Influence of chlorine or fluorine substitution on the estrogenic properties of 1-alkyl-2,3,5-tris(4-hydroxyphenyl)-1H-pyrroles.

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Schafer A, Wellner A, Strauss M, Schafer A, Wolber G, Gust R

Influence of chlorine or fluorine substitution on the estrogenic properties of 1-alkyl-2,3,5-tris(4-hydroxyphenyl)-1H-pyrroles.

J Med Chem. 2012 Nov 26;55(22):9607-18. doi: 10.1021/jm300860j. Epub 2012 Oct 17.

PubMed ID
23043242 [ View in PubMed
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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 ERalpha/ERbeta receptors (HAP assay) and in transactivation assays using ERalpha-positive MCF-7/2a as well as U2-OS/ERalpha and U2-OS/ERbeta cells. In the competition experiment at ERalpha the compounds displayed very high relative binding affinities of up to 37% (determined for 8m) but with restricted subtype selectivity (e.g., ERalpha/ERbeta (8m) = 9). The highest estrogenic potency in ERalpha-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/ERalpha 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/ERbeta cells for all pyrroles no transactivation could be observed, which indicates that they are selective ERalpha agonists in cellular systems.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
EstradiolEstrogen receptor alphaEC 50 (nM)0.1N/AN/ADetails
EstradiolEstrogen receptor alphaEC 50 (nM)0.004N/AN/ADetails
EstradiolEstrogen receptor betaEC 50 (nM)0.01N/AN/ADetails