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

Abstract

On the basis of a previously discovered anti-αβ 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 αβ (using both isolated receptors and αβ-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.

Cell-targeted c(AmpRGD)-sunitinib molecular conjugates impair tumor growth of melanoma

“…Recently, we reported a new class of molecular conjugates, compounds 1-3, where the anti-α V β 3 integrin peptidomimetic c(AmpRGD) [24][25][26][27][28] was connected to the antiangiogenic and antitumor multikinase inhibitor sunitinib through robust linkers (Fig. 1).…”

Toward Angiogenesis Inhibitors Based on the Conjugation of Organometallic Platinum(II) Complexes to RGD Peptides

“…On the other hand, as imilar angiogenesis pattern of activity to that of reference drug 1 at sub-cytotoxic concentrations was found in HUVECs for 3,w hich opened the way to exploring the development of novel potentiala ngiogenesisi nhibitors through conjugation of compounds with high antiangiogenic activity,s uch as metal complexes or small organic molecules, [42] to cyclic RGD-containingp eptides or peptidomimetic analogues. Peptide conjugation resulted in a non-cytotoxic compound (IC 50 > 100 mm)i na ll tested tumor cell lines (AE a V b 3 and a V b 5 integrin receptors), which suggested that the mechanism of action of the parentP tc omplex had been modified.…”

“…Peptide conjugation resulted in a non-cytotoxic compound (IC 50 > 100 mm)i na ll tested tumor cell lines (AE a V b 3 and a V b 5 integrin receptors), which suggested that the mechanism of action of the parentP tc omplex had been modified. On the other hand, as imilar angiogenesis pattern of activity to that of reference drug 1 at sub-cytotoxic concentrations was found in HUVECs for 3,w hich opened the way to exploring the development of novel potentiala ngiogenesisi nhibitors through conjugation of compounds with high antiangiogenic activity,s uch as metal complexes or small organic molecules, [42] to cyclic RGD-containingp eptides or peptidomimetic analogues.…”

New strategies in achieving antiangiogenic effect: Multiplex inhibitors suppressing compensatory activations of RTKs

“…Zanardi and co‐workers prepared three dual conjugates featuring the covalent linkage between two active modules, AmpRGD and VEGFR‐2 inhibitor (sunitinib) . These compounds exhibited promising antiangiogenic potency in vitro.…”

“…Zanardi and co-workers prepared three dual conjugates featuring the covalent linkage between two active modules, AmpRGD and VEGFR-2 inhibitor (sunitinib). 127 These compounds exhibited promising antiangiogenic potency in vitro. Compound (24) displayed potent antiangiogenic activity and was even superior than the combination of RGD (Arg-Gly-Asp) and sunitinib.…”