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

J Med Chem. 2009 Nov 26;52(22):7273-83. doi: 10.1021/jm901298x.

Abstract

Two cyclic polyamine-polycarboxylate ligands, 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (H(2)L3) and 4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (H(2)L4), and two noncyclic scaffolds, N-(2-hydroxyethyl)ethylenediamine-N,N',N'-triacetic acid (H(3)L1) and ethylene-bisglycol-tetracetic acid (H(4)L2), 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.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / metabolism
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / toxicity
  • Carboxylic Acids / chemistry
  • Cell Line
  • Cell Survival / drug effects
  • Drug Design
  • Drug Stability
  • Electrochemistry
  • Free Radical Scavengers / chemistry*
  • Free Radical Scavengers / metabolism
  • Free Radical Scavengers / pharmacology*
  • Free Radical Scavengers / toxicity
  • Hydrophobic and Hydrophilic Interactions
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Intracellular Space / metabolism
  • Ligands
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Manganese / chemistry*
  • Mice
  • Organometallic Compounds / chemistry*
  • Organometallic Compounds / metabolism
  • Organometallic Compounds / pharmacology*
  • Organometallic Compounds / toxicity
  • Oxidation-Reduction
  • Oxidative Stress / drug effects*
  • Rats
  • Superoxides / metabolism*
  • Xanthine / metabolism
  • Xanthine Oxidase / metabolism

Substances

  • Anti-Inflammatory Agents
  • Carboxylic Acids
  • Free Radical Scavengers
  • Ligands
  • Organometallic Compounds
  • Superoxides
  • Xanthine
  • Manganese
  • Xanthine Oxidase