Total Synthesis and Bioactivity Mapping of Geodiamolide H |
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Authors: | Veselin Nasufović Dr Florian Küllmer Johanna Bößneck Dr Hans-Martin Dahse Dr Helmar Görls Dr Peter Bellstedt Dr Pierre Stallforth Prof Dr Hans-Dieter Arndt |
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Institution: | 1. Institut für Organische Chemie und Makromolekulare Chemie, Friedrich-Schiller-Universität (FSU), Humboldtstr. 10, 07743 Jena, Germany;2. Abteilungen Infektionsbiologie und Paläobiotechnologie, Leibniz-Institut für Naturstoffforschung – Hans-Knöll-Institut, Beutenbergstr. 11a, 07745 Jena, Germany;3. Institut für Anorganische und Analytische Chemie, Friedrich-Schiller-Universität (FSU), Humboldtstr. 8, 07743 Jena, Germany;4. NMR-Plattform, Friedrich-Schiller-Universität (FSU), Humboldtstr. 10, 07743 Jena, Germany |
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Abstract: | The first total synthesis of the actin-stabilizing marine natural product geodiamolide H was achieved. Solid-phase based peptide assembly paired with scalable stereoselective syntheses of polyketide building blocks and an optimized esterification set the stage for investigating the key ring-closing metathesis. Geodiamolide H and synthetic analogues were characterized for their toxicity and for antiproliferative effects in cellulo, by characterising actin polymerization induction in vitro, and by docking on the F-actin target and property computation in silico, for a better understanding of structure-activity relationships (SAR). A non-natural analogue of geodiamolide H was discovered to be most potent in the series, suggesting significant potential for tool compound design. |
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Keywords: | Actin antitumor agents natural products structure-activity relationship total synthesis |
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