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,p roduced by Streptomyces species QL37. Lugdunomycin has unique structural characteristics, including ah eptacyclic ring system, as piroatom, two allcarbon stereocenters,a nd ab enzaza-[4,3,3]propellane motif. Considering the structural novelty,w ep ropose that lugdunomycin represents an ovel subclass of aromatic polyketides. Metabolomics,c ombined with MS-based molecular networking analysis of Streptomyces sp.Q L37, elucidated 24 other rearranged and non-rearranged angucyclines,11ofwhichwere previously undescribed. Ab iosynthetic route for the lugdunomycin and limamycins is also proposed. This work demonstrates that revisiting well-known compound families and their producer strains still is ap romising approach for drug discovery.Actinobacteria are Gram-positive,a nd often filamentous, bacteria that are am ajor source of bioactive natural products, [1,2] and most of these are produced by actinomycetesSupportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.

Iso‐maleimycin, a Constitutional Isomer of Maleimycin, from Streptomyces sp. QL37

“…QL37 was isolated from soil in the Qinling mountains (P. R. China) and deposited to the collection of the Centraal Bureau voor Schimmelcultures (CBS) in Utrecht, The Netherlands, under deposit number 138593. [7a], [7b] The extract was prepared as indicated in the experimental section. GC‐MS was selected for the analysis due to the low molecular mass and hence relatively volatile nature of 2 and 5 .…”

“…Recently, we reported the isolation and characterization of several previously undescribed angucycline derivatives in the extracts of Streptomyces sp. QL37,[7a] an antibiotic‐producing actinomycete originating from mountain soil. [7b] Noticeable was the succinimide‐containing compound lugdunomycin 4 , an antibiotic with a rare chemical structure derived from the angucycline polyketide backbone.…”

“…QL37,[7a] an antibiotic‐producing actinomycete originating from mountain soil. [7b] Noticeable was the succinimide‐containing compound lugdunomycin 4 , an antibiotic with a rare chemical structure derived from the angucycline polyketide backbone. Angucyclines and their derivatives are the most diverse known family of polyketides, many of which have antibacterial and/or anticancer activity.…”

“…During our investigations, a trace compound with the nominal mass of 2 was detected by LC‐MS. As inspection of 4 suggested constitutional isomer 5 , rather than 2 , to be involved in its biosynthesis,[7a] we decided to determine the structure of this compound. Preliminary supporting evidence for the presence of 2 or 5 was obtained by additional MS/MS fragmentation experiments and we dubbed the name of 5 to be iso ‐maleimycin.…”

“…Preliminary supporting evidence for the presence of 2 or 5 was obtained by additional MS/MS fragmentation experiments and we dubbed the name of 5 to be iso ‐maleimycin. [7a]…”