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.

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.

(4R,5S)/(4S,5R)-4,5-Bis(4-hydroxyphenyl)-2-imidazolines: ligands for the estrogen receptor with a novel binding mode.

(4R,5S)/(4S,5R)-4,5-Bis(4-hydroxyphenyl)-2-imidazolines 1-7 were synthesized by the reaction of the methoxy-substituted (1R,2S)/(1S,2R)-1,2-diarylethylenediamines 1b-7b with triethyl orthoformate and subsequent ether cleavage with BBr(3). All compounds were tested for estrogen receptor (ER) binding in a competition experiment with [(3)H]-estradiol and for gene activation in a luciferase assay using ER positive MCF-7-2a breast cancer cells stably transfected with the plasmid ERE(wtc)luc. The relative binding affinities of the 2-imidazolines were very low (RBA < 0.

Synthesis, structural evaluation, and estrogen receptor interaction of 2,3-diarylpiperazines.

To develop novel estrogen receptor (ER) ligands, ring-fused derivatives of the hormonally active (1R,2S)/(1S,2R)-1-(2-chloro-4-hydroxyphenyl)-2-(2,6-dichloro-4-hydroxyphenyl)ethylenediamine 4b were synthesized. (2R,3S)/(2S,3R)-2-(2-Chloro-4-hydroxyphenyl)-3-(2,6-dichloro-4-hydroxyphenyl)piperazine 4 induced ligand-dependent gene expression in MCF-7-2a cells, stably transfected with the plasmid ERE(wtc)luc and was therefore used as a lead structure. The influence of the substitution pattern in the aromatic rings (4-OH (1), 2-F,4-OH (2), 2-Cl,4-OH (3), 2,6-Cl2,3-OH (5), and 2,6-Cl2,4-OH (6)) and the effect of N-ethyl chains on the ER binding and activation of gene expression were studied.

Investigations of new lead structures for the design of selective estrogen receptor modulators.

Heterocyclic derivatives of (R,S)/(S,R)-1-(2-chloro-4-hydroxyphenyl)-2-(2,6-dichloro-4-hydroxyphenyl)ethylenediamine (L1) were synthesized and tested for estrogen receptor binding. The selection of the heterocycles was based on theoretical consideration. (2R,3S)/(2S,3R)-2-(2-Chloro-4-hydroxyphenyl)-3-(2,6-dichloro-4-hydroxyphenyl)piperazine 2, (4R,5S)/(4S,5R)-4-(2-chloro-4-hydroxyphenyl)-5-(2,6-dichloro-4-hydroxyphenyl)-2-imidazoline 3, and 4-(2-chloro-4-hydroxyphenyl)-5-(2,6-dichloro-4-hydroxyphenyl)imidazole 4 possess a spatial structure with neighboring aromatic rings as is realized in hormonally active [1,2-diphenylethylenediamine]platinum(II) complexes.