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Cited by 212Alzheimer's disease research and treatmentsMolecular Sensors and Ion DetectionCholinesterase and Neurodegenerative Diseases

Design, Selection, and Characterization of Thioflavin-Based Intercalation Compounds with Metal Chelating Properties for Application in Alzheimer’s Disease

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Rodríguez-Rodríguez, Cristina, Sánchez de Groot, Natalia, Rimola, Albert, Álvarez-Larena, Ángel, Lloveras, Vega, Vidal-Gancedo, José, Ventura, Salvador, Vendrell, Josep +2 more·2009·Journal of the American Chemical Society
DOI 10.1021/ja806062g
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Abstract

Metal chelation is considered a rational therapeutic approach for interdicting Alzheimer's amyloid pathogenesis. At present, enhancing the targeting and efficacy of metal-ion chelating agents through ligand design is a main strategy in the development of the next generation of metal chelators. Inspired by the traditional dye Thioflavin-T, we have designed new multifunctional molecules that contain both amyloid binding and metal chelating properties. In silico techniques have enabled us to identify commercial compounds that enclose the designed molecular framework (M1), include potential antioxidant properties, facilitate the formation of iodine-labeled derivatives, and can be permeable through the blood-brain barrier. Iodination reactions of the selected compounds, 2-(2-hydroxyphenyl)benzoxazole (HBX), 2-(2-hydroxyphenyl)benzothiazole (HBT), and 2-(2-aminophenyl)-1H-benzimidazole (BM), have led to the corresponding iodinated derivatives HBXI, HBTI, and BMI, which have been characterized by X-ray diffraction. The chelating properties of the latter compounds toward Cu(II) and Zn(II) have been examined in the solid phase and in solution. The acidity constants of HBXI, HBTI, and BMI and the formation constants of the corresponding ML and ML2 complexes [M = Cu(II), Zn(II)] have been determined by UV-vis pH titrations. The calculated values for the overall formation constants for the ML2 complexes indicate the suitability of the HBXI, HBTI, and BMI ligands for sequestering Cu(II) and Zn(II) metal ions present in freshly prepared solutions of beta-amyloid (Abeta) peptide. This was confirmed by Abeta aggregation studies showing that these compounds are able to arrest the metal-promoted increase in amyloid fibril buildup. The fluorescence features of HBX, HBT, BM, and the corresponding iodinated derivatives, together with fluorescence microscopy studies on two types of pregrown fibrils, have shown that HBX and HBT compounds could behave as potential markers for the presence of amyloid fibrils, whereas HBXI and HBTI may be especially suitable for radioisotopic detection of Abeta deposits. Taken together, the results reported in this work show the potential of new multifunctional thioflavin-based chelating agents as Alzheimer's disease therapeutics.

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  • Two approaches have been pursued in BFC design: direct incorporation of metal-binding atom donors into the structural framework of an Aβ-interacting compound, and linking the metal-chelating and Aβ-binding molecular fragments.

    “In this context, two approaches have been pursued in BFC design. 31,49–58 One strategy is based on the direct incorporation of metal-binding atom donors into the structural framework of an Aβ-interacting compoud (Scheme 1, approach A), and the other involves linking the metal-chelating and Aβ-binding molecular fragments (Scheme 1, approach B).”

    From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [57]

    The Introduction (page not provided) describes adding chelating properties to compounds with amyloid affinity, and the Summary says the resulting molecular framework integrates amyloid binding and metal chelation. This supports the direct-incorporation approach, but the paper does not describe the claimed alternative of linking separate metal-chelating and Aβ-binding fragments. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • The pM values compare favorably with Kd values reported for Cu-Aβ (nM-μM) and Zn-Aβ (μM).

    “These pM values represent approximate dissociation constants and compare favorably with the Kd values reported for Cu-Aβ (nM-μM) and Zn-Aβ (μM).26,29,31,57,76,79,80”

    From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [57]

    In the discussion following Table 5 (page unavailable), the paper reports nanomolar binding constants for Cu–Aβ and micromolar constants for Zn–Aβ, and uses them to predict that its ligands could sequester those metals. It does not report the claimed micromolar end of the Cu–Aβ range. It also defines its pM values as −log of the free-metal concentration, rather than as approximate dissociation constants. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • In Rodríguez-Rodríguez et al., only solution coordination properties were investigated in detail, while Aβ-binding and antiaggregation properties were only qualitatively evaluated through epifluorescence microscopy and turbidity assays.

    “However, in that report, only the solution coordination properties of those compounds were investigated in detail, while the Aβ-binding and antiaggregation properties were only qualitatively evaluated through epifluorecense microscopy and turbidity assays.”

    From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [33]

    The Fluorescence Microscopy Binding Assays section describes imaging fibrils, and the Figure 10 caption (p. 40) explicitly calls its binding-intensity scale qualitative. The paper also investigates aggregation with turbidity assays, but the Turbidity Measurements section reports repeated, blank-corrected absorbance measurements, and the aggregation discussion gives a numerical result. Thus, describing the antiaggregation evaluation as only qualitative overstates the source. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Previously, an iodinated HPB and related compounds were shown to have potential as metal-chelating agents by Rodríguez-Rodríguez et al.

    “Previously, an iodinated HPB and a few related compounds were shown to have potential as metal-chelating agents by Rodríguez-Rodríguez et al.33”

    From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [33]

    The Summary (page not available) reports that the iodinated compounds HBXI, HBTI and BMI can chelate Cu(II) and Zn(II), supporting the metal-chelating point. Our copy identifies these compounds as derivatives of HBX, HBT and BM; it does not identify an iodinated compound called HPB. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Molecules having log BB values higher than −0.3 are generally expected to cross the BBB.

    “Molecules having log BB values higher than −0.3 are generally expected to cross the BBB.33”

    From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [33]

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Authors
Rodríguez-Rodríguez, C., Sánchez de Groot, N., Rimola, A., Álvarez-Larena, Á., Lloveras, V., Vidal-Gancedo, J., Ventura, S., Vendrell, J., Sodupe, M., & González-Duarte, P.
Affiliations
  • Departament de Química, Departament de Bioquímica i Biologia Molecular and Institut de Biotecnologia i de Biomedicina, and Servei de Difracció de Raigs X, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Barcelona, Spain, and Institut de Ciència de Materials de Barcelona (CSIC) and Networking Centre on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Campus Universitari de Bellaterra, E-08193 Bellaterra, Barcelona, Spain
  • Universitat Autònoma de Barcelona (ES)
ORCID
Venue
Journal of the American Chemical Society
Publisher
American Chemical Society (ACS)
Published
2009-01-09
Volume
131
Issue
4
Pages
1436-1451
ISSN
  • 0002-7863 (ISSN-L)
  • 1520-5126
DOI
10.1021/ja806062g
OpenAlex
W2072467039
Cited by
210
References
84
Citations by year
2026: 3 · 2025: 3 · 2024: 8 · 2023: 7 · 2022: 6 · 2021: 10 · 2020: 12 · 2019: 12 · 2018: 12 · 2017: 10 · 2016: 14 · 2015: 15 · 2014: 14 · 2013: 16 · 2012: 22
FWCI
15.21
Type
journal article
Language
en
Open access
Licence
public-domain
Locations
  • Journal of the American Chemical Society (publishedVersion)
  • PubMed (publishedVersion)
  • Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, public-domain)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
Funders
Departament d'Universitats, Recerca i Societat de la Informació
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Physical Sciences › Chemistry › Spectroscopy › Molecular Sensors and Ion Detection
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
Keywords
thioflavin T, metal chelation, Alzheimer's disease, amyloid-beta, copper(II) complexes, zinc(II) complexes, benzoxazole, benzothiazole, benzimidazole, amyloid fibril binding, fluorescence imaging, blood-brain barrier permeability, antioxidant activity, ligand design
MeSH terms
Alzheimer Disease, Chelating Agents, Copper, Drug Evaluation, Preclinical, Humans, Hydrogen-Ion Concentration, Iodine, Models, Molecular, Magnetic Resonance Spectroscopy, Peptide Fragments, Thiazoles, Zinc, Drug Design, Molecular Structure, Amyloid beta-Peptides, Crystallography, X-Ray, Benzothiazoles

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