Antiangiogenic effect of dual/selective α5 β1/αvβ3 integrin antagonists designed on partially modified retro-inverso cyclotetrapeptide mimetics

Recent evidence highlighted the role of α5β 1 integrin in angiogenesis and in regulating α vβ3 integrin function. As a consequence, selective α5β1 integrin inhibitors or dual α5β1/αvβ3 integrin inhibitors are considered promising candidates for the development of cancer therapeutic agents. In this paper, we describe the synthesis and pharmacological characterization of a minilibrary of cyclotetrapeptide mimetics containing a PMRI Arg-Gly-Asp sequence. In particular, c[(R)- βPheψ(NHCO)Aspψ-(NHCO)Gly-Arg] (3) displayed a good activity in inhibiting the αvβ3 integrin-mediated cell adhesion of fibronectin or vitronectin, as well as the adhesion of fibronectin to the α5β1 integrin. Interestingly, the diastereomeric compound c[(S)-βPheψ(NHCO)Aspψ(NHCO)Gly-Arg] (2) maintained a good efficacy in inhibiting α5β1 integrin while gaining a certain selectivity over αvβ 3 integrin. These two integrin antagonists significantly inhibited bFGF-induced human endothelial cell tube formation at submicromolar concentrations. Conformational analysis and Molecular Docking calculations suggest that the different α5β1 versus αvβ3 selectivity of 2 and 3 can be rationalized on the basis of the alternative display of the aromatic side chain adjacent to Asp. © 2009 American Chemical Society.