Diterpenoid, Steroid, And Triterpenoid Agonists Of Liver X Receptors From Diversified Terrestrial Plants And Marine Sources

It has been demonstrated that liver X receptors (LXR) play a significant role in cholesterol homeostasis. Agonists of LXR are expected to increase cellular cholesterol efflux, lower LDL, and raise HDL levels. Screening of a natural product library of plant extracts using a LXR-SPA binding assay and bioassay-guided fractionation of a number of plant and marine gorgonian extracts led to the isolation of a number of active compounds. These included acanthoic acid (1) and alcohol (2), viperidone (3), polycarpol (4), rosacea acid (5), a cycloartane derivative (6), a new cycloartane analogue (7), betulinic acid (8), and gorgostane derivatives (9, 10, and 11). Of these compounds, 1, 4, and 11 exhibited potent binding affinity for a-receptor with IC50 values of 0.25, 0.12, and 0.07 mu M, respectively. Functionally they also showed strong coactivator association stimulation for LXR alpha receptor with EC50 values of 0.18, 0.03, and 0.05 mu M, respectively. They also exhibited 15-, 8-, and 13-fold induction of the a-receptor in a transactivation assay in HEK-293 cells, respectively. In general these compounds were selective for the LXR a-receptor over the beta-receptor in all assays and were much better stimulators of the a-receptor than the endogenous steroid ligands.