Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity

Choi, Jung-Suk; Braymer, Joseph J.; Nanga, Ravi P. R.; Ramamoorthy, Ayyalusamy; Lim, Mi Hee

doi:10.1073/pnas.1006091107

Cited by 279Alzheimer's disease research and treatmentsCholinesterase and Neurodegenerative DiseasesDementia and Cognitive Impairment Research

Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity

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Choi, Jung-Suk, Braymer, Joseph J., Nanga, Ravi P. R., Ramamoorthy, Ayyalusamy, Lim, Mi Hee·2010·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1006091107PMC PMC3009803

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Abstract

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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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 Aβ42Peptide (2012) · cites this paper as [52]
The two lower pKa values of L1 are assigned to deprotonation of the two pyridinium groups, the third to the ammonium group, and the highest to phenol deprotonation.
“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]
CQ 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 Aβ42Peptide (2012) · cites this paper as [52]
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 Aβ42Peptide (2012) · cites this paper as [52]
Except 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 Aβ42Peptide (2012) · cites this paper as [52]

The 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 [25]
Compounds 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 [25]
Metal chelators reduce metal-mediated Aβ aggregation, ROS formation, and neurotoxicity in vitro.
“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]
The first and second pKa values of L1 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.
“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]
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.
“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]
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 [25]

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Coordination Chemistry of Bifunctional Chemical Agents Designed for Applications in 64Cu PET Imaging for Alzheimer’s Disease
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Soluble Sugar-Based Quinoline Derivatives as New Antioxidant Modulators of Metal-Induced Amyloid Aggregation
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C3N nanodots inhibits Aβ peptides aggregation pathogenic path in Alzheimer’s disease
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Recent Development of Bifunctional Small Molecules to Study Metal‐Amyloid‐β Species in Alzheimer′s Disease
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Development of Bifunctional Stilbene Derivatives for Targeting and Modulating Metal-Amyloid-β Species
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Self-citation
Review Article Recent Development of Bifunctional Small Molecules to Study Metal-Amyloid-β Species in Alzheimer’s Disease
Braymer, J. J., DeToma, A. S., Choi, J.-S., Ko, K. S., & Lim, M. H. (2013)
Self-citation
Dual-function triazole-pyridine derivatives as inhibitors of metal-induced amyloid-β aggregation.
Jones, M. R., Service, E., Thompson, J. R., Wang, M. C. P., Kimsey, I. J., DeToma, A. S., Ramamoorthy, A., Lim, M., & Storr, T. (2012) · Metallomics · doi:10.1039/c2mt20113e · Cited by 53 · see citing works
Self-citation
Development of Small Molecules as Chemical Tools for Investigating the Role of Metal-Protein Interactions in Neurodegenerative Diseases.
Beck, M. (2015) · Deep Blue (University of Michigan)

Authors: Choi, J.-S., Braymer, J. J., Nanga, R. P. R., Ramamoorthy, A., & Lim, M. H.
Affiliations: University of Michigan (US)
ORCID: Braymer, Joseph J.
Nanga, Ravi P. R.
Ramamoorthy, Ayyalusamy
Lim, Mi Hee
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
DOI: 10.1073/pnas.1006091107
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: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Pharmacology › 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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Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity

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