Homo- and Heterobinuclear Cu2+ and Zn2+ Complexes of Ditopic Aza Scorpiand Ligands as Superoxide Dismutase Mimics

Abstract

Two polytopic aza-scorpiand-like ligands, 6-[7-(diaminoethyl)-3,7-diazaheptyl]-3,6,9-triaza-1-(2,6-pyridina)cyclodecaphane (L1) and 6-[6'-[3,6,9-triaza-1-(2,6-pyridina)cyclodecaphan-6-yl]-3-azahexyl]-3,6,9-triaza-1-(2,6-pyridina)cyclodecaphane (L2), have been synthesized. The acid-base behavior and Cu²⁺, Zn²⁺, and Cu²⁺/Zn²⁺ mixed coordination have been analyzed by potentiometry, cyclic voltammetry, and UV-vis spectroscopy. The resolution of the crystal structures of [Cu₂L2Cl₂](ClO₄)₂·1.67H₂O (1), [Cu₂HL2Br₂](ClO₄)₃·1.5H₂O (2), and [CuZnL2Cl₂](ClO₄)₂·1.64H₂O (3) shows, in agreement with the solution data, the formation of homobinuclear Cu²⁺/Cu²⁺ and heterobinuclear Cu²⁺/Zn²⁺ complexes. The metal ions are coordinated within the two macrocyclic cavities of the ligand with the involvement of a secondary amino group of the bridge in the case of 1 and 3. Energy-dispersive X-ray spectroscopy confirms the 1:1 Cu²⁺/Zn²⁺ stoichiometry of 3. The superoxide dismutase (SOD) activities of the Cu²⁺/Cu²⁺ and Cu²⁺/Zn²⁺ complexes of L1 and L2 have been evaluated using nitro blue tetrazolium assays at pH 7.4. The IC₅₀ and k_cat values obtained for the [Cu₂L1]⁴⁺ complex rank among the best values reported in the literature for Cu-SOD mimics. Interestingly, the binuclear Cu²⁺ complexes of L1 and L2 have low toxicity in cultures of mammalian cell lines and show significant antioxidant activity in a copper-dependent SOD (SOD1)-defective yeast model. The results are rationalized by taking into account the binding modes of the Cu²⁺ ions in the different complexes.