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| Autores principales: | , , , , , , , , , |
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| Formato: | Artículo científico |
| Lenguaje: | en |
| Publicado: |
Angewandte Chemie (International ed. in English)
2026
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| Materias: | |
| Acceso en línea: | https://pubmed.ncbi.nlm.nih.gov/41376297/ |
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| _version_ | 1868266114430009344 |
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| author | George, Malcolm R P Elsadek, Lobna A Deering, Max de Almeida, Larissa Costa Tyler, Jasper L Noble, Adam Paul, Valerie J Luesch, Hendrik Butts, Craig P Aggarwal, Varinder K |
| author_facet | George, Malcolm R P Elsadek, Lobna A Deering, Max de Almeida, Larissa Costa Tyler, Jasper L Noble, Adam Paul, Valerie J Luesch, Hendrik Butts, Craig P Aggarwal, Varinder K George, Malcolm R P Elsadek, Lobna A Deering, Max de Almeida, Larissa Costa Tyler, Jasper L Noble, Adam Paul, Valerie J Luesch, Hendrik Butts, Craig P Aggarwal, Varinder K |
| collection | PubMed - marine biology |
| contents | Caylobolide B: Structure Revision, Total Synthesis, Biological Characterization, and Discovery of New Analogues. George, Malcolm R P Elsadek, Lobna A Deering, Max de Almeida, Larissa Costa Tyler, Jasper L Noble, Adam Paul, Valerie J Luesch, Hendrik Butts, Craig P Aggarwal, Varinder K Macrolides Structure-Activity Relationship Humans Molecular Structure Biological Products Antifungal Agents Microbial Sensitivity Tests Drug Discovery The unique potential of marine polyhydroxylated macrolides in chemical biology and drug discovery has long been constrained by their structural complexity and limited material availability, frustrating efforts in stereochemical assignment, synthesis, and mechanism-of-action elucidation. Here, we establish an integrated workflow, combining chemogenomic profiling, ultra-high-resolution 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 Okeania sp., we performed structure-activity 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 H, 1D-selective TOCSY and HSQC NMR, and developed a modular fragment-based 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-derived therapeutics. |
| format | Artículo científico |
| id | pubmed_41376297 |
| institution | PubMed |
| language | en |
| publishDate | 2026 |
| publisher | Angewandte Chemie (International ed. in English) |
| record_format | pubmed |
| spellingShingle | Caylobolide B: Structure Revision, Total Synthesis, Biological Characterization, and Discovery of New Analogues. George, Malcolm R P Elsadek, Lobna A Deering, Max de Almeida, Larissa Costa Tyler, Jasper L Noble, Adam Paul, Valerie J Luesch, Hendrik Butts, Craig P Aggarwal, Varinder K Macrolides Structure-Activity Relationship Humans Molecular Structure Biological Products Antifungal Agents Microbial Sensitivity Tests Drug Discovery Caylobolide B: Structure Revision, Total Synthesis, Biological Characterization, and Discovery of New Analogues. George, Malcolm R P Elsadek, Lobna A Deering, Max de Almeida, Larissa Costa Tyler, Jasper L Noble, Adam Paul, Valerie J Luesch, Hendrik Butts, Craig P Aggarwal, Varinder K Macrolides Structure-Activity Relationship Humans Molecular Structure Biological Products Antifungal Agents Microbial Sensitivity Tests Drug Discovery The unique potential of marine polyhydroxylated macrolides in chemical biology and drug discovery has long been constrained by their structural complexity and limited material availability, frustrating efforts in stereochemical assignment, synthesis, and mechanism-of-action elucidation. Here, we establish an integrated workflow, combining chemogenomic profiling, ultra-high-resolution 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 Okeania sp., we performed structure-activity 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 H, 1D-selective TOCSY and HSQC NMR, and developed a modular fragment-based 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-derived therapeutics. |
| title | Caylobolide B: Structure Revision, Total Synthesis, Biological Characterization, and Discovery of New Analogues. |
| topic | Macrolides Structure-Activity Relationship Humans Molecular Structure Biological Products Antifungal Agents Microbial Sensitivity Tests Drug Discovery |
| url | https://pubmed.ncbi.nlm.nih.gov/41376297/ |