Clavipines A-C, antiproliferative meroterpenoids with a fused azepine skeleton from the basidiomycete Clitocybe clavipes

Three novel meroterpenoids, clavipines A-C (1-3), possessing a benzoquinone fused to an azepine ring and a ten-membered carbocycle with alpha,beta -epoxy/unsaturated-gamma -lactone, along with a new natural compound clavilactone F (4) and two known clavilactones D (5) and A (6) were isolated from the basidiomycete Clitocybe clavipes. Their structures with absolute configurations were unambiguously established by extensive spectroscopic analyses, and ECD and X-ray methods. An unusual seven-azepine skeleton was postulated to be formed biosynthetically via a rearrangement of quinone-amino acid conjugates. The biosynthetic origin of meroterpenoids with a benzo-fused 10-membered carbocycle unit was determined by incorporation of C-13-labeled precursors. Compound 1 exhibited significant antiproliferative activity against HepG2 and A549 cells with IC50 values of 4.28 +/- 0.26 and 7.49 +/- 0.41 mu M, respectively.