Development of Isoxazoline-Containing Peptidomimetics as Dual αvβ3 and α5β1 Integrin Ligands

Article abstract of DOI:10.1002/cmdc.201100372

Isoxazoline-containing peptidomimetics, designed to be effective α_vβ₃ and α₅β₁ integrin ligands, were synthesized through an original procedure involving N,O-bis(trimethylsilyl)hydroxyamine conjugate addition to alkylidene acetoacetates, followed by intramolecular hemiketalization. To mimic the RGD recognition sequence, basic and acidic terminal appendages were introduced, and the final products were tested in cell adhesion inhibition assays. All the synthesized compounds proved to be excellent ligands for both integrin receptors, and a strong influence on intracellular signaling and phosphorylation pathways was demonstrated by evaluation of fibronectin-induced phosphorylation of ERK. The molecular basis of the observed inhibitory activity was suggested on the results of docking experiments. Molecular copycats! Isoxazoline-containing peptidomimetics, designed to be effective α_vβ₃ and α₅β₁ integrin ligands, were synthesized by hydroxyamine conjugate addition to alkylidene acetoacetates followed by intramolecular hemiketalization. Cell adhesion assay results suggest a very effective ligand-receptor interaction, as confirmed by docking studies.