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

• Published in: Bioorganic & medicinal chemistry letters 2007-08, Vol.17 (15), p.4118-4122
• Main Authors: Zhou, Hai-Bing, Collins, Margaret L., Gunther, Jillian R., Comninos, John S., Katzenellenbogen, John A.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Bicyclo[2.2.2]octanes; Binding Sites; Biological and medical sciences; Bridged Bicyclo Compounds - chemistry; Bridged Bicyclo Compounds - pharmacology; Coactivator-binding inhibitors; Estrogen receptor; Fluorescence Resonance Energy Transfer; Histone Acetyltransferases - chemistry; Histone Acetyltransferases - metabolism; Hormones. Endocrine system; Medical sciences; Miscellaneous; Models, Molecular; Molecular Mimicry; Molecular Sequence Data; Molecular Structure; Nuclear Receptor Coactivator 1; Pharmacology. Drug treatments; Steroid receptor coactivators; Transcription Factors - chemistry; Transcription Factors - metabolism
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.05.058

The design, synthesis, and initial inhibitory activity of 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 are reported. These bicyclic systems block the NR–SRC interaction with modest potency. 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.