Estrogenic diazenes: Heterocyclic non-steroidal estrogens of unusual structure with selectivity for estrogen receptor subtypes

Usha Ghosh, Deshanie Ganessunker, Viswajanani J. Sattigeri, Kathryn E. Carlson, Deborah J. Mortensen, Benita S Katzenellenbogen, John A. Katzenellenbogen

Research output: Contribution to journalArticle

Abstract

Estrogens regulate many biological functions, often acting in a tissue-selective manner. Their tissue-selective action is believed to involve differential estrogen action through the two estrogen receptor (ER) subtypes, ERα and ERβ, as well as differential interaction of the ligand-receptor complexes with promoters and coregulator proteins. In the latter case, selectivity is based on the induction of specific conformations of the ligand-ER complex, conformations that are influenced by the structure of the ligand. Estrogen pharmaceuticals having an ideal balance of tissue-selective activity are being sought for menopausal hormone replacement, breast cancer prevention and therapy, and other actions. To expand on the structural diversity of ER ligands that might show such tissue selectivity, we have prepared a series of diazenes (pyrazines, pyrimidines, and pyridazines) substituted with two to four aryl groups and various short-chain aliphatic substituents. All of the pyrazine and pyrimidines bind to ER, some with high affinity and with a considerable degree of preferential binding to either ERα or ERβ. One pyrimidine and one pyrazine have ERα affinity preferences as high as 23 and 9, respectively, and one pyrimidine has an ERβ affinity preference of 8. The pyridazines, by contrast, are quite polar and have only very low binding affinity for the ER. In cell-based transcription assays, several of the pyrimidines and a pyrazine were found to be considerably more agonistic on ERα than on ERβ. Because these triaryl diazenes have the largest volumes among the ER ligands so far investigated, their high affinity demonstrates the flexibility of the ligand binding pocket of the ERs and its tolerance for large substituents. Thus, these novel heterocyclic ligands expand the repertoire of chemical structures that bind to the estrogen receptor, and they could prove to be useful in elucidating the biological behavior of the two ER subtypes and in forming the basis for new estrogen pharmaceuticals having desirable tissue selectivity.

Original languageEnglish (US)
Pages (from-to)629-657
Number of pages29
JournalBioorganic and Medicinal Chemistry
Volume11
Issue number4
DOIs
StatePublished - Feb 1 2002

Fingerprint

Non-Steroidal Estrogens
Estrogen Receptors
Pyridazines
Pyrimidines
Ligands
Tissue
Estrogens
Conformations

ASJC Scopus subject areas

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

Cite this

Estrogenic diazenes : Heterocyclic non-steroidal estrogens of unusual structure with selectivity for estrogen receptor subtypes. / Ghosh, Usha; Ganessunker, Deshanie; Sattigeri, Viswajanani J.; Carlson, Kathryn E.; Mortensen, Deborah J.; Katzenellenbogen, Benita S; Katzenellenbogen, John A.

In: Bioorganic and Medicinal Chemistry, Vol. 11, No. 4, 01.02.2002, p. 629-657.

Research output: Contribution to journalArticle

Ghosh, Usha ; Ganessunker, Deshanie ; Sattigeri, Viswajanani J. ; Carlson, Kathryn E. ; Mortensen, Deborah J. ; Katzenellenbogen, Benita S ; Katzenellenbogen, John A. / Estrogenic diazenes : Heterocyclic non-steroidal estrogens of unusual structure with selectivity for estrogen receptor subtypes. In: Bioorganic and Medicinal Chemistry. 2002 ; Vol. 11, No. 4. pp. 629-657.
@article{87e3dd90e80d44488462c5df0d42c614,
title = "Estrogenic diazenes: Heterocyclic non-steroidal estrogens of unusual structure with selectivity for estrogen receptor subtypes",
abstract = "Estrogens regulate many biological functions, often acting in a tissue-selective manner. Their tissue-selective action is believed to involve differential estrogen action through the two estrogen receptor (ER) subtypes, ERα and ERβ, as well as differential interaction of the ligand-receptor complexes with promoters and coregulator proteins. In the latter case, selectivity is based on the induction of specific conformations of the ligand-ER complex, conformations that are influenced by the structure of the ligand. Estrogen pharmaceuticals having an ideal balance of tissue-selective activity are being sought for menopausal hormone replacement, breast cancer prevention and therapy, and other actions. To expand on the structural diversity of ER ligands that might show such tissue selectivity, we have prepared a series of diazenes (pyrazines, pyrimidines, and pyridazines) substituted with two to four aryl groups and various short-chain aliphatic substituents. All of the pyrazine and pyrimidines bind to ER, some with high affinity and with a considerable degree of preferential binding to either ERα or ERβ. One pyrimidine and one pyrazine have ERα affinity preferences as high as 23 and 9, respectively, and one pyrimidine has an ERβ affinity preference of 8. The pyridazines, by contrast, are quite polar and have only very low binding affinity for the ER. In cell-based transcription assays, several of the pyrimidines and a pyrazine were found to be considerably more agonistic on ERα than on ERβ. Because these triaryl diazenes have the largest volumes among the ER ligands so far investigated, their high affinity demonstrates the flexibility of the ligand binding pocket of the ERs and its tolerance for large substituents. Thus, these novel heterocyclic ligands expand the repertoire of chemical structures that bind to the estrogen receptor, and they could prove to be useful in elucidating the biological behavior of the two ER subtypes and in forming the basis for new estrogen pharmaceuticals having desirable tissue selectivity.",
author = "Usha Ghosh and Deshanie Ganessunker and Sattigeri, {Viswajanani J.} and Carlson, {Kathryn E.} and Mortensen, {Deborah J.} and Katzenellenbogen, {Benita S} and Katzenellenbogen, {John A.}",
year = "2002",
month = "2",
day = "1",
doi = "10.1016/S0968-0896(02)00309-7",
language = "English (US)",
volume = "11",
pages = "629--657",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "4",

}

TY - JOUR

T1 - Estrogenic diazenes

T2 - Heterocyclic non-steroidal estrogens of unusual structure with selectivity for estrogen receptor subtypes

AU - Ghosh, Usha

AU - Ganessunker, Deshanie

AU - Sattigeri, Viswajanani J.

AU - Carlson, Kathryn E.

AU - Mortensen, Deborah J.

AU - Katzenellenbogen, Benita S

AU - Katzenellenbogen, John A.

PY - 2002/2/1

Y1 - 2002/2/1

N2 - Estrogens regulate many biological functions, often acting in a tissue-selective manner. Their tissue-selective action is believed to involve differential estrogen action through the two estrogen receptor (ER) subtypes, ERα and ERβ, as well as differential interaction of the ligand-receptor complexes with promoters and coregulator proteins. In the latter case, selectivity is based on the induction of specific conformations of the ligand-ER complex, conformations that are influenced by the structure of the ligand. Estrogen pharmaceuticals having an ideal balance of tissue-selective activity are being sought for menopausal hormone replacement, breast cancer prevention and therapy, and other actions. To expand on the structural diversity of ER ligands that might show such tissue selectivity, we have prepared a series of diazenes (pyrazines, pyrimidines, and pyridazines) substituted with two to four aryl groups and various short-chain aliphatic substituents. All of the pyrazine and pyrimidines bind to ER, some with high affinity and with a considerable degree of preferential binding to either ERα or ERβ. One pyrimidine and one pyrazine have ERα affinity preferences as high as 23 and 9, respectively, and one pyrimidine has an ERβ affinity preference of 8. The pyridazines, by contrast, are quite polar and have only very low binding affinity for the ER. In cell-based transcription assays, several of the pyrimidines and a pyrazine were found to be considerably more agonistic on ERα than on ERβ. Because these triaryl diazenes have the largest volumes among the ER ligands so far investigated, their high affinity demonstrates the flexibility of the ligand binding pocket of the ERs and its tolerance for large substituents. Thus, these novel heterocyclic ligands expand the repertoire of chemical structures that bind to the estrogen receptor, and they could prove to be useful in elucidating the biological behavior of the two ER subtypes and in forming the basis for new estrogen pharmaceuticals having desirable tissue selectivity.

AB - Estrogens regulate many biological functions, often acting in a tissue-selective manner. Their tissue-selective action is believed to involve differential estrogen action through the two estrogen receptor (ER) subtypes, ERα and ERβ, as well as differential interaction of the ligand-receptor complexes with promoters and coregulator proteins. In the latter case, selectivity is based on the induction of specific conformations of the ligand-ER complex, conformations that are influenced by the structure of the ligand. Estrogen pharmaceuticals having an ideal balance of tissue-selective activity are being sought for menopausal hormone replacement, breast cancer prevention and therapy, and other actions. To expand on the structural diversity of ER ligands that might show such tissue selectivity, we have prepared a series of diazenes (pyrazines, pyrimidines, and pyridazines) substituted with two to four aryl groups and various short-chain aliphatic substituents. All of the pyrazine and pyrimidines bind to ER, some with high affinity and with a considerable degree of preferential binding to either ERα or ERβ. One pyrimidine and one pyrazine have ERα affinity preferences as high as 23 and 9, respectively, and one pyrimidine has an ERβ affinity preference of 8. The pyridazines, by contrast, are quite polar and have only very low binding affinity for the ER. In cell-based transcription assays, several of the pyrimidines and a pyrazine were found to be considerably more agonistic on ERα than on ERβ. Because these triaryl diazenes have the largest volumes among the ER ligands so far investigated, their high affinity demonstrates the flexibility of the ligand binding pocket of the ERs and its tolerance for large substituents. Thus, these novel heterocyclic ligands expand the repertoire of chemical structures that bind to the estrogen receptor, and they could prove to be useful in elucidating the biological behavior of the two ER subtypes and in forming the basis for new estrogen pharmaceuticals having desirable tissue selectivity.

UR - http://www.scopus.com/inward/record.url?scp=0037245578&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037245578&partnerID=8YFLogxK

U2 - 10.1016/S0968-0896(02)00309-7

DO - 10.1016/S0968-0896(02)00309-7

M3 - Article

C2 - 12538029

AN - SCOPUS:0037245578

VL - 11

SP - 629

EP - 657

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 4

ER -