How 3-O-Glucosylation Modulates Resveratrol Radical Scavenging: A QM-ORSA Study of Polydatin/Piceid, a Stilbenoid Glucoside.

The antioxidant properties of polydatin/piceid (3-O-β-D-glucopyranosyl-resveratrol), a stilbenoid polyphenol widely found in Vitaceae, Liliaceae, and Leguminosae plants and used in traditional medicine, have been investigated against the •OOH radical by means of a density functional theory-based QM-ORSA protocol. The central mechanistic question addressed is how 3-O-glucosylation modulates the primary antiradical activity. To provide a biologically meaningful answer, its mechanisms of action were studied in both aqueous solution at physiological pH and in a lipid-like environment. Conformational analysis performed at the outset confirmed that the trans isomer is preferred over the cis form by 4.9 kcal·mol-1, and species distribution calculations show that the neutral form dominates at pH 7.4 (98.6%). The para-hydroxyl of ring B emerges as the dominant contributor to anti-•OOH activity regardless of the milieu; however, the activity trends show that while polydatin reacts faster than Trolox in the modeled lipid-like phase (9.78 × 103 vs. 3.40 × 103 M-1·s-1), in water its apparent rate constant (4.12 × 104 M-1·s-1) falls below both trans-resveratrol (1.42 × 105 M-1·s-1) and Trolox (8.96 × 104 M-1·s-1).