Title of Abstract

Synthesis and Evaluation of Symmetrical Biphenyltetrols as Aggregation Inhibitors for Alzheimer’s Amyloid-beta Peptide

Poster Number

47

Submitting Student(s)

Sarah Wicks, Winthrop University

College

College of Arts and Sciences

Department

Chemistry, Physics and Geology

Faculty Mentor

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

Abstract

Inhibition of amyloid-beta peptide (Abeta) aggregation is one therapeutic target for prevention and treatment of Alzheimer’s disease. We have previously demonstrated that biphenyl-3,3′,4,4′-tetrol (3,4-BPT) effectively abrogates Abeta aggregation at stoichiometric concentrations. To investigate this molecular architecture and determine how the positioning of the hydroxyl hydrogen-bond donors impacts inhibitor efficacy, we have synthesized five additional symmetrical biphenyltetrols (2,3-, 2,4- 2,5- 2,6- and 3,5-BPT). Congo red and Thioflavin T dye-binding assays were employed to monitor Abeta aggregation as a function of time and determine inhibitor IC50 values for reducing equilibrium levels of aggregation. The six characterized isomers exhibit a range of IC50 values spanning more than one order of magnitude. Circular dichroism and transmission electron microscopy measurements, in progress, will enable comparison of secondary structural transitions and aggregate morphologies in the presence and absence of inhibitors. Collectively, these results will aid in the design of unsymmetrical biphenyltetrols and related inhibitor architectures.

Start Date

24-4-2015 1:20 PM

End Date

24-4-2015 2:50 PM

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Apr 24th, 1:20 PM Apr 24th, 2:50 PM

Synthesis and Evaluation of Symmetrical Biphenyltetrols as Aggregation Inhibitors for Alzheimer’s Amyloid-beta Peptide

Richardson Ballroom

Inhibition of amyloid-beta peptide (Abeta) aggregation is one therapeutic target for prevention and treatment of Alzheimer’s disease. We have previously demonstrated that biphenyl-3,3′,4,4′-tetrol (3,4-BPT) effectively abrogates Abeta aggregation at stoichiometric concentrations. To investigate this molecular architecture and determine how the positioning of the hydroxyl hydrogen-bond donors impacts inhibitor efficacy, we have synthesized five additional symmetrical biphenyltetrols (2,3-, 2,4- 2,5- 2,6- and 3,5-BPT). Congo red and Thioflavin T dye-binding assays were employed to monitor Abeta aggregation as a function of time and determine inhibitor IC50 values for reducing equilibrium levels of aggregation. The six characterized isomers exhibit a range of IC50 values spanning more than one order of magnitude. Circular dichroism and transmission electron microscopy measurements, in progress, will enable comparison of secondary structural transitions and aggregate morphologies in the presence and absence of inhibitors. Collectively, these results will aid in the design of unsymmetrical biphenyltetrols and related inhibitor architectures.