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- Title
Discovery, Structure Elucidation, and Biological Characterization of Nannocystin A, a Macrocyclic Myxobacterial Metabolite with Potent Antiproliferative Properties.
- Authors
Hoffmann, Holger; Kogler, Herbert; Heyse, Winfried; Matter, Hans; Caspers, Michael; Schummer, Dietmar; Klemke ‐ Jahn, Christine; Bauer, Armin; Penarier, Geraldine; Debussche, Laurent; Brönstrup, Mark
- Abstract
Microbial natural products are a rich source of bioactive molecules to serve as drug leads and/or biological tools. We investigated a little-explored myxobacterial genus, Nannocystis sp., and discovered a novel 21-membered macrocyclic scaffold that is composed of a tripeptide and a polyketide part with an epoxyamide moiety. The relative and absolute configurations of the nine stereocenters was determined by NMR spectroscopy, molecular dynamics calculations, chemical degradation, and X-ray crystallography. The compound, named nannocystin A ( 1), was found to inhibit cell proliferation at low nanomolar concentrations through the early induction of apoptosis. The mode of action of 1 could not be matched to that of standard drugs by transcriptional profiling and biochemical experiments. An initial investigation of the structure-activity relationship based on seven analogues demonstrated the importance of the epoxide moiety for high activity.
- Subjects
BIOLOGICAL systems; ELONGATION factors (Biochemistry); MYXOBACTERALES; METABOLITES; POLYKETIDES
- Publication
Angewandte Chemie, 2015, Vol 127, Issue 35, p10283
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201411377