Synthesis of Diarylpyridines as Aggregation Inhibitors for Alzheimer’s Amyloid-β Peptide
Poster Number
112
Session Title
Physical Sciences, Math, and Computer Science
College
College of Arts and Sciences
Department
Chemistry, Physics, Geology, & the Environment
Faculty Mentor
James M. Hanna Jr., Ph.D., and Robin K. Lammi, Ph.D.
Abstract
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. Previous studies have demonstrated that terphenyltetrols exhibit some degree of efficacy as Aβ aggregation inhibitors. For example, o-terphenyl-3,3″,4,4″-tetrol is a moderately effective inhibitor of Aβ aggregation (IC50 = 2.7±0.3X). Recent modeling studies suggest that binding of small molecules to Aβ may occur via several types of intermolecular interactions, including both hydrogen bonding and π-π interactions (i.e., π-stacking). In addition, other studies indicate that π-interactions between benzene and electron-deficient heterocyclic aromatic rings are stronger than similar benzene-benzene interactions. Based on these observations, it is hypothesized that incorporation of a pyridine unit as the central linker in the above-described tetrahydroxyteraryl scaffold may lead to increased inhibition of Aβ aggregation. Therefore, the present study set out to synthesize a series of bis(dihydroxyphenyl)pyridines via Suzuki coupling of 3,4-dimethoxybenzene-boronic acid with an appropriate dibromopyridine, followed by demethylation in refluxing aqueous HBr. In this poster, progress toward this goal and future plans for evaluation of these compounds will be discussed.
Previously Presented/Performed?
South Carolina Academy of Sciences Annual Meeting, Greenville, South Carolina, March 2020; Sixth Annual Showcase of Undergraduate Research and Creative Endeavors (SOURCE), Winthrop University, April 2020
Grant Support?
SC INBRE grant from the National Institute for General Medical Sciences (NIH-NIGMS)
Start Date
24-4-2020 12:00 AM
Synthesis of Diarylpyridines 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. Previous studies have demonstrated that terphenyltetrols exhibit some degree of efficacy as Aβ aggregation inhibitors. For example, o-terphenyl-3,3″,4,4″-tetrol is a moderately effective inhibitor of Aβ aggregation (IC50 = 2.7±0.3X). Recent modeling studies suggest that binding of small molecules to Aβ may occur via several types of intermolecular interactions, including both hydrogen bonding and π-π interactions (i.e., π-stacking). In addition, other studies indicate that π-interactions between benzene and electron-deficient heterocyclic aromatic rings are stronger than similar benzene-benzene interactions. Based on these observations, it is hypothesized that incorporation of a pyridine unit as the central linker in the above-described tetrahydroxyteraryl scaffold may lead to increased inhibition of Aβ aggregation. Therefore, the present study set out to synthesize a series of bis(dihydroxyphenyl)pyridines via Suzuki coupling of 3,4-dimethoxybenzene-boronic acid with an appropriate dibromopyridine, followed by demethylation in refluxing aqueous HBr. In this poster, progress toward this goal and future plans for evaluation of these compounds will be discussed.
