Cited by 32Alzheimer's disease research and treatmentsCholinesterase and Neurodegenerative DiseasesDementia and Cognitive Impairment Research

Tuning Reactivity of Diphenylpropynone Derivatives with Metal-Associated Amyloid-β Species via Structural Modifications

Liu, Yuzhong, Kochi, Akiko, Pithadia, Amit S., Lee, Sanghyun, Nam, Younwoo, Beck, Michael W., He, Xiaoming, Lee, Dongkuk +1 more·2013·Inorganic Chemistry

Abstract

A diphenylpropynone derivative, DPP2, has been recently demonstrated to target metal-associated amyloid-β (metal-Aβ) species implicated in Alzheimer's disease (AD). DPP2 was shown to interact with metal-Aβ species and subsequently control Aβ aggregation (reactivity) in vitro; however, its cytotoxicity has limited further biological applications. In order to improve reactivity toward Aβ species and lower cytotoxicity, along with gaining an understanding of a structure-reactivity-cytotoxicity relationship, we designed, prepared, and characterized a series of small molecules (C1/C2, P1/P2, and PA1/PA2) as structurally modified DPP2 analogues. A similar metal binding site to that of DPP2 was contained in these compounds while their structures were varied to afford different interactions and reactivities with metal ions, Aβ species, and metal-Aβ species. Distinct reactivities of our chemical family toward in vitro Aβ aggregation in the absence and presence of metal ions were observed. Among our chemical series, the compound (C2) with a relatively rigid backbone and a dimethylamino group was observed to noticeably regulate both metal-free and metal-mediated Aβ aggregation to different extents. Using our compounds, cell viability was significantly improved, compared to that with DPP2. Lastly, modifications on the DPP framework maintained the structural properties for potential blood-brain barrier (BBB) permeability. Overall, our studies demonstrated that structural variations adjace…

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Crossref · 10.1021/ic400851w

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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”

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Authors
Liu, Y., Kochi, A., Pithadia, A. S., Lee, S., Nam, Y., Beck, M. W., He, X., Lee, D., & Lim, M. H.
Affiliations
  • University of Michigan (US)
  • Seoul National University of Science and Technology (KR)
Corresponding author
Lim, Mi Hee
Venue
Inorganic Chemistry
Published
2013-06-27
Volume
52
Issue
14
Pages
8121-8130
ISSN
  • 0020-1669 (ISSN-L)
  • 1520-510X
OpenAlex
W2315735625
Cited by
30
References
40
Citations by year
2025: 1 · 2024: 1 · 2023: 2 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 3 · 2017: 1 · 2016: 3 · 2015: 5 · 2014: 8 · 2013: 2
FWCI
4.17
Type
journal article
Language
en
Open access
closed
Locations
  • Inorganic Chemistry (publishedVersion)
  • PubMed (publishedVersion)
  • Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
  • The Keep (Eastern Illinois University) (submittedVersion)
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
Alzheimer's disease, amyloid-beta aggregation, metal ion binding, structure-reactivity relationships, cytotoxicity, structure-activity optimization, blood-brain barrier permeability, metal ions, dimethylamino group, chemical probes
MeSH terms
Alzheimer Disease, Anilides, Blood-Brain Barrier, Cell Line, Cell Survival, Humans, Ketones, Metals, Pyridines, Amyloid beta-Peptides, Molecular Docking Simulation

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