Volume 11, Issue 16 p. 1752-1761
Full Paper

Cyclic Ketoximes as Estrogen Receptor β Selective Agonists

Dr. Carlotta Granchi

Corresponding Author

Dr. Carlotta Granchi

Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy

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Margherita Lapillo

Margherita Lapillo

Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy

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Concetta Russo Spena

Concetta Russo Spena

Graduate School in Chemistry, University of Trieste, Italy

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Dr. Flavio Rizzolio

Dr. Flavio Rizzolio

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

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Prof. Dr. Tiziano Tuccinardi

Prof. Dr. Tiziano Tuccinardi

Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy

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Dr. Teresa A. Martin

Dr. Teresa A. Martin

Department of Chemistry, University of Illinois, 600 S. Mathews Avenue, Urbana, IL, 61801 USA

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Kathryn E. Carlson

Kathryn E. Carlson

Department of Chemistry, University of Illinois, 600 S. Mathews Avenue, Urbana, IL, 61801 USA

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Prof. Dr. John A. Katzenellenbogen

Prof. Dr. John A. Katzenellenbogen

Department of Chemistry, University of Illinois, 600 S. Mathews Avenue, Urbana, IL, 61801 USA

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Prof. Dr. Filippo Minutolo

Prof. Dr. Filippo Minutolo

Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy

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First published: 02 May 2016
Citations: 1

Graphical Abstract

What a nice cycle tour! A new class of ERβ-selective agonists was developed by introducing a cyclic portion in the salicylketoxime scaffold. This structural modification gives rise to potent and selective ligands for ERβ. Cell-free coactivator binding and recruitment assays prove that ERβ is able to recruit co-regulator proteins upon ligand activation, which confirms the agonist functional properties of these compounds.

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.