James M. Hanna, Jr., Ph.D. & Robin K. Lammi, Ph.D.
College of Arts and Sciences
Chemistry, Physics and Geology
Winthrop University McNair Scholars Program and an NIH-INBRE grant from the National Center for Research Resources and the National Institute for General Medical Sciences.
Inhibiting the aggregation of amyloid-beta peptide (Aβ) is one therapeutic target for the prevention and treatment of Alzheimer’s disease. We have previously demonstrated that biphenyl-3,3′,4,4′-tetrol (3,4-BPT) effectively abrogates Aβ aggregation at stoichiometric concentrations. To investigate molecular architecture and determine how the positioning of the hydroxyl hydrogen-bond donors impacts inhibitor efficacy, we have synthesized four additional symmetrical biphenyltetrols (2,3-, 2,4- 2,5- and 3,5-BPT). We have evaluated these inhibitors by means of Congo red and Thioflavin T dye-binding assays to monitor Aβ aggregation as a function of time and to determine inhibitor IC50 values for reducing equilibrium levels of aggregation. 2,3- and 2,5-BPT were observed to be promising inhibitors of Aβ aggregation: we have qualitatively assessed their IC50 values to be approximately 7X and 3-4X, respectively. In contrast, 2,4- and 3,5-BPT showed little to no inhibition. Thus, 2,5-BPT was the most successful of the four inhibitors evaluated, however; it was not as effective as 3,4-BPT, studied previously (IC50 = 1.0 ± 0.3X). The four isomers we have characterized exhibit a range of IC50 values spanning more than one order of magnitude, likely due to varying abilities to bind to A assemblies. Future work will involve further evaluation of the symmetrical biphenyltetrols, by methods including circular dichroism and transmission electron microscopy, which will afford greater insight into the Aβ assemblies formed in the presence and absence of inhibitors. These results will aid in the rational design of additional small-molecule aggregation inhibitors, including unsymmetrical biphenyltetrols and other architectures bearing hydroxyl substituents in those positions associated with the greatest inhibitory efficacy.
Wicks, Sarah L.; Hanna, James M.; and Lammi, Robin
"Synthesis and evaluation of symmetrical biphenyltetrols as aggregation inhibitors for Alzheimer’s amyloid-β peptide,"
The Winthrop McNair Research Bulletin: Vol. 1, Article 15.
Available at: https://digitalcommons.winthrop.edu/wmrb/vol1/iss1/15