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

Abstract 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).