Synthesis, conformational preferences, and biological activity of conformational analogues of the microtubule-stabilizing agents, (−)-zampanolide and (−)-dactylolide
| Autor: | Jeffrey L. Henry, Matthew R. Wilson, Taylor R. Quinn, Richard E. Taylor, Dan L. Sackett, Michael P. Mulligan |
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| Rok vydání: | 2019 |
| Předmět: |
Pharmacology
Zampanolide 010405 organic chemistry Chemistry Stereochemistry Organic Chemistry Dactylolide Pharmaceutical Science Total synthesis Biological activity 01 natural sciences Biochemistry 0104 chemical sciences 010404 medicinal & biomolecular chemistry Microtubule Drug Discovery Molecular Medicine Cancer cell lines Stabilizing Agents Cytotoxicity |
| Zdroj: | MedChemComm. 10:800-805 |
| ISSN: | 2040-2511 2040-2503 |
| Popis: | Zampanolide and dactylolide are microtubule-stabilizing polyketides possessing potent cytotoxicity towards a variety of cancer cell lines. Using our understanding of the conformational preferences of the macrolide core in both natural products, we hypothesized that analogues lacking the C17-methyl group would maintain the necessary conformation for bioactivity while reducing the number of synthetic manipulations necessary for their synthesis. Analogues 3, 4 and 5 were prepared via total synthesis, and their conformational preferences were determined through computational and high-field NMR studies. While no observable activities were present in dactylolide analogues 3 and 4, zampanolide analogue 5 exhibited sub-micromolar cytotoxicity. Herein, we describe these efforts towards understanding the structure- and conformation-activity relationships of dactylolide and zampanolide. |
| Databáze: | OpenAIRE |
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