Succinylhydroxamic derivatives of alpha-amino acids as MMP inhibitors. Study of complex-formation equilibria with Cu2+, Ni2+ and Zn2+.
A series of Pro- and Phe-succinyl hydroxamate derivatives, whose nanomolar inhibitory activity towards a series of matrix metalloproteinases (MMPs) was previously reported, have been studied and described herein in their interaction with Cu(2+), Zn(2+), Ni(2+) in aqueous solution, by using potentiometric, spectroscopic and ESI-MS (electrospray ionization mass) spectrometric techniques. A systematic study at various ligand-to-metal molar ratios allowed the determination of the stability constants of the complexes as well as the estimation of the coordination modes. The similarity in the biological activity of these compounds seems to be paralleled by the identical metal-complexation behaviour at neutral pH, namely in terms of chelating effectiveness and coordination modes, irrespective of the presence of one carboxylic or hydroxamate as extra groups, or also of the type of amino-acid residue at the other flank of the succinyl chain, which seems to be enough away from the succinyl hydroxamate metal-binding group. The stability order of the metal complexes with these ligands follows the Irving-Williams trend for this type of complex systems. Noteworthy is the identification of an interesting pentanuclear copper(II) species with the monohydroxamic ligands which structure was ascribed to a 12-metallacrown-4.
Tegoni
Matteo
M
Dipartimento di Chimica Generale ed Inorganica, Chimica Analitica, Chimica Fisica, Università di Parma, Parco Area delle Scienze 17A, I-43100 Parma, Italy.
Dallavalle
Francesco
F
Amélia Santos
M
M
D000596:Amino Acids / Q000737:chemistry*; D003300:Copper / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D019216:Metals, Heavy / Q000737:chemistry*; D009532:Nickel / Q000737:chemistry / Q000378:metabolism; D011199:Potentiometry; D021241:Spectrometry, Mass, Electrospray Ionization; D013386:Succinates / Q000737:chemistry*; D015032:Zinc / Q000737:chemistry / Q000378:metabolism
D000596:Amino Acids; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D019216:Metals, Heavy; D013386:Succinates; D003300:Copper; D009532:Nickel; D020782:Matrix Metalloproteinases; D015032:Zinc