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Herein, we report the cryogenic electron microscopy (cryoEM) structure of cruentaren\u2005A bound to ATP synthase, which allowed the design of new inhibitors through semisynthetic modification. Examples of cruentaren\u2005A derivatives include a <jats:italic>trans<\/jats:italic>\u2010alkene isomer, which was found to exhibit similar activity to cruentaren\u2005A 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\u2005A derivatives as potential therapeutics for the treatment of cancer.<\/jats:p>","DOI":"10.1002\/chem.202300262","type":"journal-article","created":{"date-parts":[[2023,3,3]],"date-time":"2023-03-03T14:43:13Z","timestamp":1677854593000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CryoEM Structure with ATP Synthase Enables Late\u2010Stage Diversification of Cruentaren\u2005A"],"prefix":"10.1002","volume":"29","author":[{"given":"Xiaozheng","family":"Dou","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry The University of Notre Dame  Notre Dame IN 46556 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Guo","sequence":"additional","affiliation":[{"name":"Molecular Medicine Program The Hospital for Sick Children  Toronto ON M5G 0A4 Canada"},{"name":"Department of Medical Biophysics University of Toronto  Toronto ON M5G 1L7 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Terin","family":"D'Amico","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry The University of Notre Dame  Notre Dame IN 46556 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leah","family":"Abdallah","sequence":"additional","affiliation":[{"name":"Department of Surgery University of Michigan  Ann Arbor MI 48109 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chitra","family":"Subramanian","sequence":"additional","affiliation":[{"name":"Departments of Surgery and Bioengineering Carle Illinois College of Medicine University of Illinois  Urbana-Champaign IL 61801 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bhargav A.","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry The University of Notre Dame  Notre Dame IN 46556 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Cohen","sequence":"additional","affiliation":[{"name":"Departments of Surgery and Bioengineering Carle Illinois College of Medicine University of Illinois  Urbana-Champaign IL 61801 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John L.","family":"Rubinstein","sequence":"additional","affiliation":[{"name":"Molecular Medicine Program The Hospital for Sick Children  Toronto ON M5G 0A4 Canada"},{"name":"Department of Medical Biophysics University of Toronto  Toronto ON M5G 1L7 Canada"},{"name":"Departments of Biochemistry University of Toronto  Toronto ON M5S 1A8 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6200-3480","authenticated-orcid":false,"given":"Brian S. 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