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

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).