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

On the basis of a previously discovered anti-alpha(v)beta(3) 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 alpha(v)beta(3) (using both isolated receptors and avi63-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 Matrigelylug 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.