title: Subtle side-chain modifications of the hop phytoestrogen 8-prenylnaringenin result in distinct agonist/antagonist activity profiles for estrogen receptors alpha and beta.
abstract: In search of therapeutic agents for estrogen-related pathologies, phytoestrogens are being extensively explored. In contrast to naringenin, 8-prenylnaringenin is a potent hop-derived estrogenic compound, highlighting the importance of the prenyl group for hormonal activity. We investigated the effects of substituting the prenyl group at C(8) with alkyl chains of varying lengths and branching patterns on estrogen receptor (ER) subtype ERalpha- and ERbeta-binding affinities and transcriptional activities. In addition, features of the ligand-induced receptor conformations were explored using a set of specific ER-binding peptides. The new 8-alkylnaringenins were found to span an activity spectrum ranging from full agonism to partial agonism to antagonism. Most strikingly, 8-(2,2-dimethylpropyl)naringenin exhibited full agonist character on ERalpha, but pronounced antagonist character on ERbeta. Knowledge on how ER-subtype-selective activities can be designed provides valuable information for future drug or tool compound discovery.
authors.affiliation: Faculty of Pharmaceutical Sciences, Laboratory of Pharmacognosy and Phytochemistry, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Frederik
authors.initials: F
authors.lastname: Roelens
authors.forename: Nina
authors.initials: N
authors.lastname: Heldring
authors.forename: Willem
authors.initials: W
authors.lastname: Dhooge
authors.forename: Martin
authors.initials: M
authors.lastname: Bengtsson
authors.forename: Frank
authors.initials: F
authors.lastname: Comhaire
authors.forename: Jan-Ake
authors.initials: JA
authors.lastname: Gustafsson
authors.forename: Eckardt
authors.initials: E
authors.lastname: Treuter
authors.forename: Denis
authors.initials: D
authors.lastname: De Keukeleire
mesh_terms: D001667:Binding, Competitive; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry; D044950:Flavanones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D048789:Phytoestrogens / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D011869:Radioligand Assay; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic; D020798:Two-Hybrid System Techniques
chemical_list: C517231:8-(2,2-dimethylpropyl)naringenin; C119737:8-prenylnaringenin; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D044950:Flavanones; D048789:Phytoestrogens