Click-Chemistry-Derived Triazole Ligands of Arginine-Glycine-Aspartate (RGD) Integrins with a Broad Capacity To Inhibit Adhesion of Melanoma Cells and Both in Vitro and in Vivo Angiogenesis

A click chemistry approach was applied for the discovery of triazole-based arginine-glycine-aspartate (RGD) mimetics by Cu(1)-catalyzed 1,3-dipolar alkyne azide coupling reaction, which showed binding all properties toward alpha(v)beta(3)/alpha(v)beta(5) integrins. Biological assays showed compound 18 capable of binding alpha(v)beta(3) integrin with nanomolar affinity according, to a two-sites model, and molecular modeling studies revealed a peculiar pi-stacking interaction between the triazole ring and Tyr178 side chain. Accordingly, compound 18 inhibited the adhesion of integrin-expressing human melanoma cells to RGD-containing proteins of the extracellular matrix, such as vitronectin, fibronectin, and osteopontin. and also angiogenesis in in vitro and in vivo experimental models. The relevant biological effects exerted by compound 18 suggest its potential application as an antiangiogenic agent in the diagnosis and therapy of tumors where alpha(v)beta(3) integrin expression is up-regulated.