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Issue 4, 2011
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N-Aryl-substituted 3-(β-D-glucopyranosyloxy)-2-methyl-4(1H)-pyridinones as agents for Alzheimer's therapy

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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 ion-induced amyloid peptide aggregation to screen promising lead compounds. Finally, in a brain uptake study with a radiolabeled glucoconjugate pyridinone, 3-(β-D-glucopyranosyloxy)-1-[4-(4-[125I]iodophenyl)-2-thiazolyl]-2-methyl-4(1H)-pyridinone ([125I]-GL7) was shown to cross the blood–brain barrier using an in situ rat brain perfusion technique.

Graphical abstract: N-Aryl-substituted 3-(β-D-glucopyranosyloxy)-2-methyl-4(1H)-pyridinones as agents for Alzheimer's therapy

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Supplementary files

Article information


Submitted
27 Oct 2010
Accepted
03 Dec 2010
First published
23 Dec 2010

Chem. Sci., 2011,2, 642-648
Article type
Edge Article

N-Aryl-substituted 3-(β-D-glucopyranosyloxy)-2-methyl-4(1H)-pyridinones as agents for Alzheimer's therapy

L. E. Scott, M. Telpoukhovskaia, C. Rodríguez-Rodríguez, M. Merkel, M. L. Bowen, B. D. G. Page, D. E. Green, T. Storr, F. Thomas, D. D. Allen, P. R. Lockman, B. O. Patrick, M. J. Adam and C. Orvig, Chem. Sci., 2011, 2, 642
DOI: 10.1039/C0SC00544D

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