Event Title

Synthesis of Small Molecules for Inhibiting Aggregation of Alzheimer’s Amyloid-β Peptide

Poster Number

08

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

Rutledge

Start Date

21-4-2017 12:00 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 to enable binding to Aβ. We previously demonstrated that 3,3′,4,4′-biphenyltetrol (3,4-BPT) effectively abrogates Aβ aggregation at stoichiometric concentrations. To further investigate this molecular architecture and determine how the positioning of the hydroxyl hydrogen-bond donors impacts inhibitor efficacy, we also synthesized four additional symmetrical biphenyltetrols (2,3-, 2,4- 2,5- and 3,5-BPT). However, 2,2′,6,6′-tetramethoxybiphenyl, the intermediate for 2,6-BPT, eluded synthesis using our standard Suzuki-coupling chemistry, presumably due to significant steric hindrance in the coupling partners. This limitation was overcome by employing a catalyst comprised of Pd2(dba)3 and the bulky phosphine ligand 2-diphenylphosphino-2′-(N,N-dimethylamino)biphenyl; 2,2′,6,6′-tetramethoxybiphenyl was thus obtained in 60% yield. Demethylation with BBr3 afforded a 72% yield of the desired 2,6-BPT. To expand our investigation into the inhibitory efficacy of biaryls containing multiple hydroxy groups, 4-(3-pyridyl)catechol was synthesized via a Suzuki coupling/demethylation protocol. 3-(3,4-Dimethoxyphenyl)pyridine was synthesized in 76% yield from 3-pyridylboronic acid and 4-bromoveratrole using PdCl2(dppf) as the catalyst; demethylation with BBr3 produced the desired 4-(3-pyridyl)catechol.

Previously Presented/Performed?

68th Southeastern Regional Meeting of the American Chemical Society (SERMACS), Columbia, South Carolina, October 2016

Grant Support?

Support provided by a grant from the National Institutes of Health IDeA Networks for Biomedical Excellence (NIH-INBRE)

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Apr 21st, 12:00 PM

Synthesis of Small Molecules for Inhibiting Aggregation of Alzheimer’s Amyloid-β Peptide

Rutledge

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 to enable binding to Aβ. We previously demonstrated that 3,3′,4,4′-biphenyltetrol (3,4-BPT) effectively abrogates Aβ aggregation at stoichiometric concentrations. To further investigate this molecular architecture and determine how the positioning of the hydroxyl hydrogen-bond donors impacts inhibitor efficacy, we also synthesized four additional symmetrical biphenyltetrols (2,3-, 2,4- 2,5- and 3,5-BPT). However, 2,2′,6,6′-tetramethoxybiphenyl, the intermediate for 2,6-BPT, eluded synthesis using our standard Suzuki-coupling chemistry, presumably due to significant steric hindrance in the coupling partners. This limitation was overcome by employing a catalyst comprised of Pd2(dba)3 and the bulky phosphine ligand 2-diphenylphosphino-2′-(N,N-dimethylamino)biphenyl; 2,2′,6,6′-tetramethoxybiphenyl was thus obtained in 60% yield. Demethylation with BBr3 afforded a 72% yield of the desired 2,6-BPT. To expand our investigation into the inhibitory efficacy of biaryls containing multiple hydroxy groups, 4-(3-pyridyl)catechol was synthesized via a Suzuki coupling/demethylation protocol. 3-(3,4-Dimethoxyphenyl)pyridine was synthesized in 76% yield from 3-pyridylboronic acid and 4-bromoveratrole using PdCl2(dppf) as the catalyst; demethylation with BBr3 produced the desired 4-(3-pyridyl)catechol.