Subtle side-chain modifications of the hop phytoestrogen 8-prenylnaringenin result in distinct agonist/antagonist activity profiles for estrogen receptors α and β

Frederik Roelens, Nina Heldring, Willem Dhooge, Martin Bengtsson, Frank Comhaire, Jan Åke Gustafsson, Eckardt Treuter, Denis De Keukeleire

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

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 ERα- and ERβ-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 ERα, but pronounced antagonist character on ERβ. Knowledge on how ER-subtype-selective activities can be designed provides valuable information for future drug or tool compound discovery.

Original languageEnglish (US)
Pages (from-to)7357-7365
Number of pages9
JournalJournal of Medicinal Chemistry
Volume49
Issue number25
DOIs
StatePublished - Dec 14 2006

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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