Journal of Medicinal Chemistry p. 248 - 262 (2017)
Update date:2022-08-16
Topics:
Sartori, Andrea
Portioli, Elisabetta
Battistini, Lucia
Calorini, Lido
Pupi, Alberto
Vacondio, Federica
Arosio, Daniela
Bianchini, Francesca
Zanardi, Franca
On the basis of a previously discovered anti-αVβ3 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 αVβ3 (using both isolated receptors and αVβ3-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.
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