A novel manganese complex effective as superoxide anion scavenger and therapeutic agent against cell and tissue oxidative injury.

Two cyclic polyamine-polycarboxylate ligands, 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (H2L3) and 4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (H2L4), and two noncyclic scaffolds, N-(2-hydroxyethyl)ethylenediamine-N,N0,N0-triacetic acid (H3L1) and ethylene-bisglycoltetracetic acid (H4L2), form stable complexes with Mn(II) in aqueous solutions. Cyclic voltammograms show that the complexes with the most hydrophobic ligands, [MnL2]2- and [MnL4], are oxidized at higher potential than [MnL1]- and [MnL3]. The pharmacological properties of these molecules were evaluated as superoxide ion scavengers and anti-inflammatory compounds. Among the four complexes, [MnL4] was the most bioactive, being effective in the nanomolar/micromolar range. It abates the levels of key markers of oxidative injury on cultured cells and ameliorates the outcome parameters in animal models of acute and chronic inflammation. [MnL4] toxicity was very low on both cell cultures in vitro and mice in vivo. Hence, we propose [MnL4] as a novel stable oxygen radical scavenging molecule, active at low doses and with a low toxicity.