Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 27, Issue 45, Pages 11633-11642Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.202100989
Keywords
Actin; antitumor agents; natural products; structure-activity relationship; total synthesis
Categories
Funding
- DAAD predoctoral fellowship
- Deutsche Forschungsgemeinschaft (German Research Foundation) collaborative research center [SFB1127/2 ChemBioSys, 239748522]
- Leibniz Association
- Werner Siemens-Stiftung
- Projekt DEAL
- DFG [INST 275/33-1-1 FUGG]
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The first total synthesis of geodiamolide H, an actin-stabilizing marine natural product, was achieved in this study. Geodiamolide H and synthetic analogues were characterized for toxicity and antiproliferative effects, revealing a non-natural analogue with significant potential for tool compound design.
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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