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

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.

Graphical abstractThe 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.Figure optionsDownload full-size imageDownload as PowerPoint slide