Lugdunomycin, an Angucycline-Derived Molecule with Unprecedented Chemical Architecture

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.

Figure 1

Angucyclines isolated from Streptomyces sp. QL37. Lugdunomycin (1) is a novel angucycline derivative. All the previously undescribed compounds are shown in red.

Figure 2

ORTEP drawing of the crystal structure of lugdunomycin. The absolute configurations of the five chiral centers of lugdunomycin are 9R*, 16S*, 17R*, 19S*, and 21S*.

Figure 3

MS²‐based molecular networking of Streptomyces sp. QL37. A) Subnetwork for lugdunomycin reveals an analogue at m/z 502. Comparison of MS² spectra of 1 at m/z 474.151 and its analogue at m/z 502.147 suggests an additional aldehyde group in the latter; see the fragmentation pattern above the ion peak. B) Rearranged angucyclines. The edge thickness between connecting nodes corresponds to the similarity of the MS/MS spectra. The full GNPS network is presented in Figure S3 in the Supporting Information, and the subnetwork for non‐rearranged angucyclines in Figure S4 in the Supporting Information.

Figure 4

Biosynthetic route to limamycins and proposed pathway towards lugdunomycin. A) Biosynthesis of limamycins. Baeyer–Villiger oxidative cleavage at the quinone ring of compounds 2 and/or 6 is pivotal for the biosynthesis of lugdunomycin and rearranged limamycins 13–19. B) Proposed pathway for lugdunomycin biosynthesis. As possible final step for the assembly of lugdunomycin a Diels–Alder reaction is proposed. As dienophile for the Diels–Alder reaction an isomer of maleimycin (Supporting Information, Figure S6) is a likely candidate. We propose its formation from the oxidative ring contraction in the D‐ring of limamycins. The limamycin and emycin biosynthetic pathways are drawn in blue and red, respectively.