Synthesis of Small Molecules for Inhibiting Aggregation of Alzheimer’s Amyloid-β Peptide
Poster Number
08
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 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)
Start Date
21-4-2017 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.
