Isocoumarins as estrogen receptor beta selective ligands: Isomers of isoflavone phytoestrogens and their metabolites

Meri De Angelis, Fabio Stossi, Michael Waibel, Benita S. Katzenellenbogen, John A. Katzenellenbogen

Research output: Contribution to journalArticle

Abstract

In a search for new ligands selective for the estrogen receptor beta (ERβ), we prepared a series of non-steroidal compounds having an isocoumarin core structure. An interesting feature of these derivatives is that they bear the same functionalities as the well-known ERβ -selective, isoflavone phytoestrogens daidzein and genistein, but in an isomeric arrangement. These compounds could be prepared efficiently by electrophilic cyclization of acetylenic ester precursors, followed by simple manipulations to introduce additional substituents. Through a reduction of some of the isocoumarins, we also obtained isomeric analogs of the isoflavone metabolites equol and dehydroequol. The compounds we prepared were evaluated in ER binding assays, and selected compounds were studied further in cell-based gene transcription assays. Several of the isocoumarins and their analogs are high-affinity ligands that show considerable selectivity for ERβ in terms of binding affinity, and strikingly high ERβ selectivity in terms of potency in gene transcription assays. Two of the best compounds, which combine high transcriptional potency with an ERβ selectivity greater than 1000, should prove to be excellent probes of ERβ function in vivo.

Original languageEnglish (US)
Pages (from-to)6529-6542
Number of pages14
JournalBioorganic and Medicinal Chemistry
Volume13
Issue number23
DOIs
StatePublished - Dec 1 2005

Fingerprint

Isocoumarins
Phytoestrogens
Estrogen Receptor beta
Isoflavones
Metabolites
Isomers
Ligands
Assays
Transcription
Genes
Equol
Genistein
Cyclization
Esters
Derivatives

Keywords

  • Equol
  • Estrogen receptor alpha
  • Estrogen receptor beta
  • Genistein
  • Isocoumarin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Isocoumarins as estrogen receptor beta selective ligands : Isomers of isoflavone phytoestrogens and their metabolites. / De Angelis, Meri; Stossi, Fabio; Waibel, Michael; Katzenellenbogen, Benita S.; Katzenellenbogen, John A.

In: Bioorganic and Medicinal Chemistry, Vol. 13, No. 23, 01.12.2005, p. 6529-6542.

Research output: Contribution to journalArticle

De Angelis, Meri ; Stossi, Fabio ; Waibel, Michael ; Katzenellenbogen, Benita S. ; Katzenellenbogen, John A. / Isocoumarins as estrogen receptor beta selective ligands : Isomers of isoflavone phytoestrogens and their metabolites. In: Bioorganic and Medicinal Chemistry. 2005 ; Vol. 13, No. 23. pp. 6529-6542.
@article{c3a6c499b6a54e35a534259533c2f141,
title = "Isocoumarins as estrogen receptor beta selective ligands: Isomers of isoflavone phytoestrogens and their metabolites",
abstract = "In a search for new ligands selective for the estrogen receptor beta (ERβ), we prepared a series of non-steroidal compounds having an isocoumarin core structure. An interesting feature of these derivatives is that they bear the same functionalities as the well-known ERβ -selective, isoflavone phytoestrogens daidzein and genistein, but in an isomeric arrangement. These compounds could be prepared efficiently by electrophilic cyclization of acetylenic ester precursors, followed by simple manipulations to introduce additional substituents. Through a reduction of some of the isocoumarins, we also obtained isomeric analogs of the isoflavone metabolites equol and dehydroequol. The compounds we prepared were evaluated in ER binding assays, and selected compounds were studied further in cell-based gene transcription assays. Several of the isocoumarins and their analogs are high-affinity ligands that show considerable selectivity for ERβ in terms of binding affinity, and strikingly high ERβ selectivity in terms of potency in gene transcription assays. Two of the best compounds, which combine high transcriptional potency with an ERβ selectivity greater than 1000, should prove to be excellent probes of ERβ function in vivo.",
keywords = "Equol, Estrogen receptor alpha, Estrogen receptor beta, Genistein, Isocoumarin",
author = "{De Angelis}, Meri and Fabio Stossi and Michael Waibel and Katzenellenbogen, {Benita S.} and Katzenellenbogen, {John A.}",
year = "2005",
month = "12",
day = "1",
doi = "10.1016/j.bmc.2005.07.014",
language = "English (US)",
volume = "13",
pages = "6529--6542",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "23",

}

TY - JOUR

T1 - Isocoumarins as estrogen receptor beta selective ligands

T2 - Isomers of isoflavone phytoestrogens and their metabolites

AU - De Angelis, Meri

AU - Stossi, Fabio

AU - Waibel, Michael

AU - Katzenellenbogen, Benita S.

AU - Katzenellenbogen, John A.

PY - 2005/12/1

Y1 - 2005/12/1

N2 - In a search for new ligands selective for the estrogen receptor beta (ERβ), we prepared a series of non-steroidal compounds having an isocoumarin core structure. An interesting feature of these derivatives is that they bear the same functionalities as the well-known ERβ -selective, isoflavone phytoestrogens daidzein and genistein, but in an isomeric arrangement. These compounds could be prepared efficiently by electrophilic cyclization of acetylenic ester precursors, followed by simple manipulations to introduce additional substituents. Through a reduction of some of the isocoumarins, we also obtained isomeric analogs of the isoflavone metabolites equol and dehydroequol. The compounds we prepared were evaluated in ER binding assays, and selected compounds were studied further in cell-based gene transcription assays. Several of the isocoumarins and their analogs are high-affinity ligands that show considerable selectivity for ERβ in terms of binding affinity, and strikingly high ERβ selectivity in terms of potency in gene transcription assays. Two of the best compounds, which combine high transcriptional potency with an ERβ selectivity greater than 1000, should prove to be excellent probes of ERβ function in vivo.

AB - In a search for new ligands selective for the estrogen receptor beta (ERβ), we prepared a series of non-steroidal compounds having an isocoumarin core structure. An interesting feature of these derivatives is that they bear the same functionalities as the well-known ERβ -selective, isoflavone phytoestrogens daidzein and genistein, but in an isomeric arrangement. These compounds could be prepared efficiently by electrophilic cyclization of acetylenic ester precursors, followed by simple manipulations to introduce additional substituents. Through a reduction of some of the isocoumarins, we also obtained isomeric analogs of the isoflavone metabolites equol and dehydroequol. The compounds we prepared were evaluated in ER binding assays, and selected compounds were studied further in cell-based gene transcription assays. Several of the isocoumarins and their analogs are high-affinity ligands that show considerable selectivity for ERβ in terms of binding affinity, and strikingly high ERβ selectivity in terms of potency in gene transcription assays. Two of the best compounds, which combine high transcriptional potency with an ERβ selectivity greater than 1000, should prove to be excellent probes of ERβ function in vivo.

KW - Equol

KW - Estrogen receptor alpha

KW - Estrogen receptor beta

KW - Genistein

KW - Isocoumarin

UR - http://www.scopus.com/inward/record.url?scp=27544470970&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=27544470970&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2005.07.014

DO - 10.1016/j.bmc.2005.07.014

M3 - Article

C2 - 16099659

AN - SCOPUS:27544470970

VL - 13

SP - 6529

EP - 6542

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 23

ER -