663944-64-7Relevant articles and documents
Invesgations on the Influence of Halide Substituents on the Estrogen Receptor Interaction of 2,4,5-Tris(4-hydroxyphenyl)imidazoles
Gust, Ronald,Busch, Sandra,Keilitz, Roland,Schmidt, Kathrin,Von Rauch, Moriz
, p. 456 - 465 (2007/10/03)
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.
