Polydentate imine ligands as modulators of copper reactivity in inflammation-related diseases and in bioorthogonal coupling reactions

Abstract

In this project we will develop polydentate imine-derived ligands containing oxindole, imidazole and triazole moieties for stabilization of copper in both of its usual oxidation states in biological systems. These ligands will be investigated for two complementary applications. In one front, the polydentate ligands will be used for the synthesis of copper(II) metallodrugs aimed at the treatment of inflammation-related diseases. Copper has a central but dichotomic role related to inflammatory processes, involving reactive oxygen and/or nitrogen reactive species, as it has both pro- and anti-inflammatory properties. Furthermore, the correlation between cancer development and inflammation has become more and more clear, with a key aspect being the role of reactive oxygen and nitrogen species. That prompts us to investigate the fundamental role of copper in both processes. Based on our previous experience in studies of copper ion reactivity in biological medium, we intend to go further in our investigations on the possible mechanisms of action of potential antitumor agents based on copper, focusing on the link between cancer and inflammatory processes. Additionally, we intend to use the the polydentate imine-derived ligands as alternative co-ligands in the "click" copper(I)-catalyzed alcino-azide cycloaddition. Under the scope of Bioorthogonal Catalysis (catalysis in biological media), we aim at obtaining triazole-derived compounds with anticancer and fluorescent properties directly in aqueous media. Once these reactions are optimized, they can be translated to in cellulo and in vivo applications.