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 (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.
Department of Preclinical and Clinical Pharmacology, University of Florence, V. le G. Pieraccini 6, Florence, Italy.
Paola
P
Failli
Daniele
D
Bani
Andrea
A
Bencini
Miriam
M
Cantore
Lorenzo
L
Di Cesare Mannelli
Carla
C
Ghelardini
Claudia
C
Giorgi
Massimo
M
Innocenti
Francesco
F
Rugi
Alessio
A
Spepi
Roberto
R
Udisti
Barbara
B
Valtancoli
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D002264:Carboxylic Acids / Q000737:chemistry; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004355:Drug Stability; D004563:Electrochemistry; D016166:Free Radical Scavengers / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D057927:Hydrophobic and Hydrophilic Interactions; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D008024:Ligands; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008345:Manganese / Q000737:chemistry*; D051379:Mice; D009942:Organometallic Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D013481:Superoxides / Q000378:metabolism*; D019820:Xanthine / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D002264:Carboxylic Acids; D016166:Free Radical Scavengers; D008024:Ligands; D009942:Organometallic Compounds; D013481:Superoxides; D019820:Xanthine; D008345:Manganese; D014969:Xanthine Oxidase