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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• 作者：Anja Sch盲fer ; Anja Wellner ; Martin Strauss ; Andreas Sch盲fer ; Gerhard Wolber ; Ronald Gust
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 26, 2012
• 年：2012
• 卷：55
• 期：22
• 页码：9607-9618
• 全文大小：581K
• 年卷期：v.55,no.22(November 26, 2012)
• ISSN：1520-4804

文摘

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 ER伪/ER尾 receptors (HAP assay) and in transactivation assays using ER伪-positive MCF-7/2a as well as U2-OS/ER伪 and U2-OS/ER尾 cells. In the competition experiment at ER伪 the compounds displayed very high relative binding affinities of up to 37% (determined for 8m) but with restricted subtype selectivity (e.g., ER伪/ER尾 (8m) = 9). The highest estrogenic potency in ER伪-positive MCF-7/2a cells was determined for 2,3,5-tris(2-fluoro-4-hydroxyphenyl)-1-propyl-1H-pyrrole 8m (EC₅₀ = 23 nM), while in U2-OS/ER伪 cells 2-(2-fluoro-4-hydroxyphenyl)-3,5-bis(4-hydroxyphenyl)-1-propyl-1H-pyrrole 8b (EC₅₀ = 0.12 nM) was the most potent agonist, only 30-fold less active than estradiol (E2, EC₅₀ = 0.004 nM). In U2-OS/ER尾 cells for all pyrroles no transactivation could be observed, which indicates that they are selective ER伪 agonists in cellular systems.