Antiangiogenic Effect of Dual/Selective α5β1/αvβ3 Integrin Antagonists Designed on Partially Modified Retro-Inverso Cyclotetrapeptide Mimetics

Recent evidence highlighted the role of α5β1 integrin in angiogenesis and in regulating αvβ3 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 αvβ3 integrin.