The DOI matches its Crossref record; 34 of the 34 references it cites were found in a registry or an index.
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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“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 Aβ42Peptide (2012) · cites this paper as [51]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“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 Aβ42Peptide (2012) · cites this paper as [51]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“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 Aβ42Peptide (2012) · cites this paper as [51]
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“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“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]
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“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]
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“Since metal-Aβ species have been shown to be neurotoxic,25,51,92”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ42Peptide (2012) · cites this paper as [51]
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“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 Aβ42Peptide (2012) · cites this paper as [51]
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“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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Cites
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[27] Determination of binding stoichiometry by the continuous variation method: The job plot
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Copper Binding to the Amyloid-β (Aβ) Peptide Associated with Alzheimer's Disease
Syme, C. D., Nadal, R. C., Rigby, S. E. J., & Viles, J. H. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m313572200 · Cited by 459
The chemistry of Alzheimer’s disease
Rauk, A. (2009) · Chemical Society Reviews · doi:10.1039/b807980n · Cited by 417
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Research works printed but not linked: 3
- 2007, Neurological disorders
- Newberg A. B., 2006, J. Nucl. Med., 47, 748
- Saeed A. A. H., 1979, Indian J. Chem., 18, 338
Cited by
Sorted by citations
Savelieff, M. G., Nam, G., Kang, J., Lee, H. J., Lee, M., & Lim, M. H. (2018) · Chemical Reviews · doi:10.1021/acs.chemrev.8b00138 · Cited by 612
Self-citationBiological metals and metal-targeting compounds in major neurodegenerative diseases
Barnham, K. J., & Bush, A. I. (2014) · Chem. Soc. Rev. · doi:10.1039/c4cs00138a · Cited by 497
Leon, R. M., García, A. G., & Marco, J. L. (2011) · Medicinal Research Reviews · doi:10.1002/med.20248 · Cited by 447
Misfolded proteins in Alzheimer's disease and type II diabetes
DeToma, A. S., Salamekh, S., Ramamoorthy, A., & Lim, M. H. (2011) · Chemical Society Reviews · doi:10.1039/c1cs15112f · Cited by 363
Self-citationZhang, X., Tian, Y., Zeng, L., Tian, X., Sun, H., Liu, H., Moore, A. V., & Ran, C. (2013) · Journal of the American Chemical Society · doi:10.1021/ja405239v · Cited by 354
Metadata
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Physical Sciences › Chemistry › Spectroscopy › Molecular Sensors and Ion Detection
- Health Sciences › Medicine › Pharmacology (medical) › 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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