Synthesis and Evaluation of Unsymmetrical Biphenyltetrols as Aggregation Inhibitors for Alzheimer’s Amyloid-β Peptide
Poster Number
19
College
College of Arts and Sciences
Department
Chemistry, Physics, Geology, & the Environment
Faculty Mentor
Dr. Robin K. Lammi & Dr. James M. Hanna, Jr.
Abstract
Amyloid-β peptide (Aβ) self-assembles into neurotoxic, β-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 Aβ. 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 may also be successful inhibitors. 2,3',4',5-BPT, 2,3,3',4'-BPT, and 2,2',3,5'-BPT were therefore synthesized and evaluated for inhibitory efficacy using the Congo red (CR) spectral-shift assay, which exploits CR’s specific binding to β-structured aggregates to enable monitoring of Aβ aggregation as a function of time. Preliminary results indicate that neither 2,3,3',4'-BPT nor 2,2',3,5'-BPT were effective inhibitors; however 2,3',4',5-BPT appeared to be a promising inhibitor of Aβ aggregation (preliminary IC50 ~ 2X).
Previously Presented/Performed?
Joint 67th Southeast and 71st Southwest Regional Meeting of the American Chemical Society, Memphis, Tennessee, November, 2015
Grant Support?
Supported by a grant from the National Institutes of Health IDeA Networks for Biomedical Research Excellence (NIH INBRE)
Start Date
22-4-2016 12:00 PM
End Date
22-4-2016 2:00 PM
Synthesis and Evaluation of Unsymmetrical Biphenyltetrols as Aggregation Inhibitors for Alzheimer’s Amyloid-β Peptide
Rutledge
Amyloid-β peptide (Aβ) self-assembles into neurotoxic, β-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 Aβ. 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 may also be successful inhibitors. 2,3',4',5-BPT, 2,3,3',4'-BPT, and 2,2',3,5'-BPT were therefore synthesized and evaluated for inhibitory efficacy using the Congo red (CR) spectral-shift assay, which exploits CR’s specific binding to β-structured aggregates to enable monitoring of Aβ aggregation as a function of time. Preliminary results indicate that neither 2,3,3',4'-BPT nor 2,2',3,5'-BPT were effective inhibitors; however 2,3',4',5-BPT appeared to be a promising inhibitor of Aβ aggregation (preliminary IC50 ~ 2X).
