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

Abstract

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 alpha-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 alpha-D-tocopherol showed potent anti-proliferative activities in S-cells, with GI50 values of 0.203 mu M (SSNU638) and 0.156 mu M (SSK4), respectively, over 10-fold more potent than alpha-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 GI50 = 5.623 mu M) and 17 (GA265T GI50 = 6.347 mu M) 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 alpha-TOS (6; GA265T GI50 = 12.660 mu M). In vivo studies further demonstrated that compound markedly inhibited tumor growth in SSK4 xenograft models with miniaml systemic toxicity, outperforming the reference compound alpha-TOS. These results support that selective targeting of SDHC by alpha-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.