title: Influence of chlorine or fluorine substitution on the estrogenic properties of 1-alkyl-2,3,5-tris(4-hydroxyphenyl)-1H-pyrroles.
abstract: In continuation of our previous work, several 1-alkyl-2,3,5-tris(4-hydroxyphenyl)aryl-1H-pyrroles with chlorine or fluorine substituents in the aryl residues were synthesized and tested for estrogen receptor (ER) binding at isolated ERα/ERβ receptors (HAP assay) and in transactivation assays using ERα-positive MCF-7/2a as well as U2-OS/ERα and U2-OS/ERβ cells. In the competition experiment at ERα the compounds displayed very high relative binding affinities of up to 37% (determined for 8m) but with restricted subtype selectivity (e.g., ERα/ERβ (8m) = 9). The highest estrogenic potency in ERα-positive MCF-7/2a cells was determined for 2,3,5-tris(2-fluoro-4-hydroxyphenyl)-1-propyl-1H-pyrrole 8m (EC(50) = 23 nM), while in U2-OS/ERα cells 2-(2-fluoro-4-hydroxyphenyl)-3,5-bis(4-hydroxyphenyl)-1-propyl-1H-pyrrole 8b (EC(50) = 0.12 nM) was the most potent agonist, only 30-fold less active than estradiol (E2, EC(50) = 0.004 nM). In U2-OS/ERβ cells for all pyrroles no transactivation could be observed, which indicates that they are selective ERα agonists in cellular systems.
authors.affiliation: Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Strasse 2+4, D-14195 Berlin, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Schäfer
authors.forename: Anja
authors.initials: A
authors.lastname: Wellner
authors.forename: Martin
authors.initials: M
authors.lastname: Strauss
authors.forename: Andreas
authors.initials: A
authors.lastname: Schäfer
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
authors.forename: Ronald
authors.initials: R
authors.lastname: Gust
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002713:Chlorine / Q000737:chemistry*; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000378:metabolism; D005260:Female; D005461:Fluorine / Q000737:chemistry*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008958:Models, Molecular; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C577937:2,3,5-tris(2-fluoro-4-hydroxyphenyl)-1-propyl-1H-pyrrole; C577938:2-(2-fluoro-4-hydroxyphenyl)-3,5-bis(4-hydroxyphenyl)-1-propyl-1H-pyrrole; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D010636:Phenols; D011758:Pyrroles; D005461:Fluorine; D002713:Chlorine; D008156:Luciferases