Exploring the Immunomodulatory Properties of Red Onion (Allium cepa L.) Skin: Isolation, Structural Elucidation, and Bioactivity Study of Novel Onion Chalcones Targeting the A2A Adenosine Receptor

Onions are versatile and nutritious food widely used in various cuisines around the world. In our ongoing pursuit of bioactive substances with health benefits from red onion (Allium cepa L.) skin, a comprehensive chemical investigation was undertaken. Consequently, a total of 44 compounds, including three previously unidentified chalcones (1-3) were extracted from red onion skin. Of these isolates, chalcones 1-4 showed high affinity to A(2A) adenosine receptor (A(2A)AR), and chalcone 2 displayed the best binding affinity to A(2A)AR, with the IC50 value of 33.5 nM, good A(2A)AR selectivity against A(1)AR, A(2B)AR, and A(3)AR, and high potency in the cAMP functional assay (IC50 of 913.9 nM). Importantly, the IL-2 bioassay and the cell-mediated cytotoxicity assay demonstrated that chalcone 2 could boost T-cell activation. Furthermore, the binding mechanism of chalcone 2 with hA(2A)AR was elucidated by molecular docking. This work highlighted that the active chalcones in red onion might have the potential to be developed as A(2A)AR antagonists used in cancer immunotherapy.