BE-24566B

Liver X receptors (LXR) are nuclear hormone receptors that play a critical role in cholesterol homeostasis. They regulate the expression of the ABCA1 gene, which mediates the efflux of cholesterol out of cells. LXR agonists are expected to increase cholesterol efflux, lower LDL, and raise HDL levels. Screening of a natural product library of microbial extracts using a LXR-SPA binding assay and bioassay-guided fractionation of an active extract of a Streptomyces sp. (MA6657) led to the discovery of two new hexacyclic aromatic ketones, (-)-anthrabenzoxocinone [(-)-ABX (1)], an enantiomer of BE-24566B, and (-)-bischloroanthrabenzoxocinone [(-)-BABX (2)]. The IC50 values of LXRalpha-SPA binding are 2 microM for (-)-ABX and 10 microM for (-)-BABX. This extract was also found to inhibit type II fatty acid synthesis, and its active component, (-)-BABX, was responsible for the majority of the inhibition. All three compounds showed good Gram-positive antibacterial activity (MIC 0.5-2 microg/mL). Details of the isolation, structure elucidation, LXR ligand binding, antibacterial activity, and selectivity of inhibition of 1 and 2 are described.