Development of isoxazoline-containing peptidomimetics as dual alpha-v-beta-3 and alpha-5-beta-1 integrin ligands.

Isoxazoline-containing peptidomimetics, designed to be effective alpha-v-beta-3 and alpha-5-beta-1 integrin ligands, have been synthesized through an original procedure involving N,O-(bistrimethylsilyl)hydroxylamine conjugate addition to alkylidene acetoacetates, followed by intramolecular hemiketalisation. To mimic RGD recognition sequence, basic and acid terminal appendages have been introduced and the final products have been tested in cell adhesion inhibition assays. All the synthesized compounds showed to be excellent ligands, for both integrin receptors and a strong influence on intracellular signaling and phosphorylation pathway was demonstrated by evaluation of fibronectin induced phosphorylation of ERK. The molecular basis of the observed inhibitory activity was suggested on the basis of docking experiments.