Shikonin is a natural naphthoquinone with anticancer activity; however, its therapeutic potential is limited by modest potency and suboptimal drug-like properties. To address these limitations, we designed and synthesized 31 shikonin derivatives through a medicinal chemistry hybridization strategy that retained the redox-active naphthoquinone core while introducing privileged structural motifs frequently associated with enhanced biomolecular interactions and cellular activity. Structure–activity relationship analysis identified compound 3k as a lead, exhibiting approximately 10-fold greater antiproliferative potency than shikonin, with preferential sensitivity observed in gastric cancer cell lines relative to other tested cancer types and normal gastric epithelial cells. The anticancer activity of 3k was further validated in a gastric cancer xenograft model in vivo. Proteomic profiling and mechanistic studies revealed activation of the integrated stress response (ISR) and reactive oxygen species (ROS) pathways, which were also enriched in gastric cancer data sets, leading to the induction of both apoptosis and ferroptosis. Collectively, these findings establish a structure-dependent optimization of shikonin-derived naphthoquinones and identify 3k as a promising lead compound for further development of redox-active anticancer agents.
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