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[Display omitted] • Novel GNA derivatives were synthesized and screened for their antitumor activities. • Introduction of sulfoximines increased the antitumor activity of GNA derivatives. • 12 k with CF 3 group displayed the most pronounced anti-cancer efficacy. • 12 k triggered pyroptosis in cancer cells via the caspase-3/GSDME pathway. Gambogenic acid (GNA), a caged xanthone derived from Garcinia hanburyi , exhibits a wide range of anti-cancer properties. The caged skeleton of GNA serves as the fundamental pharmacophore responsible for its antitumor effects. However, limited exploration has focused on the structural modifications of GNA. This study endeavors to diversify the structure of GNA and enhance its anti-cancer efficacy. Sulfoximines, recognized as pivotal motifs in medicinal chemistry due to their outstanding properties, have featured in several anti-cancer drugs undergoing clinical trials. Accordingly, a series of 33 GNA derivatives combined with sulfoximines were synthesized and evaluated for their anti-cancer effects against MIAPaCa2, MDA-MB-231, and A549 cells in vitro. The activity screening led to the identification of compound 12 k , which exhibited the most potent anti-cancer effect. Mechanistic studies revealed that 12 k primarily induced pyroptosis in MIAPaCa2 and MDA-MB-231 cells by activating the caspase-3/gasdermin E (GSDME) pathway. These findings suggested that 12 k is a promising drug candidate in cancer therapy and highlighted the potential of sulfoximines as a valuable functional group in drug discovery. [ABSTRACT FROM AUTHOR]