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Please use this identifier to cite or link to this item: http://apo.ansto.gov.au/dspace/handle/10238/9206

Title: Novel fluorinated 8-hydroxyquinoline based metal Ionophores for exploring the metal hypothesis of alzheimer’s disease
Authors: Liang, SH
Southon, AG
Fraser, BH
Krause-Heuer, AM
Zhang, B
Shoup, TM
Lewis, R
Volitakis, I
Han, Y
Greguric, I
Bush, AI
Vasdev, Y
Keywords: Reaction product transport systems
Metals
Central nervous system
Agglomeration
Drugs
Diseases
Aging
Emission computed tomography
Issue Date: 10-Aug-2015
Publisher: American Chemical Society
Citation: Liang, S. H., Southon, A. G., Fraser, B. H., Krause-Heuer, A. M., Zhang, B., Shoup, T. M., Lewis, R., Volitakis, I., Han, Y., Greguric, I., Bush, A. I., &. Vasdev, N. (2015). Novel fluorinated 8-hydroxyquinoline based metal ionophores for exploring the metal hypothesis of Alzheimer’s disease. ACS Medicinal Chemistry Letters, 6(9), 1025-1029. doi:10.1021/acsmedchemlett.5b00281
Abstract: Zinc, copper, and iron ions are involved in amyloid-beta (Aβ) deposition and stabilization in Alzheimer’s disease (AD). Consequently, metal binding agents that prevent metal-Aβ interaction and lead to the dissolution of Aβ deposits have become well sought therapeutic and diagnostic targets. However, direct intervention between diseases and metal abnormalities has been challenging and is partially attributed to the lack of a suitable agent to determine and modify metal concentration and distribution in vivo. In the search of metal ionophores, we have identified several promising chemical entities by strategic fluorination of 8-hydroxyquinoline drugs, clioquinol, and PBT2. Compounds 15–17 and 28–30 showed exceptional metal ionophore ability (6–40-fold increase of copper uptake and >2-fold increase of zinc uptake) and inhibition of zinc induced Aβ oligomerization (EC50s < ∼5 μM). These compounds are suitable for further development as drug candidates and/or positron emission tomography (PET) biomarkers if radiolabeled with 18F. © 2015 American Chemical Society
URI: http://dx.doi.org/10.1021/acsmedchemlett.5b00281
http://apo.ansto.gov.au/dspace/handle/10238/9206
ISSN: 1948-5875
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