title: Diethylstilbestrol-scaffold-based pregnane X receptor modulators.
abstract: Due to its function as a regulator of drug-metabolizing enzymes and transporters, pregnane X receptor (PXR) represents an important factor involved in drug metabolism. In this work, we describe the discovery of diethylstilbestrol-based PXR modulators, which were designed from marine sulfated steroids with PXR agonistic activity, solomonsterols A and B, and our recently reported bazedoxifene scaffold-derived PXR antagonists. The methylated diethylstilbestrol derivative 1 displayed potent PXR agonistic activity with an EC50 value of 10.5 μM, whereas compounds 3, 4 and 6 (IC50 for 6 = 27.4 μM) and diethylstilbestrol (2) itself (IC50 = 14.6 μM) exhibited PXR antagonistic effects in HepG2 cells. The PXR modulatory effects of the synthesized diethylstilbestrol derivatives were further confirmed by the induction of PXR-regulated CYP3A4 expression with compound 1, as well as by the inhibition of the rifaximin-promoted up-regulation of CYP3A4 expression with 2 and its derivative 6.
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Žiga
authors.initials: Ž
authors.lastname: Hodnik
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Tihomir
authors.initials: T
authors.lastname: Tomašič
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Domen
authors.initials: D
authors.lastname: Smodiš
authors.affiliation: University of Perugia, Dipartimento di Medicina Clinica e Sperimentale, Nuova Facultàdi Medicina e Chirurgia, S. Andrea delle Fratte, 06132 Perugia, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: D'Amore
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Lucija Peterlin
authors.initials: LP
authors.lastname: Mašič
authors.affiliation: University of Perugia, Dipartimento di Medicina Clinica e Sperimentale, Nuova Facultàdi Medicina e Chirurgia, S. Andrea delle Fratte, 06132 Perugia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia. Electronic address: danijel.kikelj@ffa.uni-lj.si.
authors.forename: Danijel
authors.initials: D
authors.lastname: Kikelj
mesh_terms: D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000378:metabolism; D004054:Diethylstilbestrol / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D056945:Hep G2 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000819:agonists* / Q000037:antagonists & inhibitors*; D012294:Rifamycins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000078262:Rifaximin; D013329:Structure-Activity Relationship; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D012294:Rifamycins; D004054:Diethylstilbestrol; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000078262:Rifaximin
keywords: Diethylstilbestrol; Mimetic; PXR agonist; PXR antagonist; Pregnane X receptor; Solomonsterol