Redox-Mediated Amination of Pyrogallol-Based Polyphenols.

ABSTRACT

Flavonoids are known to covalently modify amyloidogenic peptides by amination reactions. The underlying coupling process between polyphenols and N-nucleophiles is assessed by several in vitro and in silico approaches. The coupling reaction involves a sequence of oxidative dearomatization, amination, and reductive amination (ODARA) reaction steps. The C6-regioselectivity of the product is confirmed by crystallographic analysis. Under aqueous conditions, the reaction of baicalein with lysine derivatives yields C-N coupling as well as hydrolysis products of transient imine intermediates. The observed C-N coupling reactions work best for flavonoids combining a pyrogallol substructure with an electron-withdrawing group attached to the C4a-position. Thermodynamic properties such as bond dissociation energies also highlight the key role of pyrogallol units for the antioxidant ability. Combining the computed electronic properties and in vitro antioxidant assays suggests that the studied pyrogallol-containing flavonoids act by various radical-scavenging mechanisms working in synergy. Multivariate analysis indicates that a small number of descriptors for transient intermediates of the ODARA process generates a model with excellent performance (r=0.93) for the prediction of cross-coupling yields. The same model has been employed to predict novel antioxidant flavonoid-based molecules as potential covalent inhibitors, opening a new avenue to the design of therapeutically relevant anti-amyloid compounds.