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Thiosemicarbazone Derivatives as Inhibitors of Amyloid-β Aggregation: Effect of Metal Coordination

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    Thiosemicarbazone Derivatives as Inhibitors of Amyloid-β Aggregation: Effect of Metal Coordination
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    • Ana I. Matesanz
      Ana I. Matesanz
      Department of Inorganic Chemistry (M-07), School of Sciences, Universidad Autónoma de Madrid, 28049 Madrid, Spain
      More by Ana I. Matesanz
      Orcidhttp://orcid.org/0000-0002-6113-0656
    • Ana B. Caballero
      Ana B. Caballero
      nanoBIC, Departament de Química Inorgànica i Orgànica, Facultat de Química, Universitat de Barcelona, Martí i Franquès, 1-11, 08028 Barcelona, Spain
      Institute of Nanoscience and Nanotechnology (IN2UB), Universitat de Barcelona, 08028 Barcelona, Spain
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      Orcidhttp://orcid.org/0000-0001-9294-9085
    • Carmen Lorenzo
      Carmen Lorenzo
      Department of Inorganic Chemistry (M-07), School of Sciences, Universidad Autónoma de Madrid, 28049 Madrid, Spain
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    • Alba Espargaró
      Alba Espargaró
      Departament de Fisicoquímica, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, Avda. Joan XXIII 27-31, 08028 Barcelona, Spain
      Institute of Nanoscience and Nanotechnology (IN2UB), Universitat de Barcelona, 08028 Barcelona, Spain
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    • Raimon Sabaté
      Raimon Sabaté
      Departament de Fisicoquímica, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, Avda. Joan XXIII 27-31, 08028 Barcelona, Spain
      Institute of Nanoscience and Nanotechnology (IN2UB), Universitat de Barcelona, 08028 Barcelona, Spain
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      Orcidhttp://orcid.org/0000-0003-3894-2362
    • Adoración G. Quiroga*
      Adoración G. Quiroga
      Institute for Advanced Research in Chemical Sciences (IAdChem), Universidad Autónoma de Madrid, Madrid 28049, Spain
      Department of Inorganic Chemistry (M-07), School of Sciences, Universidad Autónoma de Madrid, 28049 Madrid, Spain
      *A.G.Q.: email, [email protected]
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      Orcidhttp://orcid.org/0000-0002-9261-9542
    • Patrick Gamez*
      Patrick Gamez
      nanoBIC, Departament de Química Inorgànica i Orgànica, Facultat de Química, Universitat de Barcelona, Martí i Franquès, 1-11, 08028 Barcelona, Spain
      Institute of Nanoscience and Nanotechnology (IN2UB), Universitat de Barcelona, 08028 Barcelona, Spain
      Catalan Institution for Research and Advanced Studies, Passeig Lluís Companys 23, 08010 Barcelona, Spain
      *P.G.: tel, +34 934 021274; email, [email protected]
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      Orcidhttp://orcid.org/0000-0003-2602-9525
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    Inorganic Chemistry

    Cite this: Inorg. Chem. 2020, 59, 10, 6978–6987
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    https://doi.org/10.1021/acs.inorgchem.0c00467
    Published May 5, 2020
    Copyright © 2020 American Chemical Society
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    Abstract

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    Three thiosemicarbazone derivatives, namely 4-(dimethylamino)benzaldehyde 4,4-dimethylthiosemicarbazone (HL1), 4-(dimethylamino)benzaldehyde thiosemicarbazone (HL2), and 4-(dimethylamino)benzaldehyde 4-methylthiosemicarbazone (HL3), have been synthesized and characterized. The three palladium(II) complexes 1–3 were prepared respectively from HL1, HL2, and HL3. The crystal structures of two coordination compounds, namely Pd(L2)2 (2) and Pd(L3)2 (3), were obtained, which showed the expected square-planar environment for the metal centers. The ligand HL3 and the Pd(II) complexes 1–3, which are stable in buffered solutions containing up to 5% DMSO, exhibit remarkable inhibitory properties against the aggregation of amyloid-β, reducing the formation of fibrils. HL1, HL3, 2, and 3 display IC50 values (i.e., the concentrations required to reduce Aβ fibrillation by 50%) below 1 μM, lower that of the reference compound catechin (IC50 = 2.8 μM). Finally, in cellulo studies with E. coli cells revealed that the palladium(II) compounds are significantly more efficient than the free ligands in inhibiting Aβ aggregation inside bacterial inclusion bodies, thus illustrating a beneficial effect of metal coordination.

    Copyright © 2020 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.inorgchem.0c00467.

    • Crystallographic data for compounds 2 and 3, time-dependent NMR spectra of 1–3 in DMSO-d6, time-dependent UV–vis spectra for 1–3 in Tris-HCl/5% DMSO, UV–vis spectra for 1–3 interacting with lysozyme, NMR and mass spectra for compounds HL1–HL3, and schematic representation of Aβ fibrillation (PDF)

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    CCDC 1884751–1884752 contain 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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    Inorganic Chemistry

    Cite this: Inorg. Chem. 2020, 59, 10, 6978–6987
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.inorgchem.0c00467
    Published May 5, 2020
    Copyright © 2020 American Chemical Society
    Request reuse permissions

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