ABSTRACT
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 alpha-receptor with IC(50) values of 0.25, 0.12, and 0.07 microM, respectively. Functionally they also showed strong coactivator association stimulation for LXRalpha receptor with EC50 values of 0.18, 0.03, and 0.05 microM, respectively. They also exhibited 15-, 8-, and 13-fold induction of the alpha-receptor in a transactivation assay in HEK-293 cells, respectively. In general these compounds were selective for the LXR alpha-receptor over the beta-receptor in all assays and were much better stimulators of the alpha-receptor than the endogenous steroid ligands.
Subject(s)
DNA-Binding Proteins/agonists , Diterpenes/isolation & purification , Plants, Medicinal/chemistry , Polycyclic Aromatic Hydrocarbons/isolation & purification , Receptors, Cytoplasmic and Nuclear/agonists , Steroids/isolation & purification , Triterpenes/isolation & purification , Animals , Annonaceae/chemistry , Anthozoa/chemistry , Bahamas , Cactaceae/chemistry , Campanulaceae/chemistry , Cells, Cultured , Costa Rica , Diterpenes/chemistry , Diterpenes/pharmacology , Guyana , Humans , Inhibitory Concentration 50 , Liver X Receptors , Molecular Structure , Olacaceae/chemistry , Orphan Nuclear Receptors , Pentacyclic Triterpenes , Peru , Pinaceae/chemistry , Polycyclic Aromatic Hydrocarbons/chemistry , Polycyclic Aromatic Hydrocarbons/pharmacology , Steroids/chemistry , Steroids/pharmacology , Triterpenes/chemistry , Triterpenes/pharmacology , United States , Betulinic AcidABSTRACT
Four new congeners, rediocides B-E (2-5), of the previously reported rediocide A (1) were isolated from a methanol extract of the roots of the plant Trigonostemon reidioides. The structures of these minor analogues were elucidated by comparison of their NMR and mass spectral data with those of rediocide A and confirmed by extensive 2D NMR spectral analysis. They all possess potent activity against fleas (Ctenocephalides felis) in an artificial membrane feeding system and exhibited LD(90) values ranging from 0.25 to 0.5 ppm.