title: Diterpenoid, steroid, and triterpenoid agonists of liver X receptors from diversified terrestrial plants and marine sources.
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.
authors.affiliation: Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA.
authors.forename: Hiranthi
authors.initials: H
authors.lastname: Jayasuriya
authors.forename: Kithsiri B
authors.initials: KB
authors.lastname: Herath
authors.forename: John G
authors.initials: JG
authors.lastname: Ondeyka
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Guan
authors.forename: Robert P
authors.initials: RP
authors.lastname: Borris
authors.forename: Suroojnauth
authors.initials: S
authors.lastname: Tiwari
authors.forename: Wil
authors.initials: W
authors.lastname: de Jong
authors.forename: Flor
authors.initials: F
authors.lastname: Chavez
authors.forename: Jeremy
authors.initials: J
authors.lastname: Moss
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Stevenson
authors.forename: Hans T
authors.initials: HT
authors.lastname: Beck
authors.forename: Marc
authors.initials: M
authors.lastname: Slattery
authors.forename: Nelson
authors.initials: N
authors.lastname: Zamora
authors.forename: Marvin
authors.initials: M
authors.lastname: Schulman
authors.forename: Aisha
authors.initials: A
authors.lastname: Ali
authors.forename: Neelam
authors.initials: N
authors.lastname: Sharma
authors.forename: Karen
authors.initials: K
authors.lastname: MacNaul
authors.forename: Nancy
authors.initials: N
authors.lastname: Hayes
authors.forename: John G
authors.initials: JG
authors.lastname: Menke
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
mesh_terms: D000818:Animals; D029061:Annonaceae / Q000737:chemistry; D037421:Anthozoa / Q000737:chemistry; D001444:Bahamas; D029421:Cactaceae / Q000737:chemistry; D029422:Campanulaceae / Q000737:chemistry; D002478:Cells, Cultured; D003364:Costa Rica; D004268:DNA-Binding Proteins / Q000819:agonists*; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D006172:Guyana; D006801:Humans; D020128:Inhibitory Concentration 50; D000071518:Liver X Receptors; D015394:Molecular Structure; D031656:Olacaceae / Q000737:chemistry; D057093:Orphan Nuclear Receptors; D053978:Pentacyclic Triterpenes; D010568:Peru; D028201:Pinaceae / Q000737:chemistry; D010946:Plants, Medicinal / Q000737:chemistry*; D011084:Polycyclic Aromatic Hydrocarbons / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D013256:Steroids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D014315:Triterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D014481:United States; D000094062:Betulinic Acid
chemical_list: D004268:DNA-Binding Proteins; D004224:Diterpenes; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D053978:Pentacyclic Triterpenes; D011084:Polycyclic Aromatic Hydrocarbons; D018160:Receptors, Cytoplasmic and Nuclear; D013256:Steroids; D014315:Triterpenes; C099958:acanthoic acid; C460801:polycarpol; D000094062:Betulinic Acid