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Combating Alzheimer's Disease With Multifunctional Molecules Designed for Metal Passivation

Authors


  • This work was supported by the Natural Sciences and Engineering Research Council (NSERC) and the Canadian Institutes of Health Research (CIHR). The authors wish to thank Profs. D. Devine and C. Overall for allowing us to use their turbidometric assay facilities in the Centre for Blood Research, University of British Columbia; Prof. S. G. Withers for supplying Abg, and technical assistance in the glycosidase enzyme assays; Drs. Mike Adam and Jianming Liu at TRIUMF for assistance with radiolabeling and supply of Na125I; and MDS Nordion, Inc. for Na123I. L.E.S. is the recipient of an Alzheimer Society of Canada Fellowship, T.S. of an NSERC Postgraduate Scholarship, and M.M. of a Feodor Lynen fellowship.

Abstract

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A trifunctional approach: 3-hydroxy-4-pyridinones that contain phenol groups for antioxidant functionality are further elaborated with pendant glucosyl moieties for improved blood–brain barrier targeting (see structure; R=phenyl, 4-hydroxyphenyl). Glycosidase removal of the carbohydrate substituents gives ligands that are ready to passivate excess metal ions, especially copper and zinc, in the brain. These molecules are potential prodrugs for treatment of neurodegenerative diseases, including Alzheimer's disease.

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