(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 < 0.1%). Nevertheless, 4-7 possessed full agonistic activity in the luciferase assay. The relative transcription potency increased in the order 5 (2,2'-I) < 6 (2,6-Cl(2), 2'-F) < 4 (2,2'-Cl) < 7 (2,6-Cl(2), 2'-Cl). These data together with spectroscopic and molecular modeling studies were used to investigate the preferred binding mode adopted by the imidazoline ligands. The 1,2-diarylethane pharmacophor takes a Z-stilbene-like structure with pseudoaxially oriented phenyl rings at the planar heterocyclic ring. Because of this unusual spatial structure, the (4R,5S)/(4S,5R)-4,5-bis(4-hydroxyphenyl)-2-imidazolines have to be assigned to a second class of estrogenically active compounds (type II estrogens). In contrast to type I estrogens, e.g., estradiol (E2), diethylstilbestrol (DES), and meso-hexestrol (HES), which are connected to His 524 in the binding site, type II estrogens are very likely H-bonded to Asp 351 in a hydrophobic side pocket.