title: Incisterols, highly degraded marine sterols, are a new chemotype of PXR agonists.
abstract: During the chromatographic purification of organic extracts obtained from Plakortis cfr. lita we obtained three highly degraded steroid derivatives, the known incisterol A2 (1) and the new incisterols A5 (2) and A6 (3). The new compounds were characterized basing on NMR and MS evidences along with comparison with model compounds. Incisterol A5 proved to bear a 17S-ethyl-15E,18-diene (incisterol numbering system) side chain, found for the first time in a marine organism. The new incisterols A5 and A6 proved to be potent inducers of transactivation of the pregnane X receptor (PXR) and they also stimulate the expression of CYP7A4 and MDR1 with a potency comparable to that of Rifaximin. These observations prompt to consider incisterols A5 and A6 as new potent agonists of PXR. On the other hand, the 17R-methyl analogue incisterol A2 shows only a poor PXR agonist activity. Molecular docking simulations elucidated the binding mechanism of the active incisterols in the ligand binding domain of PXR.
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano, 49, I-80131 Napoli, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Chianese
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano, 49, I-80131 Napoli, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Sepe
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano, 49, I-80131 Napoli, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Limongelli
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, Nuova Facoltà di Medicina, Via Gambuli 1, 06132 Perugia, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Renga
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, Nuova Facoltà di Medicina, Via Gambuli 1, 06132 Perugia, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: D'Amore
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano, 49, I-80131 Napoli, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Zampella
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano, 49, I-80131 Napoli, Italy. Electronic address: scatagli@unina.it.
authors.forename: Orazio
authors.initials: O
authors.lastname: Taglialatela-Scafati
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, Nuova Facoltà di Medicina, Via Gambuli 1, 06132 Perugia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
mesh_terms: D059001:Aquatic Organisms / Q000737:chemistry*; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D000077297:Pregnane X Receptor; D060888:Real-Time Polymerase Chain Reaction; D011987:Receptors, Steroid / Q000819:agonists*; D013261:Sterols / Q000737:chemistry* / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D013261:Sterols
keywords: Incisterols; Molecular docking; Nuclear receptors; Plakortis cfr. lita; Pregnane X receptor