Apicularen A and B, Cytotoxic 10-Membered Lactones with a Novel Mechanism of Action fromChondromyces Species (Myxobacteria): Isolation, Structure Elucidation, and Biosynthesis

A novel highly cytotoxic metabolite, apicularen A (1), was isolated in a screening of the myxobacterial genus Chondromyces. The structure of 1 is characterized by a salicylic acid residue as part of a 10-membered lactone, which bears an acylenamine side chain. Compound 1 is an inhibitor of the proliferation of human cancer cell lines and induces apoptosis. Apicularen A (1) is present in nearly every strain of C. apiculatus, C. pediculatus, C. lanuginosus 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-β-D-glucopyranosyl)apicularen. According to feeding experiments with 13C-labeled acetates, glycine, and methionine, apicularen A (1) is an acetate-derived polyketide containing a glycine residue as precursor of the enamine. Uncommonly, the C3 starter unit is not assembled from propionate but from acetate and methionine.