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

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

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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.

Original languageEnglish
Pages (from-to)8995-9003
Number of pages9
JournalInorganic Chemistry
Issue number14
StatePublished - 25 Jun 2019

Bibliographical note

Funding Information:
The authors acknowledge the Italian Ministry of Education, University, and Research (MIUR)-Research Projects of National Interest (PRIN) 2015, prot. 2015T778JW, for funding. Prof. Valeria Amendola and Dr. Ana Miljkovic are gratefully acknowledged for their help in performing and analyzing potentiometric titration.

Publisher Copyright:
© 2019 American Chemical Society.


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