Antibiotics from gliding bacteria, LXXXVI - Apicularen A and B, cytotoxic 10-membered lactones with a novel mechanism of action from Chondromyces species (Myxobacteria): Isolation, structure elucidation, and biosynthesis

A novel highly cytotoxic metabolite, apicularen A (1), was isolated in a sc reening of the myxobacterial genus Chondromyces. The structure of 1 is char acterized by a salicylic acid residue as part of a 10-membered lactone, whi ch bears an acylenamine side chain. Compound 1 is an inhibitor of the proli feration of human cancer cell lines and induces apoptosis. Apicularen A (1) is present in nearly every strain of C. apiculatus, C. pediculatus, C. lan uginosus and C. robustus. Habitually 1 is accompanied by different amounts of a more polar variant, apicularen B (2), which was identified as 11-O-(2- N-acetamido-2-deoxy-beta-D-glucopyranosyl) apicularen. According to feeding experiments with C-13-labeled acetates, glycine, and methionine, apiculare n A (1) is an acetate-derived polyketide containing a glycine residue as pr ecursor of the enamine. Uncommonly, the C-3 Starter unit is not assembled f rom propionate but from acetate and methionine.