Free Phenolic Hydroxyl Groups Govern the Anticancer Activity of α‐Mangostin: A Structure–Activity Relationship Insight

The α‐mangostin ( MGT ) is a natural xanthone obtained from the pericarp of mangosteen fruit ( Garcinia mangostana Linn.), possessing a widely reported biological activity, including anticancer, anti‐inflammatory, antibacterial, and antiviral properties. However, the impact of its free phenolic hydroxyl groups on achieving biological activity has not yet been evaluated. In this context, the present work isolated and characterized MGT from mangosteen and obtained the semisynthetic acetylated mangostin ( AcMGT ) to evaluate its drug‐likeness, interaction profile with the serine/threonine‐protein kinase AKT (isoform AKT1), and anticancer profile using in silico and in vitro approaches. The semisynthetic compound AcMGT is stable for up to 48 h under mimetic biological conditions; however, the acetylation decreased the anticancer profile of MGT in murine colon cancer, murine triple negative breast cancer, and human osteosarcoma cancer (CT26, 4T1, and U2OS, respectively), for example, from 7.55 ± 0.10 to 29.90 ± 1.20 µM in 4T1, which might be expected due to the decrease in the interactive profile with AKT1. The fluorescence microscopy indicated that acetylation reduced MGT 's capacity to induce vacuolization in 4T1 cells, and the drug‐likeness prediction for AcMGT decreased markedly compared with the natural product, highlighting the importance of free phenolic hydroxyl groups in MGT for achieving the expected anticancer profile.