Event Title

Synthesis and Evaluation of Heterocyclic Biaryls as Aggregation Inhibitors for Alzheimer’s Amyloid-β Peptide

Poster Number

055

Faculty Mentor

James M. Hanna Jr., Ph.D., and Robin K. Lammi, 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

19-4-2018 4:15 PM

Description

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 differences in ability 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 pyridine-benzene and pyridinium-benzene π-interactions are stronger than similar benzene-benzene interactions. Based on these observations, we hypothesized that incorporation of pyridine and/or pyridinium moieties into the above-described hydroxybiaryl scaffold may lead to increased inhibition of Aβ aggregation. Therefore, a series of dihydroxyphenylpyridines and pyridones were synthesized for evaluation via a Suzuki coupling/demethylation protocol. An appropriate bromopyridine was coupled with 3,4-dimethoxyphenylboronic acid; excellent yields of intermediates were obtained. Demethylation with BBr3 or 48% aqueous HBr gave the final products. N-methylation with dimethyl sulfate gave the corresponding cationic pyridinium substrates. Preliminary evaluation results indicate that molecules expected to exhibit stronger π-π interactions with Phe residues of Aβ do indeed exhibit greater inhibitory activity.

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)

Course Assignment

CHEM 551, 552H – Hanna)

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Apr 20th, 2:15 PM Apr 19th, 4:15 PM

Synthesis and Evaluation of Heterocyclic Biaryls as Aggregation Inhibitors for Alzheimer’s Amyloid-β Peptide

Richardson Ballroom (DIGS)

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 differences in ability 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 pyridine-benzene and pyridinium-benzene π-interactions are stronger than similar benzene-benzene interactions. Based on these observations, we hypothesized that incorporation of pyridine and/or pyridinium moieties into the above-described hydroxybiaryl scaffold may lead to increased inhibition of Aβ aggregation. Therefore, a series of dihydroxyphenylpyridines and pyridones were synthesized for evaluation via a Suzuki coupling/demethylation protocol. An appropriate bromopyridine was coupled with 3,4-dimethoxyphenylboronic acid; excellent yields of intermediates were obtained. Demethylation with BBr3 or 48% aqueous HBr gave the final products. N-methylation with dimethyl sulfate gave the corresponding cationic pyridinium substrates. Preliminary evaluation results indicate that molecules expected to exhibit stronger π-π interactions with Phe residues of Aβ do indeed exhibit greater inhibitory activity.