title: Cyclic Ketoximes as Estrogen Receptor β Selective Agonists.
abstract: The development of estrogen receptor β (ERβ)-selective agonists represents a therapeutic strategy against several kinds of cancers, but the high homology between the two receptor subtypes, ERα and ERβ, makes the achievement of this goal very challenging. In the past, we developed salicylaldoxime- and salicylketoxime-based molecules that proved to bind well to ERβ. In this paper, further structural evolution of the salicylketoximes is presented: two of the newly synthesized five-membered cyclic ketoximes bind with nanomolar affinities to ERβ, and they show selectivity for this subtype over ERα. Their agonist character was confirmed by cell-free coactivator recruitment assays, in which we demonstrated the ability of these compounds to form an active complex with ERβ capable of recruiting coactivator proteins; this indicated their efficacy as agonists. Finally, their potency and selectivity for ERβ binding were rationalized by molecular-modeling studies.
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126, Pisa, Italy. carlotta.granchi@farm.unipi.it.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Granchi
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126, Pisa, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Lapillo
authors.affiliation: Graduate School in Chemistry, University of Trieste, Italy.
authors.forename: Concetta Russo
authors.initials: CR
authors.lastname: Spena
authors.affiliation: Division of Experimental and Clinical Pharmacology, Department of Molecular Biology and Translational Research, CRO National Cancer Institute and Center for Molecular Biomedicine, IRCCS, 33081, Aviano, Pordenone, Italy.
authors.forename: Flavio
authors.initials: F
authors.lastname: Rizzolio
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126, Pisa, Italy.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
authors.affiliation: Department of Chemistry, University of Illinois, 600 S. Mathews Avenue, Urbana, IL, 61801, USA.
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Martin
authors.affiliation: Department of Chemistry, University of Illinois, 600 S. Mathews Avenue, Urbana, IL, 61801, USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carlson
authors.affiliation: Department of Chemistry, University of Illinois, 600 S. Mathews Avenue, Urbana, IL, 61801, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126, Pisa, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Minutolo
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003500:Cyclization; D004305:Dose-Response Relationship, Drug; D047629:Estrogen Receptor beta / Q000819:agonists*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047629:Estrogen Receptor beta; D010091:Oximes
keywords: cancer; estrogen; ligand binding; oximes; receptors