Synthesis and Evaluation of (Dihydroxyphenyl)pyridones as Aggregation Inhibitors for Alzheimer’s Amyloid-β Peptide
Poster Number
007
College
College of Arts and Sciences
Department
Chemistry, Physics, Geology, & the Environment
Faculty Mentor
Robin K. Lammi, Ph.D., and James M. Hanna Jr., 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 in our group have demonstrated that biphenyltetrols exhibit varying degrees of efficacy as Aβ aggregation inhibitors. 3,3′,4,4′-biphenyltetrol (3,4-BPT) effectively abrogates Aβ aggregation at stoichiometric concentrations (IC50 ~ 1X); other biphenyltetrol isomers were found to be less effective (IC50 ~ 2X to >10X), perhaps due to differing abilities to bind to Aβ through hydrogen bonding. 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, we hypothesized that incorporation of a pyridone unit into the above-described hydroxybiaryl scaffold may lead to increased inhibition of Aβ aggregation. We therefore synthesized 5-(3′,4′-dihydroxyphenyl)-2-pyridone (1) and 4-(3′,4′-dihydroxyphenyl)-2-pyridone (2) via Suzuki coupling of 3,4-dimethoxybenzeneboronic acid with an appropriate bromomethoxypyridine, followed by demethylation in aqueous HBr. Evaluation of these compounds using a Congo red spectral shift assay gave preliminary IC50 values of 3.3 ± 0.3X for 1 and 2.9 ± 0.5X for 2.
Previously Presented/Performed?
Southeast Regional Meeting of the American Chemical Society (SERMACS), Augusta, Georgia, November, 2018
Grant Support?
Supported by an SC INBRE grant from the National Institute for General Medical Sciences (NIH-NIGMS)
Start Date
12-4-2019 12:00 PM
End Date
April 2019
Synthesis and Evaluation of (Dihydroxyphenyl)pyridones as Aggregation Inhibitors for Alzheimer’s Amyloid-β Peptide
Rutledge Building
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 in our group have demonstrated that biphenyltetrols exhibit varying degrees of efficacy as Aβ aggregation inhibitors. 3,3′,4,4′-biphenyltetrol (3,4-BPT) effectively abrogates Aβ aggregation at stoichiometric concentrations (IC50 ~ 1X); other biphenyltetrol isomers were found to be less effective (IC50 ~ 2X to >10X), perhaps due to differing abilities to bind to Aβ through hydrogen bonding. 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, we hypothesized that incorporation of a pyridone unit into the above-described hydroxybiaryl scaffold may lead to increased inhibition of Aβ aggregation. We therefore synthesized 5-(3′,4′-dihydroxyphenyl)-2-pyridone (1) and 4-(3′,4′-dihydroxyphenyl)-2-pyridone (2) via Suzuki coupling of 3,4-dimethoxybenzeneboronic acid with an appropriate bromomethoxypyridine, followed by demethylation in aqueous HBr. Evaluation of these compounds using a Congo red spectral shift assay gave preliminary IC50 values of 3.3 ± 0.3X for 1 and 2.9 ± 0.5X for 2.
