title: Differential estrogen receptor subtype modulators: assessment of estrogen receptor subtype-binding selectivity and transcription-regulating properties of new cycloalkyl pyrazoles.
abstract: Several new cycloalkyl-fused diaryl pyrazoles were synthesized and their binding affinity for the estrogen receptor (ER) subtypes, ERalpha and ERbeta, and subtype-specific agonist/antagonist properties were determined. Cyclopentane- and cyclohexane-fused pyrazoles with p-hydroxyphenyl rings at positions 1 and 3 displayed modest ERbeta-binding selectivity and variable agonism through ERalpha, while behaving as full estrogen antagonists through ERbeta in estrogen-responsive element (ERE)-dependent gene expression assays. By contrast, the 2,3-diphenolic derivatives were non-selective and considerably less effective ERbeta antagonists compared to 1,3-diphenolic ones. The cyclohexane-fused 1,3-diphenolic pyrazole 8, in particular, behaved as full ERalpha agonist/ERbeta antagonist in these assays. Molecular modelling revealed the structural determinants possibly accounting for the differential regulation of transcription through the two ERs exhibited by 8. The data also shows that the ER subtype-binding selectivity and agonist/antagonist efficacy of the 1,3-diphenolic pyrazoles is influenced by the cycloalkyl ring fused to the pyrazole core. Using 8 we show that, though the mutant androgen receptor (AR) of LNCaP cells is required for estrogen as well as androgen stimulation of cell growth, estrogen responsiveness of the cells depends on ERbeta and AR but not on ERalpha.
authors.affiliation: Molecular Endocrinology Program, Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
authors.forename: Xanthippi
authors.initials: X
authors.lastname: Alexi
authors.forename: Konstantinos M
authors.initials: KM
authors.lastname: Kasiotis
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Fokialakis
authors.forename: George
authors.initials: G
authors.lastname: Lambrinidis
authors.forename: Aggeliki K
authors.initials: AK
authors.lastname: Meligova
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mikros
authors.forename: Serkos A
authors.initials: SA
authors.lastname: Haroutounian
authors.forename: Michael N
authors.initials: MN
authors.lastname: Alexis
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D001665:Binding Sites; D045744:Cell Line, Tumor; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008297:Male; D008958:Models, Molecular; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology*; D020849:Raloxifene Hydrochloride / Q000378:metabolism / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000145:classification / Q000187:drug effects* / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000378:metabolism / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D011720:Pyrazoles; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride; D004958:Estradiol