Stereodivergent Synthesis of 5-Aminopipecolic Acids and Application in the Preparation of a Cyclic RGD Peptidomimetic as a Nanomolar αVβ3 Integrin Ligand
Lorenzo Sernissi, Luciano Ricci, Dina Scarpi, Francesca Bianchini, Daniela Arosio, Alessandro Contini, Ernesto Giovanni Occhiato
A stereodivergent strategy was devised to obtain enantiopure cis and trans 5-aminopipecolic acids (5-APAs) in suitably protected forms to be employed in peptide synthesis as conformationally constrained α- and δ-amino acids. The cis isomer was used as a δ-amino acid to construct a cyclic RGD-containing peptidomimetic, the ability of which to compete with biotinylated vitronectin for the binding to the isolated αVβ3 integrin was measured (IC50 = 4.2 ± 0.9 nM). A complete 1H NMR and computational conformational analysis was performed to elucidate the reasons for the high affinity of this cyclic peptidomimetic in comparison with Cilengitide.