Click Chemistry for advancing the development of dual RGD integrin/MMP ligands.

Through the process of angiogenesis, tumor cells generate new blood vessels to ensure supply and a route of elimination of waste metabolites. So, tumor cells can grow and spread out to the body generating metastasis. Integrin receptors and Matrix Metallo-Proteases (MMPs) are proteins deeply involved in tumor cell invasion and metastatic diffusion, interacting each other to facilitate these processes [1]. Indeed, Integrins are responsible of cellular adhesion with the extracellular matrix (ECM), while MMPs have a role in tissue remodeling and in the degradation of several structural proteins in the ECM. Recently, we developed L-tyrosine-derived dual RGD integrin/MMP ligands [2], that demonstrated the similarity of the active sites of these two proteins and the possibility of targeting both with a ligand possessing three main Functional Groups (FGs): a chelating FG for interacting with the metal ion, a basic FG for establishing a salt bridge with acidic amino acid residues, and a hydrophobic moiety for penetrating a lipophilic pocket. In this view, we reasoned exploiting the click chemistry for synthesizing novel compounds as dual RGD integrin/MMP ligands possessing the aforementioned interacting FGs and the triazole ring as central scaffold, resulting in the identification of a serine-derived compound with significant bioactivity.