Synthesis of Novel c(AmpRGD)–Sunitinib Dual Conjugates as Molecular Tools Targeting the α<sub>v</sub>β<sub>3</sub> Integrin/VEGFR2 Couple and Impairing Tumor-Associated Angiogenesis

On the basis of a previously discovered anti-α<sub>V</sub>β<sub>3</sub> integrin peptidomimetic (c­(AmpRGD)) and the clinically approved antiangiogenic kinase inhibitor sunitinib, three novel dual conjugates were synthesized (compounds <b>1</b>–<b>3</b>), featuring the covalent and robust linkage between these two active modules. In all conjugates, the ligand binding competence toward α<sub>V</sub>β<sub>3</sub> (using both isolated receptors and α<sub>V</sub>β<sub>3</sub>-overexpressing endothelial progenitor EP cells) and the kinase inhibitory activity (toward both isolated kinases and EPCs) remained almost untouched and comparable to the activity of the single active units. Compounds <b>1</b>–<b>3</b> showed interesting antiangiogenesis properties in an in vitro tubulogenic assay; furthermore, dimeric-RGD conjugate <b>3</b> strongly inhibited in vivo angiogenesis in Matrigel plug assays in FVB mice. These results offer proof-of-concept of how the covalent conjugation of two angiogenesis-related small modules may result in novel and stable molecules, which impair tumor-related angiogenesis with equal or even superior ability as compared to the single modules or their simple combinations.