Journal
MEDCHEMCOMM
Volume 10, Issue 5, Pages 800-805Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c9md00164f
Keywords
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Funding
- Notre Dame's Chemistry-Biochemistry-Biology Interface Program, an NIH [T32GM075762]
- National Institutes of Health [GM084922]
- Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [ZIAHD008765] Funding Source: NIH RePORTER
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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.
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