Synthesis and biological evaluation of α-D-tocopherol derivatives as anticancer agents targeting mitochondrial metabolism.

Cancer, driven by mitochondrial and nuclear DNA mutations, presents opportunities for targeted therapies. Gastric cancer (GC), the 4th leading cause of cancer-related deaths, has poor prognosis due to cancer stem cells (CSCs), which depend on mitochondrial complex II (CII) respiration. Among CSC-enriched subtypes, the aggressive stem-like/EMT/Mesenchymal (SEM) GC subtype exhibits high plasticity, chemotherapy resistance, and metabolic adaptations that promote tumor survival. This study explores α-d-tocopherol derivatives targeting GC cells with enriched cancer stemness (S-cells) by inhibiting succinate dehydrogenase (SDH), also known as the CII complex. Malonate (10) and primary amide (17) derivatives of α-D-tocopherol showed potent anti-proliferative activities in S-cells, with GI values of 0.203 μM (SSNU638) and 0.156 μM (SSK4), respectively, over 10-fold more potent than α-TOS (6). Mechanistic studies showed that both 10 and 17 inhibit SDHC activity, reduce CII-specific oxygen consumption rates (OCR), and induce increased ROS production, leading to apoptosis. Furthermore, in patient-derived organoid (PDO) models, derivative 10 (GA265T GI = 5.623 μM) and 17 (GA265T GI = 6.347 μM) exhibited enhanced anti-proliferative activity in SEM-type GC PDOs (SDHC-high) compared to non-SEM-type PDOs (SDHC-low), with over a 2-fold increase in anti-proliferative activity against the GA265T SEM-type PDO model compared to α-TOS (6; GA265T GI = 12.660 μM). In vivo studies further demonstrated that compound markedly inhibited tumor growth in SSK4 xenograft models with miniaml systemic toxicity, outperforming the reference compound α-TOS. These results support that selective targeting of SDHC by α-TOS derivatives 10 and 17 disrupts mitochondrial complex II function and redox homeostasis, thereby inducing apoptosis in SEM-type gastric cancer both in vitro and in vivo.