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Issue 5, 2019
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Synthesis, conformational preferences, and biological activity of conformational analogues of the microtubule-stabilizing agents, (−)-zampanolide and (−)-dactylolide

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Abstract

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.

Graphical abstract: Synthesis, conformational preferences, and biological activity of conformational analogues of the microtubule-stabilizing agents, (−)-zampanolide and (−)-dactylolide

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Article information


Submitted
15 Mar 2019
Accepted
08 Apr 2019
First published
09 Apr 2019

Med. Chem. Commun., 2019,10, 800-805
Article type
Research Article

Synthesis, conformational preferences, and biological activity of conformational analogues of the microtubule-stabilizing agents, (−)-zampanolide and (−)-dactylolide

J. L. Henry, M. R. Wilson, M. P. Mulligan, T. R. Quinn, D. L. Sackett and R. E. Taylor, Med. Chem. Commun., 2019, 10, 800
DOI: 10.1039/C9MD00164F

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