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Issue 31, 2012
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Modification in the side chain of solomonsterol A: discovery of cholestan disulfate as a potent pregnane-X-receptor agonist

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Abstract

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.

Graphical abstract: Modification in the side chain of solomonsterol A: discovery of cholestan disulfate as a potent pregnane-X-receptor agonist

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Publication details

The article was received on 26 Apr 2012, accepted on 01 Jun 2012 and first published on 13 Jun 2012


Article type: Paper
DOI: 10.1039/C2OB25800E
Org. Biomol. Chem., 2012,10, 6350-6362

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    Modification in the side chain of solomonsterol A: discovery of cholestan disulfate as a potent pregnane-X-receptor agonist

    V. Sepe, R. Ummarino, M. V. D'Auria, G. Lauro, G. Bifulco, C. D'Amore, B. Renga, S. Fiorucci and A. Zampella, Org. Biomol. Chem., 2012, 10, 6350
    DOI: 10.1039/C2OB25800E

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