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Text
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URL Address
<a href="http://doi.org/10.1039/c0sc00544d" target="_blank" rel="noreferrer noopener">http://doi.org/10.1039/c0sc00544d</a>
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Pages
642-648
Issue
4
Volume
2
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Title
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N-Aryl-substituted 3-(beta-D-glucopyranosyloxy)-2-methyl-4(1H)-pyridinones as agents for Alzheimer's therapy
Publisher
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Chemical Science
Date
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2011
2011
Subject
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4(1h)-pyridinone; biological evaluation; Blood-brain barrier; Chemistry; copper; Crystal structure; derivatives; disease; iron chelators; physicochemical properties; targeting a-beta; transgenic mice
Creator
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Scott L E; Telpoukhovskaia M; Rodriguez-Rodriguez 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
Description
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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 ion-induced amyloid peptide aggregation to screen promising lead compounds. Finally, in a brain uptake study with a radiolabeled glucoconjugate pyridinone, 3-(beta-Dglucopyranosyloxy)-1-[4-(4-[I-125] iodophenyl)-2-thiazolyl]-2-methyl-4(1H)-pyridinone ([I-125]-GL(7)) was shown to cross the blood-brain barrier using an in situ rat brain perfusion technique.
Identifier
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<a href="http://doi.org/10.1039/c0sc00544d" target="_blank" rel="noreferrer noopener">10.1039/c0sc00544d</a>
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Journal Article
2011
4(1h)-pyridinone
Adam M J
Allen D D
biological evaluation
Blood-brain barrier
Bowen M L
Chemical science
Chemistry
copper
Crystal structure
derivatives
Disease
Green D E
iron chelators
Journal Article
Lockman P R
Merkel M
Orvig C
Page B D G
Patrick B O
physicochemical properties
Rodriguez-Rodriguez C
Scott L E
Storr T
targeting a-beta
Telpoukhovskaia M
Thomas F
Transgenic mice