Three New Stigmatellin Derivatives Reveal Biosynthetic Insights of Its Side Chain Decoration

Myxobacteria generate natural products with unique chemical structures, which not only feature remarkable biological functions, but also demonstrate unprecedented biosynthetic assembly strategies. The stigmatellins have been previously described as potent inhibitors of the mitochondrial and photosynthetic respiratory chain and originate from an unusual polyketide synthase assembly line. While previous biosynthetic investigations were focused on the formation of the 5,7-dimethoxy-8-hydroxychromone ring, side chain decoration of the hydrophobic alkenyl chain in position 2 was investigated less thoroughly. We report here the full structure elucidation, as well as cytotoxic and antimicrobial activities of three new stigmatellins isolated from the myxobacterium Vitiosangium cumulatum MCy10943^T with side chain decorations distinct from previously characterized members of this compound family. The hydrophobic alkenyl chain in position 2 of the herein described stigmatellins feature a terminal carboxylic acid group (1), a methoxy group at C-12' (2) or a vicinal diol (3). These findings provide further implications considering the side chain decoration of these aromatic myxobacterial polyketides and their underlying biosynthesis.