Peptoids on steroids:: Precise multivalent estradiol-peptidomimetic conjugates generated via azide-alkyne [3+2] cycloaddition reactions

We have developed a family of functionalized peptidomimetic oligomers for the multivalent display of bioactive ligands in a site-directed manner. Sequence-specific N-substituted glycine peptoid oligomer scaffolds were synthesized on solid phase to include up to six azidoalkyl sidechains. These constructs were used as substrates for Cu(I)-catalyzed azide-alkyne [3+2] cycloaddition reactions. 17 alpha-ethynylestradiol was conjugated at up to six positions along the peptoid backbone, generating estradiol-peptidomimetic conjugates in good yield. We evaluate how the binding avidities of these compounds to the estrogen receptor are enhanced when the valency of hormone ligand presentation is increased.