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Invesgations on the Influence of Halide Substituents on the Estrogen Receptor Interaction of 2, 4, 5‐Tris(4‐hydroxyphenyl)imidazoles
Author(s) -
Gust Ronald,
Busch Sandra,
Keilitz Roland,
Schmidt Kathrin,
von Rauch Moriz
Publication year - 2003
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.200300729
Subject(s) - halide , tris , chemistry , estrogen receptor , estrogen , stereochemistry , medicinal chemistry , combinatorial chemistry , organic chemistry , biochemistry , medicine , cancer , breast cancer
Previously, we reported on the synthesis and estrogen receptor (ER) interaction of imidazoles, which had to be 1‐alkyl‐4, 5‐bis(2‐halo‐4‐hydroxyphenyl) substituted for a high relative binding affinity (RBA >1 %). This led to the assumption that a shielding of the polar heterocyclic system is a prerequisite for ER binding. In continuation of this study we synthesized 2, 4, 5‐tris(4‐hydroxyphenyl)imidazoles with Cl‐or F‐atoms in the ortho ‐positions of the aromatic rings and evaluated whether they mediate sufficient hydrophobicity for ER interaction. 2‐(2, 6‐Dichloro‐3/4‐hydroxyphenyl)‐4, 5‐bis(2‐halo‐4‐hydroxyphenyl)imidazoles were synthesized by reaction of the respective methoxy‐substituted benzil with either the 2, 6‐dichloro‐4‐methoxy‐or the 2, 6‐dichloro‐3‐methoxybenzaldehyde in ammonium acetate solution. The required ether cleavage was performed subsequently with BBr 3 . In the competition experiment with [ 3 H]estradiol the imidazoles with the a C2‐standing (2, 6‐dichloro‐4‐hydroxyphenyl) ring showed an RBA >0.02 %, but did not activate the luciferase gene in estrogen receptor positive MCF‐7‐2a breast cancer cells stably transfected with the plasmid ERE wtc luc. In the test for antagonistic potency only the 2‐(2, 6‐dichloro‐4‐hydroxyphenyl)‐4, 5‐bis(4‐hydroxyphenyl)imidazole 3 antagonized the effects of 1 nM estradiol slightly. From these data, it can be concluded that a C2‐standing 2, 6‐dichloro‐4‐hydroxyphenyl ring is not appropriate to optimize the ER interaction of 4, 5‐(4‐hydroxyphenyl)imidazoles.