Title of Abstract

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

Poster Number

39

Submitting Student(s)

Jake Roberts, 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

Amyloid-beta peptide (Abeta) self-assembles into neurotoxic, beta-structured aggregates, which are the primary component of the extracellular senile plaques characteristic of Alzheimer’s disease. A variety of small molecules have been shown to inhibit the aggregation process; typically, these contain aromatic groups and one or more hydrogen-bond donors to enable binding to Abeta. We have previously identified biphenyltetrols (BPTs) as a class of molecules exhibiting promising inhibitory efficacy. 3,3¢,4,4¢-tetrahydroxybiphenyl (3,4-BPT) is the most promising, reducing equilibrium aggregation by 50 % when present in stoichiometric concentrations (i.e., IC50 = 1X); 2,5- and 2,3-BPT also show significant inhibition. Based on these results, we hypothesized that “hybrid,” unsymmetrical biphenyltetrols combining these arrangements of hydroxyl groups – specifically, 3,4 plus 2,5 and 3,4 plus 2,3 – may also be successful inhibitors. 2,3¢,4¢,5-BPT and 2,3¢,4¢,3-BPT were synthesized and evaluated for inhibitory efficacy using the Congo red (CR) spectral-shift assay, which exploits CR’s specific binding to beta-structured aggregates to enable monitoring of Abeta aggregation as a function of time. Preliminarily, 2,3¢,4¢,3-BPT showed little to no inhibition of Abeta aggregation; however, 10 equivalents (i.e., 10X) of 2,3¢,4¢,5-BPT completely abrogated Abeta aggregation. Further tests will be completed to verify these preliminary results and determine a quantitative IC50 value for 2,3¢,4¢,5-BPT. Additional hydroxy-substituted biphenyls will also be investigated.

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 Unsymmetrical Biphenyltetrols as Aggregation Inhibitors for Alzheimer’s Amyloid-beta Peptide

Richardson Ballroom

Amyloid-beta peptide (Abeta) self-assembles into neurotoxic, beta-structured aggregates, which are the primary component of the extracellular senile plaques characteristic of Alzheimer’s disease. A variety of small molecules have been shown to inhibit the aggregation process; typically, these contain aromatic groups and one or more hydrogen-bond donors to enable binding to Abeta. We have previously identified biphenyltetrols (BPTs) as a class of molecules exhibiting promising inhibitory efficacy. 3,3¢,4,4¢-tetrahydroxybiphenyl (3,4-BPT) is the most promising, reducing equilibrium aggregation by 50 % when present in stoichiometric concentrations (i.e., IC50 = 1X); 2,5- and 2,3-BPT also show significant inhibition. Based on these results, we hypothesized that “hybrid,” unsymmetrical biphenyltetrols combining these arrangements of hydroxyl groups – specifically, 3,4 plus 2,5 and 3,4 plus 2,3 – may also be successful inhibitors. 2,3¢,4¢,5-BPT and 2,3¢,4¢,3-BPT were synthesized and evaluated for inhibitory efficacy using the Congo red (CR) spectral-shift assay, which exploits CR’s specific binding to beta-structured aggregates to enable monitoring of Abeta aggregation as a function of time. Preliminarily, 2,3¢,4¢,3-BPT showed little to no inhibition of Abeta aggregation; however, 10 equivalents (i.e., 10X) of 2,3¢,4¢,5-BPT completely abrogated Abeta aggregation. Further tests will be completed to verify these preliminary results and determine a quantitative IC50 value for 2,3¢,4¢,5-BPT. Additional hydroxy-substituted biphenyls will also be investigated.