Synthesis, conformational preferences, and biological activity of conformational analogues of the microtubule-stabilizing agents, (−)-zampanolide and (−)-dactylolide. Issue 5 (18th April 2019)

• Record Type: Journal Article
• Authors: Henry, Jeffrey L.; Wilson, Matthew R.; Mulligan, Michael P.; Quinn, Taylor R.; Sackett, Dan L.; Taylor, Richard E.
• Is Part Of: MedChemComm. Volume 10:Issue 5(2019)
• Page Start: 800
• Page End: 805
• Publication Date: 2019-04-18
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19
• DOI: 10.1039/c9md00164f
• Languages: English
• ISSNs: 2040-2503

Abstract

Abstract : Zampanolide and dactylolide are microtubule-stabilizing polyketides possessing potent cytotoxicity towards a variety of cancer cell lines. 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. Analogues3, 4 and5 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 analogues3 and4, zampanolide analogue5 exhibited sub-micromolar cytotoxicity. Herein, we describe these efforts towards understanding the structure- and conformation-activity relationships of dactylolide and zampanolide.