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 Cu 2+, Zn 2+, and Cu 2+ /Zn 2+ mixed coordination have been analyzed by potentiometry, cyclic voltammetry, and UV–vis spectroscopy. The resolution of the crystal structures of [Cu 2 L2 Cl 2 ](ClO 4 ) 2 ·1.67H 2 O ( 1 ), [Cu 2 H L2 Br 2 ](ClO 4 ) 3 ·1.5H 2 O ( 2 ), and [CuZn L2 Cl 2 ](ClO 4 ) 2 ·1.64H 2 O ( 3 ) shows, in agreement with the solution data, the formation of homobinuclear Cu 2+ /Cu 2+ and heterobinuclear Cu 2+ /Zn 2+ 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 Cu 2+ /Zn 2+ stoichiometry of 3 . The superoxide dismutase (SOD) activities of the Cu 2+ /Cu 2+ and Cu 2+ /Zn 2+ complexes of L1 and L2 have been evaluated using nitro blue tetrazolium assays at pH 7.4. The IC 50 and k cat values obtained for the [Cu 2 L1 ] 4+ complex rank among the best values reported in the literature for Cu-SOD mimics. Interestingly, the binuclear Cu 2+ 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 Cu 2+ ions in the different complexes.