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 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.
Jayasuriya
Hiranthi
H
Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA.
Herath
Kithsiri B
KB
Ondeyka
John G
JG
Guan
Ziqiang
Z
Borris
Robert P
RP
Tiwari
Suroojnauth
S
de Jong
Wil
W
Chavez
Flor
F
Moss
Jeremy
J
Stevenson
Dennis W
DW
Beck
Hans T
HT
Slattery
Marc
M
Zamora
Nelson
N
Schulman
Marvin
M
Ali
Aisha
A
Sharma
Neelam
N
MacNaul
Karen
K
Hayes
Nancy
N
Menke
John G
JG
Singh
Sheo B
SB
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
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