Event Title

Evaluation of Biphenyltetrols as Aggregation Inhibitors for Alzheimer's Amyloid-β Peptide

Faculty Mentor

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

College

College of Arts and Sciences

Department

Department of Chemistry, Physics, and Geology

Location

DiGiorgio Campus Center, Room 115

Start Date

21-4-2017 3:30 PM

Description

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) was the most promising, reducing equilibrium aggregation by 50 % when present in stoichiometric concentrations (i.e., IC50 = 1X); 2,5- and 2,3-BPT were also effective, albeit less so. Other symmetrical BPTs (e.g., 2,4-BPT, 2,6-BPT, 3,5-BPT) failed to exhibit significant inhibition. Based on these results, we hypothesized that "hybrid" unsymmetrical biphenyltetrols combining the most promising 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. Our results indicate that neither 2,3,3',4'-BPT nor 2,2',3,5'-BPT are effective inhibitors; however 2,3',4',5-BPT appears to be a promising inhibitor of Aβ aggregation (IC50 = 1.8X).

Previously Presented/Performed?

68th Southeastern Regional Meeting of the American Chemical Society, Columbia, South Carolina, October 2016

Grant Support?

Supported by a grant from the National Institutes of Health IDeA Networks for Biomedical Research Excellence (NIH-INBRE)

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Apr 21st, 3:30 PM

Evaluation of Biphenyltetrols as Aggregation Inhibitors for Alzheimer's Amyloid-β Peptide

DiGiorgio Campus Center, Room 115

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) was the most promising, reducing equilibrium aggregation by 50 % when present in stoichiometric concentrations (i.e., IC50 = 1X); 2,5- and 2,3-BPT were also effective, albeit less so. Other symmetrical BPTs (e.g., 2,4-BPT, 2,6-BPT, 3,5-BPT) failed to exhibit significant inhibition. Based on these results, we hypothesized that "hybrid" unsymmetrical biphenyltetrols combining the most promising 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. Our results indicate that neither 2,3,3',4'-BPT nor 2,2',3,5'-BPT are effective inhibitors; however 2,3',4',5-BPT appears to be a promising inhibitor of Aβ aggregation (IC50 = 1.8X).