Oxidative stress due to excess
superoxide anion ([Formula: see text]) produced by dysfunctional mitochondria is a key pathogenic event of aging and
ischemia-reperfusion diseases. Here, a new [Formula: see text]-scavenging MnII complex with a new polyamino-polycarboxylate macrocycle (4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diacetate) containing 2
quinoline units (MnQ2), designed to improve complex stability and cell permeability, was compared to parental MnII complex with methyls replacing
quinolines (MnM2). MnQ2 was more stable than MnM2 (log K = 19.56(8) vs. 14.73(2) for the equilibrium Mn2+ + L2-, where L = Q2 and M2) due to the involvement of
quinoline in
metal binding and to the hydrophobic features of the
ligand which improve
metal desolvation upon complexation. As oxidative stress model, H9c2 rat cardiomyoblasts were subjected to
hypoxia-reoxygenation. MnQ2 and MnM2 (10 μmol L-1) were added at reoxygenation for 1 or 2 h. The more lipophilic MnQ2 showed more rapid cell and mitochondrial penetration than MnM2. Both MnQ2 and MnM2 abated endogenous ROS and mitochondrial [Formula: see text], decreased cell lipid peroxidation, reduced
mitochondrial dysfunction, in terms of efficiency of the respiratory chain and preservation of membrane potential (Δψ) and permeability, decreased the activation of pro-apoptotic
caspases 9 and 3, and increased cell viability. Of note, MnQ2 was more effective than MnM2 to exert cytoprotective
anti-oxidant effects in the short term. Compounds with redox-inert ZnII replacing the functional MnII were ineffective. This study provides clues which further our understanding of the structure-activity relationships of MnII-chelates and suggests that MnII-polyamino-polycarboxylate macrocycles could be developed as new
anti-oxidant drugs.