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Here, we establish an integrated workflow, combining chemogenomic profiling, ultra\u2010high\u2010resolution NMR, and modular total synthesis, for the comprehensive functional and structural interrogation of this challenging natural product class. Applying this approach to caylobolides, natural products isolated from scarce samples of\n                    <jats:italic>Okeania<\/jats:italic>\n                    sp., we performed structure\u2010activity relationship studies revealing that acetylation at C29 markedly reduces both cytotoxicity and antifungal activity, pinpointing a key pharmacophore. Mechanistic profiling suggests that these macrolides disrupt membrane integrity, similar to amantelide A. Using natural compound samples, we simultaneously revised the structure of caylobolide B through\n                    <jats:sup>1<\/jats:sup>\n                    H, 1D\u2010selective TOCSY and HSQC NMR, and developed a modular fragment\u2010based synthesis of these compounds. By providing a unified methodology for genetic sensitivity profiling, precise structure and stereochemistry determination, and modular total synthesis, this work unlocks new opportunities for the discovery and rational design of potent marine\u2010derived therapeutics.\n                  <\/jats:p>","DOI":"10.1002\/anie.202523117","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T07:46:05Z","timestamp":1765439165000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Caylobolide B: Structure Revision, Total Synthesis, Biological Characterization, and Discovery of New Analogues"],"prefix":"10.1002","volume":"65","author":[{"given":"Malcolm R. P.","family":"George","sequence":"first","affiliation":[{"name":"School of Chemistry University of Bristol  Cantock's Close Bristol BS8 1TS UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lobna A.","family":"Elsadek","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Center for Natural Products Drug Discovery and Development (CNPD3) University of Florida  PO Box 100485 Gainesville FL 32610 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Deering","sequence":"additional","affiliation":[{"name":"School of Chemistry University of Bristol  Cantock's Close Bristol BS8 1TS UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larissa Costa","family":"de Almeida","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Center for Natural Products Drug Discovery and Development (CNPD3) University of Florida  PO Box 100485 Gainesville FL 32610 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3155-1847","authenticated-orcid":false,"given":"Jasper L.","family":"Tyler","sequence":"additional","affiliation":[{"name":"School of Chemistry University of Bristol  Cantock's Close Bristol BS8 1TS UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Noble","sequence":"additional","affiliation":[{"name":"School of Chemistry University of Bristol  Cantock's Close Bristol BS8 1TS UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie J.","family":"Paul","sequence":"additional","affiliation":[{"name":"Smithsonian Marine Station  701 Seaway Drive Fort Pierce FL 34949 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hendrik","family":"Luesch","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Center for Natural Products Drug Discovery and Development (CNPD3) University of Florida  PO Box 100485 Gainesville FL 32610 USA"},{"name":"Program in Cancer and Stem Cell Biology Duke\u2010NUS Medical School  Singapore 169857 Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig P.","family":"Butts","sequence":"additional","affiliation":[{"name":"School of Chemistry University of Bristol  Cantock's Close Bristol BS8 1TS UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0344-6430","authenticated-orcid":false,"given":"Varinder K.","family":"Aggarwal","sequence":"additional","affiliation":[{"name":"School of Chemistry University of Bristol  Cantock's Close Bristol BS8 1TS 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