title: Estrogenic properties of naturally occurring prenylated isoflavones in U2OS human osteosarcoma cells: Structure-activity relationships.
abstract: Eight isoflavones derivatives, with isoprenyl and/or 7-methoxy substitution, isolated from Erythrina poeppigiana (Fabaceae) have been investigated for their estrogenic properties in receptor subtype-specific reporter gene assays. First we focused on their estrogen receptor alpha and beta (ERalpha and ERbeta) selectivity, second we addressed structure-activity relationships, using bone-derived human osteosarcoma cell line (U2OS cells) stably expressing ERalpha or transiently expressing ERbeta. Our results show that a substitution at position 3' together with a 7-methoxy substitution on the genistein skeleton is associated with a statistically significant activation of the ERalpha- and ERbeta-dependent reporter gene expression in U2OS cells starting from 0.1nM. Particularly, the 7-methoxy-3'-isoprenyl (1) and the 7-methoxy-3'-(3-methyl-2-hydroxybuten-3-yl) (3) derivatives of genistein induces an ERalpha- and ERbeta-coupled luciferase activity at a concentration ten times lower than that of genistein, for which a statistically significant effect was observable at 1nM. On the other hand, isoprenyl substitution at position 6 of the A ring, compound 5, seems to have very little impact on the genistein ability to induce ER-coupled luciferase activity in U2OS cells, while a double prenylation at positions 8 and 3', compound 7, is associated with an almost complete loss of function on the reporter gene activation in U2OS-ERalpha, but in ERbeta expressing system the effectiveness remains on a statistically significant level, demonstrating an "exclusive ERbeta-selectivity" in U2OS human osteosarcoma cells, and therefore 7 can be considered as an isotype-selective ER ligand. Finally all the tested isoflavones derivatives appear to exhibit a slightly pronounced ERbeta preference, depending upon the position and the nature of the substituent moiety on the isoflavone skeleton. The estrogen-like effect of these prenylated isoflavone derivatives could be inhibited by the pure ER antagonist ICI 182 780, indicating that these effects were primarily mediated through ERs.
authors.affiliation: Molekulare Zellphysiologie & Endokrinologie, Institut für Zoologie, Technische Universität Dresden, 01062 Dresden, Germany.
authors.forename: Sefirin
authors.initials: S
authors.lastname: Djiogue
authors.forename: Dieudonné
authors.initials: D
authors.lastname: Njamen
authors.forename: Maria
authors.initials: M
authors.lastname: Halabalaki
authors.forename: Georg
authors.initials: G
authors.lastname: Kretzschmar
authors.forename: Antje
authors.initials: A
authors.lastname: Beyer
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Mbanya
authors.forename: Alexios-Leandros
authors.initials: AL
authors.lastname: Skaltsounis
authors.forename: Günter
authors.initials: G
authors.lastname: Vollmer
mesh_terms: D045744:Cell Line, Tumor; D004895:Erythrina / Q000737:chemistry*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D019833:Genistein / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D006801:Humans; D007529:Isoflavones / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism; D054876:Prenylation; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D007529:Isoflavones; D019833:Genistein