Small Molecule Modulators of Copper-Induced Aβ Aggregation
Open accessAbstract
Our design of bifunctional metal chelators as chemical probes and potential therapeutics for Alzheimer's disease (AD) is based on the incorporation of a metal binding moiety into structural frameworks of Abeta aggregate-imaging agents. Using this strategy, two compounds 2-[4-(dimethylamino)phenyl]imidazo[1,2-a]pyridine-8-ol (1) and N(1),N(1)-dimethyl-N(4)-(pyridin-2-ylmethylene)benzene-1,4-diamine (2) were prepared and characterized. The bifunctionality for metal chelation and Abeta interaction of 1 and 2 was verified by spectroscopic methods. Furthermore, the reactivity of 1 and 2 with Cu(II)-associated Abeta aggregates was investigated. The modulation of Cu(II)-triggered Abeta aggregation by 1 and 2 was found to be more effective than that by the known metal chelating agents CQ, EDTA, and phen. These studies suggest a new class of multifunctional molecules for the development of chemical tools to unravel metal-associated events in AD and potential therapeutic agents for metal-ion chelation therapy.
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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 [51]
In the main text (page unavailable), the paper describes incorporating nitrogen or oxygen donor atoms directly into an Aβ-recognizing imaging agent, supporting the first design approach. It does not describe the second approach of linking separate metal-chelating and Aβ-binding fragments. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCQ shows <30% cell survival at concentrations >2 μM, while EDTA shows 90-95% cell survival up to 20 μM concentration.
“By comparison, the clinically tested compound CQ shows <30% cell survival at concentrations >2 μM, while EDTA shows 90–95% cell survival up to 20 μM concentration (Figure S26).51,52”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [51]
In the paper’s cell-study discussion (page unavailable), CQ is described as more toxic than compounds 1 and 2, supporting only the qualitative CQ comparison. Our copy gives neither <30% survival above 2 μM for CQ nor 90–95% survival up to 20 μM for EDTA; its approximately 90% survival figure refers to compound 2. (LLM, conf=0.85)
Experimental — accuracy not yet measuredExcept for one recent report, compounds that inhibit metal-mediated Aβ40 aggregation or promote disaggregation of amyloid fibrils were shown to lead to increased cell viability.
“Except for one recent report,99 compounds that inhibit metal-mediated Aβ40 aggregation or promote disaggregation of amyloid fibrils were shown to lead to increased cell viability.49,51,52”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [51]
In the main text (page not available), the paper reports that compounds 1 and 2 inhibit Cu-induced Aβ aggregation and promote fibril disaggregation; it also reports that compound 2 diminishes Cu-Aβ toxicity in human neuroblastoma cells, yielding about 90% cell survival. The copy does not identify the peptide in these experiments as Aβ40 or show increased cell viability for both compounds, so the broader claim is only partly supported. The ‘one recent report’ exception is attached to a different citation. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe majority of these BFCs have been studied for their effect on aggregation of the Aβ40 peptide, and fewer studies have focused on their interaction with the more neurotoxic Aβ42 peptide.
“However, the majority of these BFCs have been studied for their effect on aggregation of the Aβ40 peptide,25,31 and fewer studies have focused on their interaction with the more neurotoxic Aβ42 peptide.20,21”
From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [31]
The main text (page unavailable) reports that bifunctional chelators 1 and 2 modulate copper-induced Aβ aggregation, supporting this paper as an example of such a study. It identifies the peptide only as Aβ; our copy does not establish that it was Aβ40 or support the claim that a majority of BFC studies used Aβ40 rather than Aβ42 (searched both peptide names). (LLM, conf=0.78)
Experimental — accuracy not yet measuredCompounds that inhibit metal-mediated Aβ40 aggregation or promote disaggregation of amyloid fibrils lead to increased cell viability.
“Compounds that inhibit metal-mediated Aβ40 aggregation or promote disaggregation of amyloid fibrils were shown to lead to increased cell viability.25,31,32”
From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [31]
In the main text (page unavailable), compounds 1 and 2 inhibit Cu-induced Aβ aggregation and disassemble Cu-Aβ fibrils; a separate cell experiment reports that compound 2 reduces Cu-Aβ toxicity, yielding about 90% cell survival. The paper does not establish that aggregation inhibition or fibril disaggregation caused the improved survival, or that the result applies to such compounds generally. Our copy identifies the peptide in these passages as Aβ, not specifically Aβ40. (LLM, conf=0.84)
Experimental — accuracy not yet measured
The clinically tested compound CQ was quite toxic to cells even at 2 μM concentration, while EDTA does not show any toxicity up to 20 μM.
“the clinically tested compound CQ was quite toxic to cells even at 2 μM concentration, while EDTA does not show any toxicity up to 20 μM.25,31”
From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [31]
The cell-study passage (page not provided) reports that CQ was more toxic than the paper’s chelators 1 and 2 in the presence of CuII. It does not establish toxicity at 2 μM or report that EDTA was nontoxic up to 20 μM; the stated absence of toxicity up to 200 μM refers to compound 2, not EDTA. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMetal-Aβ species have been shown to be neurotoxic.
“Since metal-Aβ species have been shown to be neurotoxic,25,51,92”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [51]
The use of both native gel electrophoresis/Western blot analysis and transmission electron microscopy provides a more complete picture of the extent and pathways of Aβ aggregation under various conditions.
“Thus, the use of both these methods provides a more complete picture of the extent and pathways of Aβ aggregation under various conditions.51,52”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [51]
Cu2+-Aβ species have been shown to be neurotoxic.
“Because Cu2+–Aβ species have been shown to be neurotoxic,20,21,31,51,52”
From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [31]
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- Authors
- Hindo, S. S., Mancino, A. M., Braymer, J. J., Liu, Y., Vivekanandan, S., Ramamoorthy, A., & Lim, M. H.
- Affiliations
- University of Michigan (US)
- Department of Chemistry and the Life Sciences Institute, Biophysics and Department of Chemistry, University of Michigan, Ann Arbor, Michigan, 48109
- Corresponding author
- Lim, Mi Hee
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2009-10-30
- Volume
- 131
- Issue
- 46
- Pages
- 16663-16665
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- PMC
- PMC3417132
- OpenAlex
- W1976544813
- Cited by
- 203
- References
- 34
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 6 · 2023: 6 · 2022: 10 · 2021: 7 · 2020: 12 · 2019: 8 · 2018: 14 · 2017: 11 · 2016: 12 · 2015: 14 · 2014: 20 · 2013: 21 · 2012: 22
- FWCI
- 11.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R21DK078885, DK078885)
- 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
- Alzheimer's disease, amyloid-beta aggregation, copper(II) ions, metal chelators, chemical probes, chelation therapy, imidazo[1,2-a]pyridines, benzene-1,4-diamine, copper chelation
- MeSH terms
- Alzheimer Disease, Chelating Agents, Copper, Humans, Imidazoles, Phenylenediamines, Pyridines, Drug Design, Amyloid beta-Peptides, Cell Line, Tumor
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