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Aminomethylene-Phosphonate Analogue as a Cu(II) Chelator: Characterization and Application as an Inhibitor of Oxidation Induced by the Cu(II)–Prion Peptide Complex

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journal contribution
posted on 25.06.2019, 13:05 by Natalie Pariente Cohen, Eliana Lo Presti, Simone Dell’Acqua, Thomas Jantz, Linda J. W. Shimon, Naomi Levy, Molhm Nassir, Lior Elbaz, Luigi Casella, Bilha Fischer
Recently, we reported on a series of aminomethylene-phosphonate (AMP) analogues, bearing one or two heterocyclic groups on the aminomethylene moiety, as promising Zn­(II) chelators. Given the strong Zn­(II) binding properties of these compounds, they may find useful applications in metal chelation therapy. With a goal of inhibiting the devastating oxidative damage caused by prion protein in prion diseases, we explored the most promising ligand, {bis­[(1H-imidazol-4-yl)­methyl]­amino}­methylphosphonic acid, AMP-(Im)2, 4, as an inhibitor of the oxidative reactivity associated with the Cu­(II) complex of prion peptide fragment 84–114. Specifically, we first characterized the Cu­(II) complex with AMP-(Im)2 by ultraviolet–visible spectroscopy and electrochemical measurements that indicated the high chemical and electrochemical stability of the complex. Potentiometric pH titration provided evidence of the formation of a stable 1:1 [Cu­(II)-AMP-(Im)2]+ complex (ML), with successive binding of a second AMP-(Im)2 molecule yielding ML2 complex [Cu­(II)-(AMP-(Im)2)2]+ (log K′ = 15.55), and log β′ = 19.84 for ML2 complex. The CuN3O1 ML complex was demonstrated by X-ray crystallography, indicating the thermodynamically stable square pyramidal complex. Chelation of Cu­(II) by 4 significantly reduced the oxidation potential of the former. CuCl2 and the 1:2 Cu:AMP-(Im)2 complex showed one-electron redox of Cu­(II)/Cu­(I) at 0.13 and −0.35 V, respectively. Indeed, 4 was found to be a potent antioxidant that at a 1:1:1 AMP-(Im)2:Cu­(II)-PrP84–114 molar ratio almost totally inhibited the oxidation reaction of 4-methylcatechol. Circular dichroism data suggest that this antioxidant activity is due to formation of a ternary, redox inactive Cu­(II)-Prp84–114-[AMP-(Im)2] complex. Future studies in prion disease animal models are warranted to assess the potential of 4 to inhibit the devastating oxidative damage caused by PrP.

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