Steroidal and triterpenoidal fungal metabolites as ligands of liver X receptors.
Cholesterol homeostasis is tightly controlled process that involves a variety of regulators including liver X receptors (LXR). Agonists of LXR are expected to increase cholesterol efflux, lower LDL, and raise HDL levels. Screening of a natural product library of microbial extracts using a LXR-scintillation proximity assay (SPA) binding assay and bioassay-guided fractionation of a number of fungal extracts led to the isolation of five ergostane and a cycloartane derivative. These compounds exhibited IC50 value ranging 0.5 approximately 9 microM in the binding assay for a-receptor and a number of these showed in vitro agonist activity in the coactivator association assays but lacked the cell based LXR activation. The isolation and LXR activity of these compounds are described.
Ondeyka
John G
JG
Merck Research Laboratories, P. O. Box 2000, Rahway, New Jersey 07065, USA.
Jayasuriya
Hiranthi
H
Herath
Kithsiri B
KB
Guan
Ziqiang
Z
Schulman
Marvin
M
Collado
Javier
J
Dombrowski
Anne W
AW
Kwon
Soojin S
SS
McCallum
Christine
C
Sharma
Neelam
N
MacNaul
Karen
K
Hayes
Nancy
N
Menke
John G
JG
Singh
Sheo B
SB
D004268:DNA-Binding Proteins / Q000819:agonists* / Q000378:metabolism; D005658:Fungi / Q000737:chemistry / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D008024:Ligands; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D013256:Steroids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D014315:Triterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology
D004268:DNA-Binding Proteins; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013256:Steroids; D014315:Triterpenes