Selective and potent agonists for estrogen receptor beta derived from molecular refinements of salicylaldoximes

Simone Bertini; Andrea De Cupertinis; Carlotta Granchi; Barbara Bargagli; Tiziano Tuccinardi; Adriano Martinelli; Marco Macchia; Jillian R. Gunther; Kathryn E. Carlson; John A. Katzenellenbogen; Filippo Minutolo

doi:10.1016/j.ejmech.2011.03.030

Selective and potent agonists for estrogen receptor beta derived from molecular refinements of salicylaldoximes

Simone Bertini, Andrea De Cupertinis, Carlotta Granchi, Barbara Bargagli, Tiziano Tuccinardi, Adriano Martinelli, Marco Macchia, Jillian R. Gunther, Kathryn E. Carlson, John A. Katzenellenbogen, Filippo Minutolo

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

Abstract

In a continuing effort to improve the subtype selectivity and agonist potency of estrogen receptor β (ERβ) ligands, we have designed and developed a thus far unexplored structural series obtained by molecular refinements of monoaryl-substituted salicylaldoximes (Salaldox B). The most interesting compounds in this series (2c, d) show remarkably high ERβ-binding affinities, with K_i values reaching the sub-nanomolar range (K_i = 0.38 nM for 2c and 0.57 nM for 2d), and have very high levels of ERβ-subtype selectivity. Both compounds show a potent full agonist character on ERβ (EC₅₀ = 0.23 nM for 2c and 1.3 nM for 2d). Furthermore, 2d shows a remarkable functional subtype selectivity, with a β/α transcription potency ratio 50-fold higher than that of estradiol.

Original language	English (US)
Pages (from-to)	2453-2462
Number of pages	10
Journal	European Journal of Medicinal Chemistry
Volume	46
Issue number	6
DOIs	https://doi.org/10.1016/j.ejmech.2011.03.030
State	Published - Jun 2011
Externally published	Yes

Keywords

Agonists
Docking
Estrogen
Receptor binding
Salicylaldoxime

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

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Bertini, S., De Cupertinis, A., Granchi, C., Bargagli, B., Tuccinardi, T., Martinelli, A., Macchia, M., Gunther, J. R., Carlson, K. E., Katzenellenbogen, J. A., & Minutolo, F. (2011). Selective and potent agonists for estrogen receptor beta derived from molecular refinements of salicylaldoximes. European Journal of Medicinal Chemistry, 46(6), 2453-2462. https://doi.org/10.1016/j.ejmech.2011.03.030

Bertini, S, De Cupertinis, A, Granchi, C, Bargagli, B, Tuccinardi, T, Martinelli, A, Macchia, M, Gunther, JR, Carlson, KE, Katzenellenbogen, JA & Minutolo, F 2011, 'Selective and potent agonists for estrogen receptor beta derived from molecular refinements of salicylaldoximes', European Journal of Medicinal Chemistry, vol. 46, no. 6, pp. 2453-2462. https://doi.org/10.1016/j.ejmech.2011.03.030

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title = "Selective and potent agonists for estrogen receptor beta derived from molecular refinements of salicylaldoximes",

abstract = "In a continuing effort to improve the subtype selectivity and agonist potency of estrogen receptor β (ERβ) ligands, we have designed and developed a thus far unexplored structural series obtained by molecular refinements of monoaryl-substituted salicylaldoximes (Salaldox B). The most interesting compounds in this series (2c, d) show remarkably high ERβ-binding affinities, with Ki values reaching the sub-nanomolar range (Ki = 0.38 nM for 2c and 0.57 nM for 2d), and have very high levels of ERβ-subtype selectivity. Both compounds show a potent full agonist character on ERβ (EC50 = 0.23 nM for 2c and 1.3 nM for 2d). Furthermore, 2d shows a remarkable functional subtype selectivity, with a β/α transcription potency ratio 50-fold higher than that of estradiol.",

keywords = "Agonists, Docking, Estrogen, Receptor binding, Salicylaldoxime",

author = "Simone Bertini and {De Cupertinis}, Andrea and Carlotta Granchi and Barbara Bargagli and Tiziano Tuccinardi and Adriano Martinelli and Marco Macchia and Gunther, {Jillian R.} and Carlson, {Kathryn E.} and Katzenellenbogen, {John A.} and Filippo Minutolo",

note = "Funding Information: One of the authors (CG) is grateful to the Italian Ministry for University and Research (MIUR), Rome, Italy, for a triennial (2008–2010) PhD fellowship (“grandi progetti strategici”). Dr. Giorgio Placanica and Dr. Caterina Orlando are gratefully acknowledged for technical assistance in the analysis of the chemical products. Molecular graphic images were produced using the UCSF Chimera package from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIH P41 RR001081 ). Support from the National Institutes of Health is gratefully acknowledged ( PHS R37 DK015556 , JAK; NRSA F30 ES016484-01 and T32 GM070421 , JRG). ",

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doi = "10.1016/j.ejmech.2011.03.030",

language = "English (US)",

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T1 - Selective and potent agonists for estrogen receptor beta derived from molecular refinements of salicylaldoximes

AU - Bertini, Simone

AU - De Cupertinis, Andrea

AU - Granchi, Carlotta

AU - Bargagli, Barbara

AU - Tuccinardi, Tiziano

AU - Martinelli, Adriano

AU - Macchia, Marco

AU - Gunther, Jillian R.

AU - Carlson, Kathryn E.

AU - Katzenellenbogen, John A.

AU - Minutolo, Filippo

N1 - Funding Information: One of the authors (CG) is grateful to the Italian Ministry for University and Research (MIUR), Rome, Italy, for a triennial (2008–2010) PhD fellowship (“grandi progetti strategici”). Dr. Giorgio Placanica and Dr. Caterina Orlando are gratefully acknowledged for technical assistance in the analysis of the chemical products. Molecular graphic images were produced using the UCSF Chimera package from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIH P41 RR001081 ). Support from the National Institutes of Health is gratefully acknowledged ( PHS R37 DK015556 , JAK; NRSA F30 ES016484-01 and T32 GM070421 , JRG).

PY - 2011/6

Y1 - 2011/6

N2 - In a continuing effort to improve the subtype selectivity and agonist potency of estrogen receptor β (ERβ) ligands, we have designed and developed a thus far unexplored structural series obtained by molecular refinements of monoaryl-substituted salicylaldoximes (Salaldox B). The most interesting compounds in this series (2c, d) show remarkably high ERβ-binding affinities, with Ki values reaching the sub-nanomolar range (Ki = 0.38 nM for 2c and 0.57 nM for 2d), and have very high levels of ERβ-subtype selectivity. Both compounds show a potent full agonist character on ERβ (EC50 = 0.23 nM for 2c and 1.3 nM for 2d). Furthermore, 2d shows a remarkable functional subtype selectivity, with a β/α transcription potency ratio 50-fold higher than that of estradiol.

AB - In a continuing effort to improve the subtype selectivity and agonist potency of estrogen receptor β (ERβ) ligands, we have designed and developed a thus far unexplored structural series obtained by molecular refinements of monoaryl-substituted salicylaldoximes (Salaldox B). The most interesting compounds in this series (2c, d) show remarkably high ERβ-binding affinities, with Ki values reaching the sub-nanomolar range (Ki = 0.38 nM for 2c and 0.57 nM for 2d), and have very high levels of ERβ-subtype selectivity. Both compounds show a potent full agonist character on ERβ (EC50 = 0.23 nM for 2c and 1.3 nM for 2d). Furthermore, 2d shows a remarkable functional subtype selectivity, with a β/α transcription potency ratio 50-fold higher than that of estradiol.

KW - Agonists

KW - Docking

KW - Estrogen

KW - Receptor binding

KW - Salicylaldoxime

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Selective and potent agonists for estrogen receptor beta derived from molecular refinements of salicylaldoximes

Abstract

Keywords

ASJC Scopus subject areas

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