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

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

  • Eur J Med Chem. 2025 Dec 5:299:118081. doi: 10.1016/j.ejmech.2025.118081.
Younghoon Kim 1,  Jungmin Kim 2,  Kyubin Hwang 3,  Ki Cheong Park 4,  Jae-Ho Cheong 5,  Taebo Sim 6
Affiliations

Affiliations

  • 1 Department of Biomedical Sciences, Graduate School of Medical Science, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
  • 2 Department of Biomedical Sciences, Graduate School of Medical Science, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea; Department of Medical Science, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea; Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea; Chronic Intractable Disease for Systems Medicine Research Center, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
  • 3 Department of Biomedical Sciences, Graduate School of Medical Science, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea; Department of Medical Science, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
  • 4 Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
  • 5 Department of Biomedical Sciences, Graduate School of Medical Science, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea; Department of Medical Science, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea; Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea; Chronic Intractable Disease for Systems Medicine Research Center, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: JHCHEONG@yuhs.ac.
  • 6 Department of Biomedical Sciences, Graduate School of Medical Science, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea; Graduate School of Clinical Drug Discovery & Development, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea; Clinical Candidate Discovery & Development Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea; Department of Medical Science, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. Electronic address: TBSIM@yuhs.ac.
PMID: 40882437 DOI: 10.1016/j.ejmech.2025.118081
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 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 GI50 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 GI50 = 5.623 μM) and 17 (GA265T GI50 = 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 GI50 = 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.

Keywords

Cancer stemness; Complex II; Gastric cancer (GC); Mitochondrial metabolism; Molecular targeted therapy; SEM-Type GC; Succinate dehydrogenase (SDH) inhibitor.

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