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Mar. Drugs 2014, 12(6), 3091-3115; doi:10.3390/md12063091

Marine and Semi-Synthetic Hydroxysteroids as New Scaffolds for Pregnane X Receptor Modulation

1
Department of Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, I-80131 Napoli, Italy
2
Department Experimental and Clinical Medicine, University of Perugia, Via Gambuli 1, S. Andrea delle Fratte, Perugia 06132, Italy
3
CSIR-National Institute of Oceanography, Dona Paula, Goa 403004, India
*
Author to whom correspondence should be addressed.
Received: 8 April 2014 / Revised: 29 April 2014 / Accepted: 30 April 2014 / Published: 27 May 2014
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Abstract

In recent years many sterols with unusual structures and promising biological profiles have been identified from marine sources. Here we report the isolation of a series of 24-alkylated-hydroxysteroids from the soft coral Sinularia kavarattiensis, acting as pregnane X receptor (PXR) modulators. Starting from this scaffold a number of derivatives were prepared and evaluated for their ability to activate the PXR by assessing transactivation and quantifying gene expression. Our study reveals that ergost-5-en-3β-ol (4) induces PXR transactivation in HepG2 cells and stimulates the expression of the PXR target gene CYP3A4. To shed light on the molecular basis of the interaction between these ligands and PXR, we investigated, through docking simulations, the binding mechanism of the most potent compound of the series, 4, to the PXR. Our findings provide useful functional and structural information to guide further investigations and drug design. View Full-Text
Keywords: soft coral; Sinularia kavarattiensis; pregnane X receptor (PXR); hydroxysteroids; docking simulations soft coral; Sinularia kavarattiensis; pregnane X receptor (PXR); hydroxysteroids; docking simulations
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MDPI and ACS Style

Sepe, V.; Di Leva, F.S.; D'Amore, C.; Festa, C.; De Marino, S.; Renga, B.; D'Auria, M.V.; Novellino, E.; Limongelli, V.; D'Souza, L.; Majik, M.; Zampella, A.; Fiorucci, S. Marine and Semi-Synthetic Hydroxysteroids as New Scaffolds for Pregnane X Receptor Modulation. Mar. Drugs 2014, 12, 3091-3115.

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