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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

Cite this: Inorg. Chem. 2019, 58, 14, 8995–9003
Publication Date (Web):June 25, 2019
https://doi.org/10.1021/acs.inorgchem.9b00287
Copyright © 2019 American Chemical Society

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    Abstract

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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.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.9b00287.

    • Tables S1–S6 and Figures S1–S6 (PDF)

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    CCDC 1893813 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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    Cited By

    This article is cited by 1 publications.

    1. Bole Li, Chang Xu, Yanfei Lv, Guihao Liu, Xiaoliang Sun, Zeqian Sun, Xiaotong Xu, Wei Chen, Lei He, Yu-Fei Song. Vanadium-Substituted Polyoxometalates Regulate Prion Protein Fragment 106–126 Misfolding by an Oxidation Strategy. ACS Applied Materials & Interfaces 2023, 15 (29) , 34497-34504. https://doi.org/10.1021/acsami.3c04969

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