Invesgations [correction investigations] 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 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.