Exploring the Immunomodulatory Properties of Red Onion ( Allium cepa L.) Skin: Isolation, Structural Elucidation, and Bioactivity Study of Novel Onion Chalcones Targeting the A 2A 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 IC 50 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 (IC 50 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.