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_2AAR), and chalcone 2 displayed the best binding affinity to A_2AAR, with the IC₅₀ value of 33.5 nM, good A_2AAR selectivity against A₁AR, A_2BAR, and A₃AR, 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_2AAR was elucidated by molecular docking. This work highlighted that the active Chalcones in red onion might have the potential to be developed as A_2AAR antagonists used in Cancer Immunotherapy.

A2A adenosine receptor; Allium cepa L.; T-cell activation; chalcone; immunomodulatory property.