N-Aryl-substituted 3-(β-D-glucopyranosyloxy)-2-methyl-4(1H)-pyridinones as agents for Alzheimer's therapy
Abstract
Molecules designed to sequester, redistribute and/or remove metal ions are attractive therapeutic agents in neurodegenerative diseases such as Alzheimer's disease. The multifactorial nature of the condition and the generally poor target specificity associated with metal ion-binding therapy has led to the development of multifunctional 3-hydroxy-4-(1H)-pyridinone pro-ligands. The excellent qualities of the basic 3-hydroxy-4-pyridinone framework as a low toxicity metal chelator and an antioxidant, as well as its antibacterial and analgesic properties among other functions, inspired us to functionalize it with a framework derived from thioflavin-T, the well-known traditional dye used as a marker to detect amyloid deposits in tissue sections. Thus 2-methyl-3-hydroxy-1-(4-dimethylaminophenyl)-4(1H)-pyridinone (HL1), 2-methyl-3-hydroxy-1-(4-methylaminophenyl)-4(1H)-pyridinone (HL2), 1-(4-aminophenyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (HL3), 1-(6-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (HL4), 1-(2-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (HL5) and 2-methyl-3-hydroxy-1-[4-(4-bromophenyl)-2-thiazolyl]-4(1H)-pyridinone (HL6) were obtained. Glycosylation, as well as incorporation of structures mimicking those of known amyloid imaging agents, may target drug action to the site of interest, the metal-overloaded amyloid plaques in the Alzheimer's brain. The pro-ligands were assessed for their antioxidant activity, cytotoxicity and ability to interfere with metal io…
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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 [32]
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BindingDB (2022) · UC San Diego · doi:10.7270/q28p646m
- Authors
- Scott, L. E., Telpoukhovskaia, M., Rodríguez-Rodríguez, C., Merkel, M., Bowen, M. L., Page, B. D. G., Green, D. E., Storr, T., Thomas, F., Allen, D. D., Lockman, P. R., Patrick, B. O., Adam, M. J., & Orvig, C.
- Affiliations
- University of British Columbia (CA)
- Texas Tech University Health Sciences Center (US)
- Northeast Ohio Medical University (US)
- TRIUMF (CA)
- Corresponding author
- Orvig, Chris
- ORCID
- Venue
- Chem. Sci.
- Publisher
- Royal Society of Chemistry (RSC)
- Published
- 2011
- Volume
- 2
- Issue
- 4
- Pages
- 642-648
- ISSN
- 2041-6520 (ISSN-L)
- 2041-6539
- OpenAlex
- W2087011232
- Cited by
- 68
- References
- 59
- Citations by year
- 2024: 1 · 2022: 1 · 2021: 1 · 2020: 3 · 2019: 3 · 2018: 1 · 2017: 7 · 2016: 6 · 2015: 10 · 2014: 12 · 2013: 13 · 2012: 8
- FWCI
- 4.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Chemical Science (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Physical Sciences › Chemistry › Spectroscopy › Molecular Sensors and Ion Detection
- Keywords
- Alzheimer's disease, metal chelators, thioflavin T, amyloid plaques, glycosylation, antioxidant activity, cytotoxicity, brain uptake, neurodegenerative diseases, benzothiazole
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