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Angew Chem Int Ed Engl. 2019 Feb 25;58(9):2809-2814. doi: 10.1002/anie.201814581. Epub 2019 Jan 29.

Lugdunomycin, an Angucycline-Derived Molecule with Unprecedented Chemical Architecture.

Author information

1
Institute of Biology, Leiden University, Sylviusweg 72, 2333 BE, Leiden, The Netherlands.
2
State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao, 266237, P. R. China.
3
Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0751, USA.
4
Bruker AXS GmbH, Östliche Rheinbrückenstr. 49, 76187, Karlsruhe, Germany.
5
Stratingh Institute for Chemistry, University of Groningen, Groningen, The Netherlands.

Abstract

The angucyclines form the largest family of polycyclic aromatic polyketides, and have been studied extensively. Herein, we report the discovery of lugdunomycin, an angucycline-derived polyketide, produced by Streptomyces species QL37. Lugdunomycin has unique structural characteristics, including a heptacyclic ring system, a spiroatom, two all-carbon stereocenters, and a benzaza-[4,3,3]propellane motif. Considering the structural novelty, we propose that lugdunomycin represents a novel subclass of aromatic polyketides. Metabolomics, combined with MS-based molecular networking analysis of Streptomyces sp. QL37, elucidated 24 other rearranged and non-rearranged angucyclines, 11 of which were previously undescribed. A biosynthetic route for the lugdunomycin and limamycins is also proposed. This work demonstrates that revisiting well-known compound families and their producer strains still is a promising approach for drug discovery.

KEYWORDS:

Baeyer-Villiger oxidation; angucycline; molecular networking; natural product; polyketide

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