title: Discovery, Structure Elucidation, and Biological Characterization of Nannocystin A, a Macrocyclic Myxobacterial Metabolite with Potent Antiproliferative Properties.
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.
authors.affiliation: Sanofi R&D, Industriepark Hoechst, 65926 Frankfurt (Germany).
authors.forename: Holger
authors.initials: H
authors.lastname: Hoffmann
authors.affiliation: Sanofi R&D, Industriepark Hoechst, 65926 Frankfurt (Germany).|Current address: Institut für Analytische Chemie, Universität Bremen, Leobener Str. NW IIC 28359 Bremen (Germany).
authors.forename: Herbert
authors.initials: H
authors.lastname: Kogler
authors.affiliation: Sanofi R&D, Industriepark Hoechst, 65926 Frankfurt (Germany).
authors.forename: Winfried
authors.initials: W
authors.lastname: Heyse
authors.affiliation: Sanofi R&D, Industriepark Hoechst, 65926 Frankfurt (Germany).
authors.forename: Hans
authors.initials: H
authors.lastname: Matter
authors.affiliation: Sanofi R&D, Industriepark Hoechst, 65926 Frankfurt (Germany).
authors.forename: Michael
authors.initials: M
authors.lastname: Caspers
authors.affiliation: Sanofi R&D, Industriepark Hoechst, 65926 Frankfurt (Germany).|Current address: TH Mittelhessen, Wiesenstraße 14, 35390 Gießen (Germany).
authors.forename: Dietmar
authors.initials: D
authors.lastname: Schummer
authors.affiliation: Sanofi R&D, Industriepark Hoechst, 65926 Frankfurt (Germany).
authors.forename: Christine
authors.initials: C
authors.lastname: Klemke-Jahn
authors.affiliation: Sanofi R&D, Industriepark Hoechst, 65926 Frankfurt (Germany).
authors.forename: Armin
authors.initials: A
authors.lastname: Bauer
authors.affiliation: Sanofi R&D, 13 Quai Jules Guesde, Vitry sur Seine 94403 (France).
authors.forename: Geraldine
authors.initials: G
authors.lastname: Penarier
authors.affiliation: Sanofi R&D, 13 Quai Jules Guesde, Vitry sur Seine 94403 (France).
authors.forename: Laurent
authors.initials: L
authors.lastname: Debussche
authors.affiliation: Current address: Department of Chemical Biology, Helmholtz Zentrum für Infektionsforschung, Inhoffenstr 7, 38124 Braunschweig (Germany). mark.broenstrup@helmholtz-hzi.de.|Sanofi R&D, Industriepark Hoechst, 65926 Frankfurt (Germany). mark.broenstrup@helmholtz-hzi.de.
authors.forename: Mark
authors.initials: M
authors.lastname: Brönstrup
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D006801:Humans; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009231:Myxococcales / Q000502:physiology*; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000935:Antifungal Agents; D000970:Antineoplastic Agents; D001688:Biological Products; D047028:Macrocyclic Compounds; C000607748:nannocystin A
keywords: antiproliferative agents; apoptosis; drug discovery; natural products; structure elucidation