Invesgations on the Influence of Halide Substituents on the Estrogen Receptor Interaction of 2, 4, 5-Tris(4-hydroxyphenyl)imidazoles
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 pr...
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Veröffentlicht in: | Archiv der Pharmazie (Weinheim) 2003-10, Vol.336 (10), p.456-465 |
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Sprache: | eng |
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Zusammenfassung: | 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 BBr3. In the competition experiment with [3H]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 EREwtcluc. 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. |
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ISSN: | 0365-6233 1521-4184 |
DOI: | 10.1002/ardp.200300729 |