Event Title

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

Poster Number

056

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

Richardson Ballroom (DIGS)

Start Date

20-4-2018 2:15 PM

End Date

20-4-2018 4:15 PM

Description

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 >10X), 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 <2X). 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.

Previously Presented/Performed?

Fourth Annual Showcase of Undergraduate Research and Creative Endeavors (SOURCE), Winthrop University, April 2018

Grant Support?

Supported by an SC INBRE grant from the National Institute of General Medical Sciences (NIH-NIGMS)

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Apr 20th, 2:15 PM Apr 20th, 4:15 PM

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

Richardson Ballroom (DIGS)

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 >10X), 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 <2X). 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.