Polyamine-polycarboxylate metal complexes with different biological effectiveness as nitric oxide scavengers. Clues for drug design.
The synthesis of the Fe(III), Co(II), Mn(II), and Ru(III) complexes with two polyamine-polycarboxylate ligands, N-(2-hydroxyethyl)ethylenediamine-N, N', N'-triacetic acid (H3L1) and ethylene bisglycol tetraacetic acid (H4L2) is reported. Potentiometric studies showed that these ligands form stable complexes in aqueous solution and no metal release occurs, thus accounting for their low toxicity in cultured RAW 264.7 macrophages. X-ray characterization of the [Co(L1)](-) complex showed that binding sites are available at the metal for NO binding. Efficiency of these compounds to bind NO was studied by UV-vis spectrophotometry. Then their NO-scavenging properties were assayed in a cell-free system under physiological conditions, using S-nitroso-N-acetyl-D,L-penicillamine (SNAP) as NO source. The L1 complexes caused the most effective reduction of free NO, [Mn(L1)](-) being the most efficient. Conversely, in NOS II induced RAW 264.7 macrophages, the Ru(III) and Co(II) complexes with L2 were the most effective compounds. [Ru(L2)](-) also afforded significant protection against lipopolysaccharide-induced endotoxic shock in the mouse in vivo.
Bambagioni
Valentina
V
Department of Chemistry, University of Florence, Sesto Fiorentino, Florence, Italy.
Bani
Daniele
D
Bencini
Andrea
A
Biver
Tarita
T
Cantore
Miriam
M
Chelli
Riccardo
R
Cinci
Lorenzo
L
Failli
Paola
P
Ghezzi
Lisa
L
Giorgi
Claudia
C
Nappini
Silvia
S
Secco
Fernando
F
Tinè
Maria Rosaria
MR
Valtancoli
Barbara
B
Venturini
Marcella
M
D000818:Animals; D002460:Cell Line; D002614:Chelating Agents / Q000737:chemistry* / Q000494:pharmacology; D003035:Cobalt; D018360:Crystallography, X-Ray; D004492:Edetic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D007501:Iron; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008345:Manganese; D051379:Mice; D008958:Models, Molecular; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000737:chemistry; D011199:Potentiometry; D012428:Ruthenium; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D012769:Shock / Q000188:drug therapy; D013329:Structure-Activity Relationship
D002614:Chelating Agents; D008024:Ligands; D008070:Lipopolysaccharides; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D003035:Cobalt; D008345:Manganese; D004533:Egtazic Acid; D026423:S-Nitroso-N-Acetylpenicillamine; D012428:Ruthenium; D004492:Edetic Acid; D007501:Iron; C026060:N-(hydroxyethyl)ethylenediaminetriacetic acid