Event Title

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

Poster Number

39

Presenter Information

Jake Roberts, Winthrop University

Faculty Mentor

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

College

College of Arts and Sciences

Department

Chemistry, Physics and Geology

Location

Richardson Ballroom

Start Date

24-4-2015 1:20 PM

End Date

24-4-2015 2:50 PM

Description

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.

Comments

Presented at the Winthrop University Summer Undergraduate Research Experience (SURE) Symposium, July 2014, and the Department of Biology Poster Session, December 2014

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, 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.