Modification in the side chain of solomonsterol A: discovery of cholestan disulfate as a potent pregnane-X-receptor agonist.
Seven synthetic analogues of the PXR (pregnane-X-receptor) potent natural agonist solomonsterol A were prepared by total synthesis. Their activity toward PXR was assessed by transactivation and RT-PCR assays. The study discloses cholestan disulfate (8) as a new, simplified agonist of PXR. By in vitro studies on hepatic cells we have demonstrated that this compound is a potent PXR agonist and functional characterization in human macrophages and hepatic stellate cells provided evidence that cholestan disulfate (8) has the ability to modulate the immune response triggered by bacterial endotoxin as well as to counter-activate hepatic stellate cell activation induced by thrombin. Because inhibition of immune-driven circuits might have relevance in the treatment of inflammation and liver fibrosis, the present data support the development of cholestan disulfate (8) in preclinical models of inflammatory diseases.
Dipartimento di Chimica delle Sostanze Naturali, Università di Napoli Federico II, via D. Montesano 49, 80131 Napoli, Italy.
Valentina
V
Sepe
Raffaella
R
Ummarino
Maria Valeria
MV
D'Auria
Gianluigi
G
Lauro
Giuseppe
G
Bifulco
Claudio
C
D'Amore
Barbara
B
Renga
Stefano
S
Fiorucci
Angela
A
Zampella
D000818:Animals; D002460:Cell Line; D002757:Cholanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002777:Cholestanols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016207:Cytokines / Q000276:immunology; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008958:Models, Molecular; D011161:Porifera / Q000737:chemistry / Q000145:classification; D000077297:Pregnane X Receptor; D051381:Rats; D011987:Receptors, Steroid / Q000819:agonists* / Q000276:immunology; D013463:Sulfuric Acid Esters / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D002757:Cholanes; D002777:Cholestanols; D016207:Cytokines; D008070:Lipopolysaccharides; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D013463:Sulfuric Acid Esters; C561233:cholan-2,3,24-tryl-2,3,24-trisulfate