship</subject><subject>topoisomerase I</subject><subject>Topoisomerase I Inhibitors - chemical synthesis</subject><subject>Topoisomerase I Inhibitors - chemistry</subject><subject>Topoisomerase I Inhibitors - pharmacology</subject><subject>two-phase electrosynthesis</subject><subject>Umbelliferones - chemistry</subject><subject>Umbelliferones - pharmacology</subject><issn>0947-6539</issn><issn>1521-3765</issn><issn>1521-3765</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkctO3DAUhq2KqgyXbZdVJDbdZDj2seOkOzQdLhIFJIZ15DiOJjSJB3vCkF0foc_Ik-BoKJXYsDry0edPv85PyFcKUwrAjvXStFMGjAPlAJ_IhApGY5SJ2CETyLiME4HZLtnz_h4AsgTxC9nFVGLCGZ2Q34uNff7z92apvInmjdFrZ_3QrZfG1z6yVfSzXg6ls0-Dtn1r_Fp1_kdYem0fjRtGQkVXZhPdalVVtimjyrpoYVe29rY1btReRDfjqzsgnyvVeHP4OvfJ3el8MTuPL6_PLmYnl7FmIoWYpsh4wYqiMFzxVEOZFBypEVhkCkUpK8YqlmpaJhQYRQaZpExrXVCWKilwn3zfelfOPvQhc96GvKZpVGds73MEwTmiFDygR-_Qe9u7LqQLlExTwARloKZbSofjeGeqfOXqVrkhp5CPNeRjDflbDeHDt1dtX7SmfMP_3T0A2RbY1I0ZPtDls_P5r__yF_vslJg</recordid><startdate>20240711</startdate><enddate>20240711</enddate><creator>Chen, Yue‐Xi</creator><creator>Wu, Shanchao</creator><creator>Shen, Xiang</creator><creator>Xu, Dong‐Fang</creator><creator>Wang, Qian</creator><creator>Ji, Su‐Hui</creator><creator>Zhu, Huajian</creator><creator>Wu, Ge</creator><creator>Sheng, Chunquan</creator><creator>Cai, Yun‐Rui</creator><general>Wiley Subscription Services, Inc</general><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>7SR</scope><scope>8BQ</scope><scope>8FD</scope><scope>JG9</scope><scope>K9.</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-9637-9056</orcidid></search><sort><creationdate>20240711</creationdate><title>Two‐Phase Electrosynthesis of Dihydroxycoumestans: Discovery of a New Scaffold for Topoisomerase I Poison</title><author>Chen, Yue‐Xi ; Wu, Shanchao ; Shen, Xiang ; Xu, Dong‐Fang ; Wang, Qian ; Ji, Su‐Hui ; Zhu, Huajian ; Wu, Ge ; Sheng, Chunquan ; Cai, Yun‐Rui</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c2580-18324b2bbbe4a48c0d6b431e53b9a35d7f22f28c1d610213209712cccb128a753</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>antitumor</topic><topic>Antitumor agents</topic><topic>Benzoquinone</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Coumarins - chemistry</topic><topic>Coumarins - pharmacology</topic><topic>coumestan</topic><topic>DNA topoisomerase</topic><topic>DNA Topoisomerases, Type I - chemistry</topic><topic>DNA Topoisomerases, Type I - metabolism</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Electrolysis</topic><topic>Humans</topic><topic>Intermediates</topic><topic>Lead compounds</topic><topic>Natural products</topic><topic>o-benzoquinone</topic><topic>Oxidation</topic><topic>Oxidation-Reduction</topic><topic>Poisons</topic><topic>Scaffolds</topic><topic>Structural analysis</topic><topic>Structure-Activity Relationship</topic><topic>topoisomerase I</topic><topic>Topoisomerase I Inhibitors - chemical synthesis</topic><topic>Topoisomerase I Inhibitors - chemistry</topic><topic>Topoisomerase I Inhibitors - pharmacology</topic><topic>two-phase electrosynthesis</topic><topic>Umbelliferones - chemistry</topic><topic>Umbelliferones - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Yue‐Xi</creatorcontrib><creatorcontrib>Wu, Shanchao</creatorcontrib><creatorcontrib>Shen, Xiang</creatorcontrib><creatorcontrib>Xu, Dong‐Fang</creatorcontrib><creatorcontrib>Wang, Qian</creatorcontrib><creatorcontrib>Ji, Su‐Hui</creatorcontrib><creatorcontrib>Zhu, Huajian</creatorcontrib><creatorcontrib>Wu, Ge</creatorcontrib><creatorcontrib>Sheng, Chunquan</creatorcontrib><creatorcontrib>Cai, Yun‐Rui</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Engineered Materials Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Materials Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Chemistry : a European journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Yue‐Xi</au><au>Wu, Shanchao</au><au>Shen, Xiang</au><au>Xu, Dong‐Fang</au><au>Wang, Qian</au><au>Ji, Su‐Hui</au><au>Zhu, Huajian</au><au>Wu, Ge</au><au>Sheng, Chunquan</au><au>Cai, Yun‐Rui</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Two‐Phase Electrosynthesis of Dihydroxycoumestans: Discovery of a New Scaffold for Topoisomerase I Poison</atitle><jtitle>Chemistry : a European journal</jtitle><addtitle>Chemistry</addtitle><date>2024-07-11</date><risdate>2024</risdate><volume>30</volume><issue>39</issue><spage>e202401400</spage><epage>n/a</epage><pages>e202401400-n/a</pages><issn>0947-6539</issn><issn>1521-3765</issn><eissn>1521-3765</eissn><abstract>Coumestan represents a biologically relevant structural motif distributed in a number of natural products, and the rapid construction of related derivatives as well as the characterization of targets would accelerate lead compound discovery in medicinal chemistry. In this work, a general and scalable approach to 8,9‐dihydroxycoumestans via two‐electrode constant current electrolysis was developed. The application of a two‐phase (aqueous/organic) system plays a crucial role for success, protecting the sensitive o‐benzoquinone intermediates from over‐oxidation. Based on the structurally diverse products, a primary SAR study on coumestan scaffold was completed, and compound 3 r exhibited potent antiproliferative activities and a robust topoisomerase I (Top1) inhibitory activity. Further mechanism studies demonstrates that compound 3 r was a novel Top1 poison, which might open an avenue for the development of Top1‐targeted antitumor agent.
Electrosynthesis of dihydroxycoumestan and its application as topoisomerase I poison.</abstract><cop>Germany</cop><pub>Wiley Subscription Services, Inc</pub><pmid>38736421</pmid><doi>10.1002/chem.202401400</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0002-9637-9056</orcidid></addata></record> |
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| subjects | Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology antitumor Antitumor agents Benzoquinone Cell Line, Tumor Cell Proliferation - drug effects Coumarins - chemistry Coumarins - pharmacology coumestan DNA topoisomerase DNA Topoisomerases, Type I - chemistry DNA Topoisomerases, Type I - metabolism Drug Screening Assays, Antitumor Electrolysis Humans Intermediates Lead compounds Natural products o-benzoquinone Oxidation Oxidation-Reduction Poisons Scaffolds Structural analysis Structure-Activity Relationship topoisomerase I Topoisomerase I Inhibitors - chemical synthesis Topoisomerase I Inhibitors - chemistry Topoisomerase I Inhibitors - pharmacology two-phase electrosynthesis Umbelliferones - chemistry Umbelliferones - pharmacology |
| title | Two‐Phase Electrosynthesis of Dihydroxycoumestans: Discovery of a New Scaffold for Topoisomerase I Poison |
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