Redox-Mediated Amination of Pyrogallol-Based Polyphenols.

Area of Science:

• Medicinal Chemistry
• Organic Chemistry
• Biochemistry

Background:

• Flavonoids are natural compounds with potential therapeutic applications.
• Amyloidogenic peptides are implicated in neurodegenerative diseases.
• Covalent modification of peptides by flavonoids is a known phenomenon.

Purpose of the Study:

• To elucidate the mechanism of flavonoid-polyphenol coupling with N-nucleophiles.
• To identify structural determinants for efficient flavonoid cross-coupling and antioxidant activity.
• To develop a predictive model for designing novel flavonoid-based anti-amyloid compounds.

Main Methods:

• In vitro and in silico studies to assess the coupling process.
• Crystallographic analysis to confirm regioselectivity.
• Thermodynamic property calculations (bond dissociation energies).
• Multivariate analysis for predictive modeling.

Main Results:

• The coupling reaction proceeds via oxidative dearomatization, amination, and reductive amination (ODARA).
• Flavonoids with a pyrogallol substructure and an electron-withdrawing group at C4a show optimal C-N coupling.
• Pyrogallol units are crucial for antioxidant activity through synergistic radical-scavenging mechanisms.
• A predictive model achieved high accuracy (r=0.93) for cross-coupling yields.

Conclusions:

• The ODARA mechanism explains flavonoid-peptide covalent modification.
• Structural features of flavonoids significantly influence their reactivity and antioxidant capacity.
• The developed predictive model facilitates the rational design of novel flavonoid-based covalent inhibitors for anti-amyloid therapies.