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 (H2L1) and the N-benzyl-N'-hydroxypiperazine-2,6-dione (HL2), 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 M2+ metal ions (M=Cu, Zn, Ni) by using potentiometric and spectroscopic techniques. At physiological conditions, complexation of these metal ions by H2L1 mostly occurs with formation of 1:1 species by tridentate co-ordination (O,N,N) (carboxylate-amino-hydroxamate), whereas complexation with HL2 mainly involves the formation of 1:2 (M:L) species with normal (O,O) hydroxamate coordination. Moreover, at higher pH, H2L1 is able to form a pentanuclear tetrameric copper complex with an interesting 12-metallacrown-4 structure. (C) 2003 Elsevier Inc. All rights reserved.