The DOI matches its Crossref record; 53 of the 54 references it cites were found in a registry or an index.
Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity
Open accessAbstract
The accumulation of metal ions and amyloid-β (Aβ) aggregates found in the brain of patients with Alzheimer's disease (AD) has been suggested to be involved in AD pathogenesis. To investigate metal-Aβ-associated pathways in AD, development of chemical tools to target metal-Aβ species is desired. Only a few efforts, however, have been reported. Here, we report bifunctional small molecules, N-(pyridin-2-ylmethyl)aniline (L2-a) and N(1),N(1)-dimethyl-N(4)-(pyridin-2-ylmethyl)benzene-1,4-diamine (L2-b) that can interact with both metal ions and Aβ species, as determined by spectroscopic methods including high-resolution NMR spectroscopy. Using the bifunctional compound L2-b, metal-induced Aβ aggregation and neurotoxicity were modulated in vitro as well as in human neuroblastoma cells. Furthermore, treatment of human AD brain tissue homogenates containing metal ions and Aβ species with L2-b showed disassembly of Aβ aggregates. Therefore, our studies presented herein demonstrate the value of bifunctional compounds as chemical tools for investigating metal-Aβ-associated events and their mechanisms in the development and pathogenesis of AD and as potential therapeutics.
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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 [52]
In the citing paper
“Based on previously reported acidity constants for phenols, amines,76 and pyridines,52 we assigned the two lower pKa values to the deprotonation of the two pyridinium groups, and the third pKa value to the ammonium group. The highest pKa value is likely due to phenol deprotonation in L1.”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ42Peptide (2012) · cites this paper as [52]
In the citing paper
“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 [52]
In the citing paper
“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 [52]
In the citing paper
“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 [52]
In the citing paper
“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 [25]
In the citing paper
“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 [25]
In the citing paper
“metal chelators have been shown to reduce metal-mediated Aβ aggregation, ROS formation, and neurotoxicity in vitro.23−26”
From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [25]
In the citing paper
“The first and second pKa values can be assigned to deprotonation of the nitrogen atoms of the benzothiazole and diethylamino groups, while the largest pKa value is likely due to phenol deprotonation.25,42”
From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [25]
In the citing paper
“Recent efforts to control abnormal Aβ–metal interactions have focused on small molecules, bifunctional chelators (BFCs), that have binding affinity for both metal ions and Aβ aggregates.20,25,27−30”
From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [25]
In the citing paper
“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 [25]
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Self-citation
Metadata
- Authors
- Choi, J.-S., Braymer, J. J., Nanga, R. P. R., Ramamoorthy, A., & Lim, M. H.
- Affiliations
- University of Michigan (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-12-03
- Volume
- 107
- Issue
- 51
- Pages
- 21990-21995
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3009803
- OpenAlex
- W2080100823
- Cited by
- 264
- References
- 54
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 7 · 2023: 16 · 2022: 7 · 2021: 10 · 2020: 15 · 2019: 16 · 2018: 21 · 2017: 28 · 2016: 28 · 2015: 22 · 2014: 25 · 2013: 21 · 2012: 23
- FWCI
- 13.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
- Funders
- National Institute on Aging (P50AG008671, P50 AG08671)
- 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
- Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- amyloid-beta, metal ions, Alzheimer's disease, bifunctional small molecules, neurotoxicity, chemical probes, pyridine derivatives, neuroblastoma cells
- MeSH terms
- Alzheimer Disease, Copper, Humans, Phenylenediamines, Pyridines, Zinc, Amyloid beta-Peptides, Cell Line, Tumor
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