A new tripodal kojic acid derivative for iron sequestration: Synthesis, protonation, complex formation studies with Fe3+, Al3+, Cu2+ and Zn2+, and in vivo bioassays

• Published in: Journal of inorganic biochemistry 2019-04, Vol.193, p.152-165
• Main Authors: Nurchi, Valeria M., de Guadalupe Jaraquemada-Pelaez, Maria, Crisponi, Guido, Lachowicz, Joanna I., Cappai, Rosita, Gano, Lurdes, Santos, M. Amelia, Melchior, Andrea, Tolazzi, Marilena, Peana, Massimiliano, Medici, Serenella, Zoroddu, Maria Antonietta
• Format: Article
• Language: English
• Subjects: Hydroxypyrones; In vivo bioassays; Kojic acid; Metal complexation; Solution studies; Tris-hydroxypyrone chelator
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2019.01.012

This work presents the simple and low cost synthesis of a new tripodal ligand, in which three units of kojic acid are coupled to a tris(2-aminoethyl)amine (tren) backbone molecule. The protonation equilibria, together with the complex formation equilibria of this ligand with Fe3+, Al3+, Cu2+ and Zn2+ ions were studied. The complementary use of potentiometric, spectrophotometric and NMR techniques, and of Density Functional Theory (DFT) calculations, has allowed a thorough characterization of the different species involved in equilibrium. The stability of the formed complexes with Fe3+ and Al3+ are high enough to consider the new ligand for further studies for its clinical applications as a chelating agent. Biodistribution studies were carried out to assess the capacity the ligand for mobilization of gallium in 67Ga-citrate injected mice. These studies demonstrated that this ligand efficiently chelates the radiometal in our animal model, which suggests that it can be a promising candidate as sequestering agent of iron and other hard trivalent metal ions. Furthermore, the good zinc complexation capacity appears as a stimulating result taking into a potential use of this new ligand in analytical chemistry as well as in agricultural and environmental applications. The synthesis of a new tripodal ligand is presented, with the study of protonation and complex formation equilibria with Fe3+, Al3+, Cu2+ and Zn2. The complementary use of potentiometry, spectrophotometry, NMR and Density Functional Theory has allowed the characterization of the involved species. Biodistribution proved it as a promising chelator. [Display omitted] •Simple synthesis of a new ligand with three units of kojic acid properly assembled.•Study of protonation and complex formation equilibria with Fe3+, Al3+, Cu2+ and Zn2+.•Complementary use of potentiometry, spectrophotometry, NMR and Density Functional Theory.•Good stability of the formed complexes with possible forthcoming applications.•Biodistribution studies proved the new ligand a promising chelator for trivalent metals.