DISCOVERY, ISOLATION, STRUCTURE ELUCIDATION, AND BIOSYNTHESIS OF U-106305, A CHOLESTERYL ESTER TRANSFER PROTEIN INHIBITOR FROM UC-11136

During our screening of fermentation broths, culture UC 11136 was identified as producing potent inhibitor(s) of the in vitro cholesteryl ester transfer protein (CETP) reaction. Subsequent chemical isolation work identified two inhibitors of CETP produced by this culture. One of these inhibitors, U-106305, represented a novel CETP inhibitor as well as a structural class of compounds not previously reported from microbial fermentations. The structure of U-106305 was elucidated as N-isobutyl-all-trans-4,5:6,7:8,9:10,11:12,13:16,17-hexamethylene-(E,E)-2,14-octadecadienamide by extensive NMR studies, Biogenetically, the backbone of U-106305 was found to derive from nine acetates linked in a head-to-tail fashion, while the cyclopropyl methylene carbons were derived from the methyl group of L-methionine. A biosynthetic pathway is proposed based on these findings.