CryoEM Structure with ATP Synthase Enables Late‐Stage Diversification of Cruentaren A
Cruentaren A is a natural product that exhibits potent antiproliferative activity against various cancer cell lines, yet its binding site within ATP synthase remained unknown, thus limiting the development of improved analogues as anticancer agents. Herein, we report the cryogenic electron microscop...
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| Veröffentlicht in: | Chemistry : a European journal 2023-05, Vol.29 (29), p.e202300262-n/a |
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| creator | Dou, Xiaozheng Guo, Hui D'Amico, Terin Abdallah, Leah Subramanian, Chitra Patel, Bhargav A. Cohen, Mark Rubinstein, John L. Blagg, Brian S. J. |
| description | Cruentaren A is a natural product that exhibits potent antiproliferative activity against various cancer cell lines, yet its binding site within ATP synthase remained unknown, thus limiting the development of improved analogues as anticancer agents. Herein, we report the cryogenic electron microscopy (cryoEM) structure of cruentaren A bound to ATP synthase, which allowed the design of new inhibitors through semisynthetic modification. Examples of cruentaren A derivatives include a trans‐alkene isomer, which was found to exhibit similar activity to cruentaren A against three cancer cell lines as well as several other analogues that retained potent inhibitory activity. Together, these studies provide a foundation for the generation of cruentaren A derivatives as potential therapeutics for the treatment of cancer.
Pattern for a new design: The cryogenic electron microscopy (cryoEM) structure of cruentaren A bound to ATP synthase is reported; it facilitated the design of new inhibitors through semisynthetic modification. Cruentaren A derivatives were developed, and a trans‐alkene isomer was found to exhibit similar activity to cruentaren A against three cancer cell lines as well as other analogues that still retained potent inhibitory activity. |
| doi_str_mv | 10.1002/chem.202300262 |
| format | Article |
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Pattern for a new design: The cryogenic electron microscopy (cryoEM) structure of cruentaren A bound to ATP synthase is reported; it facilitated the design of new inhibitors through semisynthetic modification. Cruentaren A derivatives were developed, and a trans‐alkene isomer was found to exhibit similar activity to cruentaren A against three cancer cell lines as well as other analogues that still retained potent inhibitory activity.</description><identifier>ISSN: 0947-6539</identifier><identifier>ISSN: 1521-3765</identifier><identifier>EISSN: 1521-3765</identifier><identifier>DOI: 10.1002/chem.202300262</identifier><identifier>PMID: 36867738</identifier><language>eng</language><publisher>Germany: Wiley Subscription Services, Inc</publisher><subject>Adenosine Triphosphate ; Anticancer properties ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Antitumor agents ; ATP ; ATP synthase ; Binding sites ; Cancer ; Cell Line ; Chemistry ; cruentaren A ; Cryoelectron Microscopy ; cryoEM structure ; Electron microscopy ; Humans ; late-stage modification ; Molecular Structure ; natural product ; Natural products ; Neoplasms ; Structure-Activity Relationship ; Tumor cell lines</subject><ispartof>Chemistry : a European journal, 2023-05, Vol.29 (29), p.e202300262-n/a</ispartof><rights>2023 Wiley‐VCH GmbH</rights><rights>2023 Wiley-VCH GmbH.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c4242-1b760baeffebca9b30a32f01f3ab978a519bd4d0dd3cb85f8179961a2f87fe593</cites><orcidid>0000-0002-6200-3480</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.202300262$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fchem.202300262$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,780,784,885,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36867738$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dou, Xiaozheng</creatorcontrib><creatorcontrib>Guo, Hui</creatorcontrib><creatorcontrib>D'Amico, Terin</creatorcontrib><creatorcontrib>Abdallah, Leah</creatorcontrib><creatorcontrib>Subramanian, Chitra</creatorcontrib><creatorcontrib>Patel, Bhargav A.</creatorcontrib><creatorcontrib>Cohen, Mark</creatorcontrib><creatorcontrib>Rubinstein, John L.</creatorcontrib><creatorcontrib>Blagg, Brian S. J.</creatorcontrib><title>CryoEM Structure with ATP Synthase Enables Late‐Stage Diversification of Cruentaren A</title><title>Chemistry : a European journal</title><addtitle>Chemistry</addtitle><description>Cruentaren A is a natural product that exhibits potent antiproliferative activity against various cancer cell lines, yet its binding site within ATP synthase remained unknown, thus limiting the development of improved analogues as anticancer agents. Herein, we report the cryogenic electron microscopy (cryoEM) structure of cruentaren A bound to ATP synthase, which allowed the design of new inhibitors through semisynthetic modification. Examples of cruentaren A derivatives include a trans‐alkene isomer, which was found to exhibit similar activity to cruentaren A against three cancer cell lines as well as several other analogues that retained potent inhibitory activity. Together, these studies provide a foundation for the generation of cruentaren A derivatives as potential therapeutics for the treatment of cancer.
Pattern for a new design: The cryogenic electron microscopy (cryoEM) structure of cruentaren A bound to ATP synthase is reported; it facilitated the design of new inhibitors through semisynthetic modification. Cruentaren A derivatives were developed, and a trans‐alkene isomer was found to exhibit similar activity to cruentaren A against three cancer cell lines as well as other analogues that still retained potent inhibitory activity.</description><subject>Adenosine Triphosphate</subject><subject>Anticancer properties</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antitumor agents</subject><subject>ATP</subject><subject>ATP synthase</subject><subject>Binding sites</subject><subject>Cancer</subject><subject>Cell Line</subject><subject>Chemistry</subject><subject>cruentaren A</subject><subject>Cryoelectron Microscopy</subject><subject>cryoEM structure</subject><subject>Electron microscopy</subject><subject>Humans</subject><subject>late-stage modification</subject><subject>Molecular Structure</subject><subject>natural product</subject><subject>Natural products</subject><subject>Neoplasms</subject><subject>Structure-Activity Relationship</subject><subject>Tumor cell lines</subject><issn>0947-6539</issn><issn>1521-3765</issn><issn>1521-3765</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkb1u2zAUhYmiReOkXTsWBLp0kcsfiRSnwlDcJICDFnA6dCIo6jJmIIspKSXwliV7njFPEhlO3Z-l0wVxP344Fwehd5RMKSHsk13BesoI4-NDsBdoQgtGMy5F8RJNiMplJgquDtBhSleEECU4f40OuCiFlLycoB9V3IT5OV72cbD9EAHf-n6FZxff8HLT9SuTAM87U7eQ8ML08Hj3sOzNJeBjfwMxeeet6X3ocHC4igN0vYnQPd7dz96gV860Cd4-zyP0_cv8ojrNFl9PzqrZIrM5y1lGaylIbcA5qK1RNSeGM0eo46ZWsjQFVXWTN6RpuK3LwpVUKiWoYa6UDgrFj9Dnnfd6qNfQ2DFCNK2-jn5t4kYH4_Xfm86v9GW40ZQwUghBRsPHZ0MMPwdIvV77ZKFtTQdhSJrJkucqZ5yP6Id_0KswxG68T7MxGeMsL7bC6Y6yMaQUwe3TUKK3teltbXpf2_jh_Z837PFfPY2A2gG3voXNf3S6Op2f_5Y_ATYlpvU</recordid><startdate>20230522</startdate><enddate>20230522</enddate><creator>Dou, Xiaozheng</creator><creator>Guo, Hui</creator><creator>D'Amico, Terin</creator><creator>Abdallah, Leah</creator><creator>Subramanian, Chitra</creator><creator>Patel, Bhargav A.</creator><creator>Cohen, Mark</creator><creator>Rubinstein, John L.</creator><creator>Blagg, Brian S. J.</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><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-6200-3480</orcidid></search><sort><creationdate>20230522</creationdate><title>CryoEM Structure with ATP Synthase Enables Late‐Stage Diversification of Cruentaren A</title><author>Dou, Xiaozheng ; Guo, Hui ; D'Amico, Terin ; Abdallah, Leah ; Subramanian, Chitra ; Patel, Bhargav A. ; Cohen, Mark ; Rubinstein, John L. ; Blagg, Brian S. J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4242-1b760baeffebca9b30a32f01f3ab978a519bd4d0dd3cb85f8179961a2f87fe593</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Adenosine Triphosphate</topic><topic>Anticancer properties</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antitumor agents</topic><topic>ATP</topic><topic>ATP synthase</topic><topic>Binding sites</topic><topic>Cancer</topic><topic>Cell Line</topic><topic>Chemistry</topic><topic>cruentaren A</topic><topic>Cryoelectron Microscopy</topic><topic>cryoEM structure</topic><topic>Electron microscopy</topic><topic>Humans</topic><topic>late-stage modification</topic><topic>Molecular Structure</topic><topic>natural product</topic><topic>Natural products</topic><topic>Neoplasms</topic><topic>Structure-Activity Relationship</topic><topic>Tumor cell lines</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dou, Xiaozheng</creatorcontrib><creatorcontrib>Guo, Hui</creatorcontrib><creatorcontrib>D'Amico, Terin</creatorcontrib><creatorcontrib>Abdallah, Leah</creatorcontrib><creatorcontrib>Subramanian, Chitra</creatorcontrib><creatorcontrib>Patel, Bhargav A.</creatorcontrib><creatorcontrib>Cohen, Mark</creatorcontrib><creatorcontrib>Rubinstein, John L.</creatorcontrib><creatorcontrib>Blagg, Brian S. J.</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Chemistry : a European journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dou, Xiaozheng</au><au>Guo, Hui</au><au>D'Amico, Terin</au><au>Abdallah, Leah</au><au>Subramanian, Chitra</au><au>Patel, Bhargav A.</au><au>Cohen, Mark</au><au>Rubinstein, John L.</au><au>Blagg, Brian S. J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CryoEM Structure with ATP Synthase Enables Late‐Stage Diversification of Cruentaren A</atitle><jtitle>Chemistry : a European journal</jtitle><addtitle>Chemistry</addtitle><date>2023-05-22</date><risdate>2023</risdate><volume>29</volume><issue>29</issue><spage>e202300262</spage><epage>n/a</epage><pages>e202300262-n/a</pages><issn>0947-6539</issn><issn>1521-3765</issn><eissn>1521-3765</eissn><abstract>Cruentaren A is a natural product that exhibits potent antiproliferative activity against various cancer cell lines, yet its binding site within ATP synthase remained unknown, thus limiting the development of improved analogues as anticancer agents. Herein, we report the cryogenic electron microscopy (cryoEM) structure of cruentaren A bound to ATP synthase, which allowed the design of new inhibitors through semisynthetic modification. Examples of cruentaren A derivatives include a trans‐alkene isomer, which was found to exhibit similar activity to cruentaren A against three cancer cell lines as well as several other analogues that retained potent inhibitory activity. Together, these studies provide a foundation for the generation of cruentaren A derivatives as potential therapeutics for the treatment of cancer.
Pattern for a new design: The cryogenic electron microscopy (cryoEM) structure of cruentaren A bound to ATP synthase is reported; it facilitated the design of new inhibitors through semisynthetic modification. Cruentaren A derivatives were developed, and a trans‐alkene isomer was found to exhibit similar activity to cruentaren A against three cancer cell lines as well as other analogues that still retained potent inhibitory activity.</abstract><cop>Germany</cop><pub>Wiley Subscription Services, Inc</pub><pmid>36867738</pmid><doi>10.1002/chem.202300262</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-6200-3480</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adenosine Triphosphate Anticancer properties Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Antitumor agents ATP ATP synthase Binding sites Cancer Cell Line Chemistry cruentaren A Cryoelectron Microscopy cryoEM structure Electron microscopy Humans late-stage modification Molecular Structure natural product Natural products Neoplasms Structure-Activity Relationship Tumor cell lines |
| title | CryoEM Structure with ATP Synthase Enables Late‐Stage Diversification of Cruentaren A |
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