Palmitoyl-Epigallocatechin Gallate Modulates COX-2-Based Production of Inflammation-Related Oxylipins: Synthesis, Characterization, and Bioevaluation In Vitro and In Silico

Lipophenols are esterifications of (poly)-phenols with fatty acids, recently demonstrated to exhibit enhanced bioactivities compared to native phenolics. Among them, catechin lipophenols have been noted as powerful antioxidants present in natural products (e.g., tea leaves), although they remain underexplored. Hence, to analyze the biological advantages of catechin lipophenols, in the form of palmitoyl-epigallocatechin gallate (PEGCG), its de novo synthesis by organic chemistry procedures was implemented. The synthesis product was characterized by LC-MS and NMR. The anti-inflammatory potential was assessed in silico (molecular docking) and in vitro to unravel the PEGCG capacity to prevent inflammation and oxidative stress compared to epigallocatechin gallate (EGCG), shedding light on the biological advantages provided by the lipophilic traits conferred by the fatty acid moiety. PEGCG showed higher ability to inhibit, in vitro, the expression of cyclooxygenase-2 (COX-2) to a greater extent than EGCG (97.03 vs 116.34 ng/mL, respectively). This was further confirmed by retrieving results evidencing lower concentrations of related oxylipins (PGF2α, PGE2, and 8-iso-PGF2α). Interestingly, despite the results concerning the modulation of the COX-2 expression and the higher PEGCG binding affinity against human COX-2 relative to EGCG, as retrieved from the in silico docking assessments, additional verification of EGCG and PEGCG to modulate COX-2 enzymatic activity did not provide conclusive results about their inhibitory capacity, which would require further exploration. These results demonstrate the anti-inflammatory and oxidative stress prevention properties of PEGCG by reducing the COX-2 expression and, beyond the new scientific knowledge provided, obtaining a PEGCG standard will allow an advancement toward identifying new natural sources of lipophenols and their multipurpose applicability as an amphiphilic molecule for functional coproducts.