Abstract:
α-Mangostin is a natural oxygenated and prenylated xanthone, which is mainly isolated from the pericarps of Garcinia mangostana. It possesses numerous pharmacological properties and promising therapeutic effects. However, the limitations of α-mangostin such as highly hydrophobicity and poor bioavailability hider its therapeutic applications. To overcome these drawbacks of α-mangostin, chemical modifications have been performed to discover the improved analogs. Herein, two semi-synthetic approaches to obtain new α-mangostin derivatives were investigated by the modifications of the phenolic hydroxy groups at C-3 and C-6 positions involving Smiles rearrangement to install amine functional groups and the addition reaction of isocyanate to form the carbamate motif, which have never been reported. In this study, semi-syntheses of α-mangostin derivatives were focused on the reaction optimizations by controlling solvent, base, catalyst, and reaction time. In addition, the physicochemical property prediction was performed by in silico modeling using SwissADME. Based on ESOL model, compounds 4a and 4c having nitrogen bound to C-3 and C-6 positions potentially improved water solubility better than α-mangostin showing moderate solubility, respectively. Furthermore, the cytotoxicity was evaluated against H460 and H292 human non-small lung cancer cell lines along with nuclear staining assay. The results suggested that compound 5b exhibited the most potent cytotoxicity among all derivatives in this study, displaying 3-fold (IC50 11.52±1.32 µM) more potent than α-mangostin (IC50 38.04 ± 2.44 µM) against H460 cell lines. Although, the carbamate derivatives of α-mangostin 5a-e were unstable and prone to decompose by hydrolysis from either water or the free hydroxyl group in its structure. In summary, new chemical modifications of α-mangostin were developed to transform phenolic hydroxy groups at C-3 and C-6 positions to the nitrogen-containing functionalities such as amine, amide, and carbamate.
