Cyclic RGD‐Containing Functionalized Azabicycloalkane Peptides as Potent Integrin Antagonists for Tumor Targeting

Vitronectin receptors α v β 3 and α v β 5 have emerged as potential therapeutic targets for the treatment of osteoporosis, restenosis, ocular disease, tumor‐induced angiogenesis, metastasis, and sickle‐cell anemia. Among a collection of compounds, a new potent integrin antagonist was synthesized, and its binding toward the α v β 3 and α v β 5 receptors was evaluated. This molecule is a suitable candidate as a vector for therapeutics and diagnostics. magnified image Cyclic RGD‐containing functionalized azabicycloalkane peptides were synthesized with the aim of developing high‐affinity selective integrin ligands as carriers for therapeutic and diagnostic purposes. Herein we describe the synthesis and in vitro screening of these RGD derivatives, as well as the determination of their conformational properties in solution by spectroscopic and computational methods. Docking studies with the X‐ray crystal structure of the extracellular domain of integrin α v β 3 were also performed to elucidate the structural binding requirements and to rationalize the biological results. One compound in particular was found to be the best α v β 3 integrin binder (IC 50 =53.7 n M ) among the new functionalized RGD cyclic peptides, thus emerging as a promising candidate for covalent bonding and selective homing of useful functional units.