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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]

[Display omitted] • Total synthesis and structural elucidation of several PPAPs were achieved. • The biogenetic pathway of garcinol and its analogues was proposed. • The cytotoxicity was evaluated and the SARs were summarized. • The mechanism to induce apoptosis in BxPC3 cells was investigated. • Garcinol was found to induce pyroptosis and apoptosis simultaneously. Garcinol is a polyisoprenylated benzophenone isolated from Garcinia. It has been reported to have a variety of intriguing biological effects, including anticancer, anti-inflammatory, and antioxidant capabilities. The purpose of this research is to thoroughly evaluate garcinol and a series of its analogues in terms of synthesis, structural diversity, biosynthesis, and potential for preventing carcinoma cell proliferation. Garcinopicrobenzophenone and eugeniaphenone, which contain a unique cyclobutyl unit at C-5, were initially synthesized using the procedures utilized in the synthesis of garcinol. All the natural analogs of garcinol were produced at completion of the synthesis, and their structures and absolute configurations were clarified. Based on the synthesis, a possible biogenetic synthesis pathway towards cambogin, 13,14-didehydroxyisogarcinol via O -cyclization, and garcinopicrobenzophenone or eugeniaphenone via C -cyclization was proposed. The cytotoxicity of polyisoprenylated benzophenones produced in our group was tested, and the structure–activity relationship was summarized. The mechanism by which garcinol, cambogin, and 21′ induce apoptosis was studied. Cambogin and 21′ were shown to have a greater capacity to cause apoptosis in pancreatic cancer BXPC3 cells, and the suppression of BXPC3 cells by 21′ might be attributed to the target of STAT3 signaling. Garcinol could cause pyroptosis and apoptosis in pancreatic cancer cells at the same time, which was the first time that garcinol was identified as a possible chemotherapeutic agent that could significantly promote pyroptosis in cancer cells. [ABSTRACT FROM AUTHOR]