Design, synthesis, and antiproliferative activity evaluation of novel α-mangostin derivatives by ROS/MAPK signaling pathway.

Novel hydroxamic acid and 3,6-amide modified α-mangostin derivatives were synthesized and evaluated their antiproliferative activities against KYSE 30 (esophageal cancer), HCT 116 (colon cancer), and HGC 27 (gastric cancer) cell lines. Most of the new derivatives displayed stronger anti-proliferative activities compared to α-mangostin. Among all the derivatives, compound 4a exhibited the most potent activity, with IC₅₀ values of 0.57 ± 0.29 μM, 3.27 ± 0.16 μM, and 2.28 ± 1.02 μM against KYSE 30, HCT 116, and HGC 27 cells, respectively. Subsequent mechanism studies revealed that compound 4a inhibited cancer cells proliferation and colonies formation in a concentration-dependent manner. Additionally, compound 4a caused cell cycle arrest in a p53 dependent manner and induced apoptosis in p53 independent way. Meanwhile, 4a suppressed cell cycle related proteins (Cyclin D1 and cyclin B1) expression, increased pro-apoptotic proteins (cleaved PARP, cleaved caspase-7, and cleaved caspase-9) and decreased anti-apoptotic proteins (Bcl-2) expression. Moreover, 4a increased reactive oxygen species (ROS) levels in KYSE 30 cells and upregulated the expression of proteins related to the ROS related MAPK signaling pathway (p-ERK, p-p38, and p-JNK). These findings suggest that compound 4a holds promising potential as an antiproliferative agent by targeting MAPK signaling pathway to inhibit cell cycle progress, induce apoptosis and produce ROS in cancers.