Synthesis, structural evaluation, and estrogen receptor interaction of 4,5-bis(4-hydroxyphenyl)imidazoles

4,5-Bis(4-hydroxyphenyl)imidazoles with 2,2'-H (1),2,2'-F (2),2,2'-Cl (3), and 2,2'6-Cl (4) substituents in the aromatic rings were synthesized by oxidation of the respective methoxy-substituted (R,S)/(S,R)-4,5-diaryl-2-imidazolines with MnO2 and subsequent ether cleavage with BBr3. N-alkylation of 1 and 3 with ethyl iodide yielded the compounds 5 and 6. The imidazoles were characterized by NMR spectroscopy and tested for estrogen receptor binding in a competition experiment with [3H]estradiol using calf uterine cytosol. Gene activation was verified in a luciferase assay using estrogen receptor positive MCF-7-2a cells stably transfected with the plasmid ERE(wtc)luc. All halide substituted imidazoles competed with estradiol for the binding site at the estrogen receptor. The N-ethyl derivative 6 showed the highest relative binding affinity of 1.26 %. Treatment of MCF-7-2a cells, however, did not lead to gene activation. The relative activation of 6 amounted only to 10% at 1 microM compared to E2 (100%).