Tuning Reactivity of Diphenylpropynone Derivatives with Metal-Associated Amyloid-β Species via Structural Modifications
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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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 [28]
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Self-citation
- 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
- Publisher
- American Chemical Society (ACS)
- 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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