Event Title

Amyloid-beta Aggregation Inhibitors: Synthesis and Evaluation of a Sterically Hindered Biphenyltetrol and a Dihydroxyphenylpyridine

Presenter Information

Jessica Logan, Winthrop University

Faculty Mentor

James M. Hanna, Jr., Ph.D.; Robin K. Lammi, Ph.D.; and Nicholas Grossoehme, Ph.D.

College

College of Arts and Sciences

Department

Chemistry, Physics and Geology

Location

DiGiorgio Campus Center, Room 220

Start Date

24-4-2015 2:20 PM

Description

Alzheimer’s disease has been associated with amyloid plaques found in brain tissue. The main component of these plaques is aggregated amyloid-beta fibrils that form over time in the brain. Although the fibrils and plaques formed from amyloid-beta aggregates are toxic, it has been found that the smaller, soluble aggregates are the most toxic species. Therefore, one potential approach to treating Alzheimer's disease may be to inhibit aggregation of amyloid-beta peptide. Previous research found biphenyl-3,3′,4,4′-tetrol (3,4-BPT) to be an effective inhibitor, with an IC50 of approximately 1X. As part of this investigation, the symmetric isomer biphenyl-2,2′,6,6′-tetrol has been synthesized and evaluated to determine if the position of the hydroxyl groups affects the level of inhibition. Preliminary results indicate this compound to be less effective than 3,4-BPT, with an IC50 greater than 10X. It is also known that amyloid-beta has a phenylalanine-containing hydrophobic core, and it is suspected that pi-stacking plays an important role in aggregation. Pyridine and pyridinium moieties have been shown to form stronger pi-stacking interactions with a phenyl group than pi-stacking interactions between two phenyl groups and for this reason, the biaryl 3-(3,4-dihydroxyphenyl)pyridine is also being investigated as an amyloid-beta aggregation inhibitor. Synthesis and evaluation of this compound are currently being carried out in our laboratories.

Comments

Honors Thesis

Supported by an NIH-INBRE grant from the National Center for Research Resources and the National Institute of General Medical Sciences

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Apr 24th, 2:20 PM

Amyloid-beta Aggregation Inhibitors: Synthesis and Evaluation of a Sterically Hindered Biphenyltetrol and a Dihydroxyphenylpyridine

DiGiorgio Campus Center, Room 220

Alzheimer’s disease has been associated with amyloid plaques found in brain tissue. The main component of these plaques is aggregated amyloid-beta fibrils that form over time in the brain. Although the fibrils and plaques formed from amyloid-beta aggregates are toxic, it has been found that the smaller, soluble aggregates are the most toxic species. Therefore, one potential approach to treating Alzheimer's disease may be to inhibit aggregation of amyloid-beta peptide. Previous research found biphenyl-3,3′,4,4′-tetrol (3,4-BPT) to be an effective inhibitor, with an IC50 of approximately 1X. As part of this investigation, the symmetric isomer biphenyl-2,2′,6,6′-tetrol has been synthesized and evaluated to determine if the position of the hydroxyl groups affects the level of inhibition. Preliminary results indicate this compound to be less effective than 3,4-BPT, with an IC50 greater than 10X. It is also known that amyloid-beta has a phenylalanine-containing hydrophobic core, and it is suspected that pi-stacking plays an important role in aggregation. Pyridine and pyridinium moieties have been shown to form stronger pi-stacking interactions with a phenyl group than pi-stacking interactions between two phenyl groups and for this reason, the biaryl 3-(3,4-dihydroxyphenyl)pyridine is also being investigated as an amyloid-beta aggregation inhibitor. Synthesis and evaluation of this compound are currently being carried out in our laboratories.