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Cited by 38Alzheimer's disease research and treatmentsMolecular Sensors and Ion DetectionCholinesterase and Neurodegenerative Diseases

Reactivity of Diphenylpropynone Derivatives Toward Metal-Associated Amyloid-β Species

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Pithadia, Amit S., Kochi, Akiko, Soper, Molly T., Beck, Michael W., Liu, Yuzhong, Lee, Sanghyun, DeToma, Alaina S., Ruotolo, Brandon T. +1 more·2012·Inorganic Chemistry
DOI 10.1021/ic302084gPMC PMC3568435
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Abstract

In Alzheimer's disease (AD), metal-associated amyloid-β (metal-Aβ) species have been suggested to be involved in neurotoxicity; however, their role in disease development is still unclear. To elucidate this aspect, chemical reagents have been developed as valuable tools for targeting metal-Aβ species, modulating the interaction between the metal and Aβ, and subsequently altering metal-Aβ reactivity. Herein, we report the design, preparation, characterization, and reactivity of two diphenylpropynone derivatives (DPP1 and DPP2) composed of structural moieties for metal chelation and Aβ interaction (bifunctionality). The interactions of these compounds with metal ions and Aβ species were confirmed by UV-vis, NMR, mass spectrometry, and docking studies. The effects of these bifunctional molecules on the control of in vitro metal-free and metal-induced Aβ aggregation were investigated and monitored by gel electrophoresis and transmission electron microscopy (TEM). Both DPP1 and DPP2 showed reactivity toward metal-Aβ species over metal-free Aβ species to different extents. In particular, DPP2, which contains a dimethylamino group, exhibited greater reactivity with metal-Aβ species than DPP1, suggesting a structure-reactivity relationship. Overall, our studies present a new bifunctional scaffold that could be utilized to develop chemical reagents for investigating metal-Aβ species in AD.

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  • 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 [30]

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Authors
Pithadia, A. S., Kochi, A., Soper, M. T., Beck, M. W., Liu, Y., Lee, S., DeToma, A. S., Ruotolo, B. T., & Lim, M. H.
Affiliations
  • University of Michigan (US)
  • Department of Chemistry and §Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, United States
Corresponding author
  • Ruotolo, Brandon T.
  • Lim, Mi Hee
ORCID
Venue
Inorganic Chemistry
Publisher
American Chemical Society (ACS)
Published
2012-11-15
Volume
51
Issue
23
Pages
12959-12967
ISSN
  • 0020-1669 (ISSN-L)
  • 1520-510X
DOI
10.1021/ic302084g
PMC
PMC3568435
OpenAlex
W2005936473
Cited by
38
References
55
Citations by year
2024: 1 · 2023: 2 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 2 · 2017: 1 · 2016: 4 · 2015: 7 · 2014: 9 · 2013: 6
FWCI
4.72
Type
journal article
Language
en
Open access
Locations
  • Inorganic Chemistry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
Funders
  • National Cancer Institute (T32CA140044)
  • National Institute of General Medical Sciences (R01GM095832)
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, metal chelation, bifunctional reagents, amyloid-beta aggregation, structure-reactivity relationships, dimethylamino group
MeSH terms
Alkynes, Animals, Benzhydryl Compounds, Cell Line, Cell Survival, Metals, Models, Molecular, Organometallic Compounds, Structure-Activity Relationship, Amyloid beta-Peptides, Mice

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