Evaluation of Heterocyclic Biaryls as Aggregation Inhibitors for Alzheimer\u27s Amyloid-β Peptide

Amyloid-β (Aβ) is a peptide of 39-43 amino acids that self-assembles into neurotoxic aggregates implicated in 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 demonstrated that biphenyltetrols (BPTs) exhibit varying degrees of efficacy as Aβ aggregation inhibitors. Of nine BPT isomers studied, 3,3′,4,4′-biphenyltetrol (3,4-BPT) is the most successful, effectively abrogating Aβ aggregation at stoichiometric concentrations (IC50 ~1X); other isomers are significantly less effective (IC50 ~2X to \u3e10X), perhaps due to decreased abilities to hydrogen-bond with Aβ. Recent literature suggests that π-π interactions (i.e., π-stacking) may also be implicated in inhibitor binding to Aβ, potentially involving Phe residues in the central region of the peptide. In addition, studies with model compounds have shown that benzene-pyridine and benzene-pyridinium interactions are successively stronger than that between two benzene rings. Based on these observations, we have synthesized a series of hydroxybiaryl architectures incorporating pyridine or pyridinium rings, hypothesizing that these moieties may confer greater efficacy as aggregation inhibitors due to improved binding to Aβ. IC50 values have been determined via the Congo red spectral shift assay. We find successive, measurable improvements in inhibitory efficacy when the phenyl ring of 4-phenylcatechol (IC50 ~5X) is replaced with a pyridine ring (IC50 ~4X) or an N-methylpyridinium (methylsulfate counterion; IC50 \u3c2X). A similar trend is observed between 5-(3,4-dihydroxyphenyl)-2-methoxypyridine (IC50 ~10X) and its N-methylated derivative (IC50 ~4X). Preliminarily, these results support our hypothesis and may suggest a role for π-stacking in inhibitor binding to Aβ