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

doi:10.1021/acs.inorgchem.9b00287

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

Department of Chemistry

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Abstract

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)-PrP_84-114 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)-Prp_84-114-[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 language	English
Pages (from-to)	8995-9003
Number of pages	9
Journal	Inorganic Chemistry
Volume	58
Issue number	14
DOIs	https://doi.org/10.1021/acs.inorgchem.9b00287
State	Published - 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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10.1021/acs.inorgchem.9b00287

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Pariente Cohen, N., Lo Presti, E., Dell'Acqua, S., Jantz, T., Shimon, L. J. W., Levy, N., Nassir, M., Elbaz, L., Casella, L., & Fischer, B. (2019). Aminomethylene-Phosphonate Analogue as a Cu(II) Chelator: Characterization and Application as an Inhibitor of Oxidation Induced by the Cu(II)-Prion Peptide Complex. Inorganic Chemistry, 58(14), 8995-9003. https://doi.org/10.1021/acs.inorgchem.9b00287

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

abstract = "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.",

author = "{Pariente Cohen}, Natalie and {Lo Presti}, Eliana and Simone Dell'Acqua and Thomas Jantz and Shimon, {Linda J.W.} and Naomi Levy and Molhm Nassir and Lior Elbaz and Luigi Casella and Bilha Fischer",

note = "Publisher Copyright: {\textcopyright} 2019 American Chemical Society.",

year = "2019",

month = jun,

day = "25",

doi = "10.1021/acs.inorgchem.9b00287",

language = "אנגלית",

volume = "58",

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Pariente Cohen, N, Lo Presti, E, Dell'Acqua, S, Jantz, T, Shimon, LJW, Levy, N, Nassir, M, Elbaz, L, Casella, L & Fischer, B 2019, 'Aminomethylene-Phosphonate Analogue as a Cu(II) Chelator: Characterization and Application as an Inhibitor of Oxidation Induced by the Cu(II)-Prion Peptide Complex', Inorganic Chemistry, vol. 58, no. 14, pp. 8995-9003. https://doi.org/10.1021/acs.inorgchem.9b00287

Aminomethylene-Phosphonate Analogue as a Cu(II) Chelator: Characterization and Application as an Inhibitor of Oxidation Induced by the Cu(II)-Prion Peptide Complex. / Pariente Cohen, Natalie; Lo Presti, Eliana; Dell'Acqua, Simone et al.
In: Inorganic Chemistry, Vol. 58, No. 14, 25.06.2019, p. 8995-9003.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Aminomethylene-Phosphonate Analogue as a Cu(II) Chelator

T2 - Characterization and Application as an Inhibitor of Oxidation Induced by the Cu(II)-Prion Peptide Complex

AU - Pariente Cohen, Natalie

AU - Lo Presti, Eliana

AU - Dell'Acqua, Simone

AU - Jantz, Thomas

AU - Shimon, Linda J.W.

AU - Levy, Naomi

AU - Nassir, Molhm

AU - Elbaz, Lior

AU - Casella, Luigi

AU - Fischer, Bilha

PY - 2019/6/25

Y1 - 2019/6/25

N2 - 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.

AB - 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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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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