title: Monoaryl-substituted salicylaldoximes as ligands for estrogen receptor beta.
abstract: Salicylaldoximes possess a hydrogen-bonded pseudocyclic A' ring in place of the typical phenolic A ring that is characteristic of most estrogen receptor (ER) ligands. Monoaryl-substituted salicylaldoximes were obtained by replacing the phenol moiety (ring A) of the ERbeta pharmacophore with the pseudocycle A' ring, which has previously been shown to behave as a bioequivalent of phenols in nonselective ER ligands. In this series, small substituents (CH 3, CN, Cl) were introduced into the central phenyl scaffold. An efficient sequential halogen-selective double cross-coupling reaction was developed for the synthesis of the methyl-substituted ER ligand. The measured ERbeta affinity proved to be very sensitive to the effect of central core substituents. The binding affinities of the compounds herein reported were in good agreement with the results of computational docking analysis. The chloro-substituted derivative showed the highest beta affinity and selectivity, and it also proved to be an ERbeta partial agonist with an EC 50 of 11 nM.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Universita di Pisa, Pisa, Italy. minutolo@farm.unipi.it
authors.forename: Filippo
authors.initials: F
authors.lastname: Minutolo
authors.forename: Rosalba
authors.initials: R
authors.lastname: Bellini
authors.forename: Simone
authors.initials: S
authors.lastname: Bertini
authors.forename: Isabella
authors.initials: I
authors.lastname: Carboni
authors.forename: Annalina
authors.initials: A
authors.lastname: Lapucci
authors.forename: Letizia
authors.initials: L
authors.lastname: Pistolesi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Prota
authors.forename: Simona
authors.initials: S
authors.lastname: Rapposelli
authors.forename: Francesca
authors.initials: F
authors.lastname: Solati
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
authors.forename: Adriano
authors.initials: A
authors.lastname: Martinelli
authors.forename: Fabio
authors.initials: F
authors.lastname: Stossi
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carlson
authors.forename: Benita S
authors.initials: BS
authors.lastname: Katzenellenbogen
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.forename: Marco
authors.initials: M
authors.lastname: Macchia
mesh_terms: D001667:Binding, Competitive; D002460:Cell Line; D054333:Drug Partial Agonism; D004717:Endometrium / Q000166:cytology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic
chemical_list: C529294:3-chloro-4-(4-hydroxyphenyl)salicylaldoxime; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D010091:Oximes; D010636:Phenols