title: Structural evolutions of salicylaldoximes as selective agonists for estrogen receptor beta.
abstract: The bioisosteric replacement of the phenol ring, a signature functional group of most estrogen receptor (ER) ligands, with a hydrogen-bonded pseudocyclic ring, led to the development of a novel class of nonsteroidal ER-ligands based on a salicylaldoxime template. A series of structural modifications were applied to selected molecules belonging to the monoaryl-salicylaldoxime chemical class in an attempt to improve further their ERbeta-selective receptor affinity and agonist properties. Among several modifications, the best results were obtained by the simultaneous introduction of a meta-fluorine atom into the para-hydroxyphenyl substituent present in the 4-position of salicylaldoxime, together with the insertion of a chloro group in the 3-position of the central scaffold. The resulting compound showed the best affinity (K(i) = 7.1 nM) and selectivity for ERbeta over ERalpha. Moreover, in transcription assays, it proved to be a selective and potent ERbeta-full agonist with an EC(50) of 4.8 nM.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Universita di Pisa, Via Bonanno 6, 56126 Pisa, Italy. minutolo@farm.unipi.it
authors.forename: Filippo
authors.initials: F
authors.lastname: Minutolo
authors.forename: Simone
authors.initials: S
authors.lastname: Bertini
authors.forename: Carlotta
authors.initials: C
authors.lastname: Granchi
authors.forename: Teresa
authors.initials: T
authors.lastname: Marchitiello
authors.forename: Giovanni
authors.initials: G
authors.lastname: Prota
authors.forename: Simona
authors.initials: S
authors.lastname: Rapposelli
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
authors.forename: Adriano
authors.initials: A
authors.lastname: Martinelli
authors.forename: Jillian R
authors.initials: JR
authors.lastname: Gunther
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carlson
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.forename: Marco
authors.initials: M
authors.lastname: Macchia
mesh_terms: D003198:Computer Simulation; D016889:Endometrial Neoplasms; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000378:metabolism; D005260:Female; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D010091:Oximes; C005704:salicylaldoxime