Synthesis of Novel c(AmpRGD)–Sunitinib Dual Conjugates as Molecular Tools Targeting the α_vβ₃ Integrin/VEGFR2 Couple and Impairing Tumor-Associated Angiogenesis

On the basis of a previously discovered anti-α_Vβ₃ integrin peptidomimetic (c­(AmpRGD)) and the clinically approved antiangiogenic kinase inhibitor sunitinib, three novel dual conjugates were synthesized (compounds 1–3), featuring the covalent and robust linkage between these two active modules. In all conjugates, the ligand binding competence toward α_Vβ₃ (using both isolated receptors and α_Vβ₃-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 1–3 showed interesting antiangiogenesis properties in an in vitro tubulogenic assay; furthermore, dimeric-RGD conjugate 3 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.