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

• Published in: ChemMedChem 2009-04, Vol.4 (4), p.615-632
• Main Authors: Manzoni, Leonardo, Belvisi, Laura, Arosio, Daniela, Civera, Monica, Pilkington‐Miksa, Michael, Potenza, Donatella, Caprini, Andrea, Araldi, Elena M. V., Monferini, Eugenia, Mancino, Monica, Podestà, Francesca, Scolastico, Carlo
• Format: Article
• Language: English
• Subjects: Amides - chemistry; Aza Compounds - chemical synthesis; Aza Compounds - chemistry; Aza Compounds - pharmacology; azabicycloalkanes; Cell Adhesion - drug effects; Cells, Cultured; Computer Simulation; Cyclization; Cycloparaffins - chemistry; Humans; inhibitors; integrins; Integrins - antagonists & inhibitors; Integrins - metabolism; Ligands; Models, Molecular; Molecular Structure; Neoplasms - metabolism; Neoplasms - pathology; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology; peptidomimetics; RGD motif; Sensitivity and Specificity
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.200800422

Vitronectin receptors αvβ3 and αvβ5 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 αvβ3 and αvβ5 receptors was evaluated. This molecule is a suitable candidate as a vector for therapeutics and diagnostics. 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 αvβ3 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 αvβ3 integrin binder (IC50=53.7 nM) among the new functionalized RGD cyclic peptides, thus emerging as a promising candidate for covalent bonding and selective homing of useful functional units. Vitronectin receptors αvβ3 and αvβ5 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 αvβ3 and αvβ5 receptors was evaluated. This molecule is a suitable candidate as a vector for therapeutics and diagnostics.