Iminodiacetyl-hydroxamate derivatives as metalloproteinase inhibitors: equilibrium complexation studies with Cu(II), Zn(II) and Ni(II).
Two new iminodiacetyl-hydroxamate derivatives, the N-benzyl-N-carboxymethyl-iminoacetohydroxamic acid (H(2)L(1)) and the N-benzyl-N'-hydroxypiperazine-2,6-dione (HL(2)), have been recently reported as very effective inhibitors against a set of zinc-containing matrix metalloproteinases (MMPs). Herein, aimed at understanding that inhibitory function, these compounds are studied in their complex formation equilibria with three biologically relevant first-row transition M(2+) metal ions (M=Cu, Zn, Ni) by using potentiometric and spectroscopic techniques. At physiological conditions, complexation of these metal ions by H(2)L(1) mostly occurs with formation of 1:1 species by tridentate co-ordination (O,N,N) (carboxylate-amino-hydroxamate), whereas complexation with HL(2) mainly involves the formation of 1:2 (M:L) species with normal (O,O) hydroxamate coordination. Moreover, at higher pH, H(2)L(1) is able to form a pentanuclear tetrameric copper complex with an interesting 12-metallacrown-4 structure.
Centro de Química Estrutural, Complexo I, Instituto Superior Técnico, Av. Rovisco Pais, 1049-001, Lisboa, Portugal. masantos@ist.utl.pt
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D003300:Copper / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000494:pharmacology; D007097:Imines / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D061965:Matrix Metalloproteinase Inhibitors; D019216:Metals, Heavy / Q000737:chemistry*; D008958:Models, Molecular; D009532:Nickel / Q000737:chemistry; D011199:Potentiometry; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet; D015032:Zinc / Q000737:chemistry
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D007097:Imines; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D019216:Metals, Heavy; D003300:Copper; D009532:Nickel; D015032:Zinc