Synthesis and Evaluation of Unsymmetrical Biphenyltetrols as Aggregation Inhibitors for Alzheimer’s Amyloid-beta Peptide
Poster Number
39
College
College of Arts and Sciences
Department
Chemistry, Physics, Geology, & the Environment
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
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.
