Τίτλος:
Differential estrogen receptor subtype modulators: Assessment of estrogen receptor subtype-binding selectivity and transcription-regulating properties of new cycloalkyl pyrazoles
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Several new cycloalkyl-fused diaryl pyrazoles were synthesized and their binding affinity for the estrogen receptor (ER) subtypes, ERα and ERβ, and subtype-specific agonist/antagonist properties were determined. Cyclopentane- and cyclohexane-fused pyrazoles with p-hydroxyphenyl rings at positions 1 and 3 displayed modest ERβ-binding selectivity and variable agonism through ERα, while behaving as full estrogen antagonists through ERβ in estrogen-responsive element (ERE)-dependent gene expression assays. By contrast, the 2,3-diphenolic derivatives were non-selective and considerably less effective ERβ antagonists compared to 1,3-diphenolic ones. The cyclohexane-fused 1,3-diphenolic pyrazole 8, in particular, behaved as full ERα agonist/ERβ 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 ERβ and AR but not on ERα. © 2009 Elsevier Ltd. All rights reserved.
Συγγραφείς:
Alexi, X.
Kasiotis, K.M.
Fokialakis, N.
Lambrinidis, G.
Meligova, A.K.
Mikros, E.
Haroutounian, S.A.
Alexis, M.N.
Περιοδικό:
Journal of Steroid Biochemistry and Molecular Biology
Λέξεις-κλειδιά:
alkaline phosphatase; androgen receptor; antiestrogen; cycloalkane derivative; cyclohexane; cyclopentane; estrogen receptor; estrogen receptor alpha; estrogen receptor beta; pyrazole; selective estrogen receptor modulator, article; binding affinity; binding kinetics; cell growth; cell stimulation; cell strain MCF 7; controlled study; crystal structure; enzyme specificity; estrogen activity; estrogen responsive element; gene expression; hormone determination; human; human cell; molecular docking; molecular model; protein binding; protein expression; signal transduction; transcription regulation, Adenocarcinoma; Binding Sites; Cell Line, Tumor; Estradiol; Humans; Male; Models, Molecular; Prostatic Neoplasms; Pyrazoles; Raloxifene; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Transcription, Genetic
DOI:
10.1016/j.jsbmb.2009.09.006
