Glycosylation and ESIPT synergistically regulate the antioxidant activity of flavonoids

Flavonoids with photoluminescence were widely recognized as naturally occurring polyphenolic compounds, celebrated for their potent antioxidant properties. The antioxidant efficacy of these flavonoids can be precisely tuned by structural modification, a finding with profound implications for biomedicine, particularly in cancer diagnosis and anticancer drug development. However, despite their promising prospects, the clinical translation of flavonoids is hampered by their suboptimal aqueous solubility, low gastrointestinal bioavailability, rapid systemic clearance, and limited targeted delivery capabilities. Fortunately, glycosylation offers a promising strategy to ameliorate these constraints, thereby potentiating their pharmacodynamic activity. In the present investigation, density functional theory (DFT) and time-dependent DFT (TD-DFT) were utilized. A comprehensive evaluation of the antioxidant properties was conducted for baicalein exhibiting excited-state intramolecular proton transfer (ESIPT) with a non-existent enol^⁎ state fluorescence and 6,7,4'-trihydroxyisoflavone without ESIPT characteristics, both in aqueous solution. Research indicates that the antioxidant activity of flavonoids is significantly enhanced in their excited states. Attributed to their ESIPT properties, baicalein and its derivatives exhibit superior antioxidant performance in their keto* state. Additionally, glycosylation was found to contribute to the further enhancement of the flavonoid's antioxidant activity. These findings underscore the pivotal role of ESIPT and glycosylation in the design of high-efficacy flavonoid-based antioxidants.