Bicyclo[2.2.2]octanes: Close structural mimics of the nuclear receptor-binding motif of steroid receptor coactivators

Hai Bing Zhou; Margaret L. Collins; Jillian R. Gunther; John S. Comninos; John A. Katzenellenbogen

doi:10.1016/j.bmcl.2007.05.058

Bicyclo[2.2.2]octanes: Close structural mimics of the nuclear receptor-binding motif of steroid receptor coactivators

Hai Bing Zhou, Margaret L. Collins, Jillian R. Gunther, John S. Comninos, John A. Katzenellenbogen

Chemistry

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

Abstract

Nuclear hormone receptor (NR) function relies on association of agonist-bound receptors with steroid receptor coactivator (SRC) proteins through a small pentapeptide motif (LXXLL) of the SRC that binds to a hydrophobic groove on the NR. We have synthesized a series of bicyclo[2.2.2]octanes that are close structural mimics of the two key leucine residues of this SRC sequence as bound in the hydrophobic groove of the estrogen receptor. These bicyclic systems block the NR-SRC interaction with modest potency.

Original language	English (US)
Pages (from-to)	4118-4122
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	17
Issue number	15
DOIs	https://doi.org/10.1016/j.bmcl.2007.05.058
State	Published - Aug 1 2007

Keywords

Bicyclo[2.2.2]octanes
Coactivator-binding inhibitors
Estrogen receptor
Steroid receptor coactivators

ASJC Scopus subject areas

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

Online availability

10.1016/j.bmcl.2007.05.058

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title = "Bicyclo[2.2.2]octanes: Close structural mimics of the nuclear receptor-binding motif of steroid receptor coactivators",

abstract = "Nuclear hormone receptor (NR) function relies on association of agonist-bound receptors with steroid receptor coactivator (SRC) proteins through a small pentapeptide motif (LXXLL) of the SRC that binds to a hydrophobic groove on the NR. We have synthesized a series of bicyclo[2.2.2]octanes that are close structural mimics of the two key leucine residues of this SRC sequence as bound in the hydrophobic groove of the estrogen receptor. These bicyclic systems block the NR-SRC interaction with modest potency.",

keywords = "Bicyclo[2.2.2]octanes, Coactivator-binding inhibitors, Estrogen receptor, Steroid receptor coactivators",

author = "Zhou, {Hai Bing} and Collins, {Margaret L.} and Gunther, {Jillian R.} and Comninos, {John S.} and Katzenellenbogen, {John A.}",

note = "Funding Information: The present work was supported by grants from the NIH (PHS 5R37 DK15556). Funding for NMR and MS instrumentation is from the Keck Foundation, NIH, and NSF. We are grateful to Dr. Sung Hoon Kim and Terry Moore for helpful comments, and Jaimin Amin for conducting the coactivator-binding assays.",

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T2 - Close structural mimics of the nuclear receptor-binding motif of steroid receptor coactivators

AU - Zhou, Hai Bing

AU - Collins, Margaret L.

AU - Gunther, Jillian R.

AU - Comninos, John S.

AU - Katzenellenbogen, John A.

N1 - Funding Information: The present work was supported by grants from the NIH (PHS 5R37 DK15556). Funding for NMR and MS instrumentation is from the Keck Foundation, NIH, and NSF. We are grateful to Dr. Sung Hoon Kim and Terry Moore for helpful comments, and Jaimin Amin for conducting the coactivator-binding assays.

PY - 2007/8/1

Y1 - 2007/8/1

N2 - Nuclear hormone receptor (NR) function relies on association of agonist-bound receptors with steroid receptor coactivator (SRC) proteins through a small pentapeptide motif (LXXLL) of the SRC that binds to a hydrophobic groove on the NR. We have synthesized a series of bicyclo[2.2.2]octanes that are close structural mimics of the two key leucine residues of this SRC sequence as bound in the hydrophobic groove of the estrogen receptor. These bicyclic systems block the NR-SRC interaction with modest potency.

AB - Nuclear hormone receptor (NR) function relies on association of agonist-bound receptors with steroid receptor coactivator (SRC) proteins through a small pentapeptide motif (LXXLL) of the SRC that binds to a hydrophobic groove on the NR. We have synthesized a series of bicyclo[2.2.2]octanes that are close structural mimics of the two key leucine residues of this SRC sequence as bound in the hydrophobic groove of the estrogen receptor. These bicyclic systems block the NR-SRC interaction with modest potency.

KW - Bicyclo[2.2.2]octanes

KW - Coactivator-binding inhibitors

KW - Estrogen receptor

KW - Steroid receptor coactivators

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Bicyclo[2.2.2]octanes: Close structural mimics of the nuclear receptor-binding motif of steroid receptor coactivators

Abstract

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