Issue 5, 2019

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

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

Supplementary files

Article information

Article type
Research Article
Submitted
15 Mar 2019
Accepted
08 Apr 2019
First published
09 Apr 2019

Med. Chem. Commun., 2019,10, 800-805

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

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Spotlight

Advertisements