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• Selenium (Se), an essential micronutrient among the 15 vital elements required for human physiology, exerts its biological functions primarily through its incorporation into selenoproteins. To date, approximately 25 selenoproteins have been characterized in mammalian systems, including glutathione peroxidase (GPX), thioredoxin reductase (TrxR), and iodothyronine deiodinases (DIOs), all of which exhibit indispensable physiological functions. These selenocysteine-containing proteins play critical roles in redox homeostasis, antioxidant defense, and thyroid hormone regulation. For instance, selenocysteine (Sec), the catalytic center of GPX, serves as a critical component of this enzyme, which plays a fundamental role in modulating immune responses, maintaining redox homeostasis, and facilitating detoxification processes. Selenoproteins mediate critical biological processes through their enzymatic functions, including cellular differentiation, growth regulation, and metabolic homeostasis via redox signaling and thyroid hormone metabolism. Emerging evidences from clinical studies have indicated that selenium deficiency can disrupt the function of major organs, increasing the risk of tumorigenesis, liver disease, cardiovascular disease or other serious health conditions [1].

  Considering the crucial role of selenium in human physiology, significant research efforts have focused on developing selenium-containing compounds for disease prevention and therapeutic applications. Notably, the synthesis of selenium-containing heterocycles, including selenoisoquinoline derivatives has emerged as a promising strategy in anticancer drug development due to their enhanced biological activity and therapeutic potential. A growing number of researchers are focusing on the synthesis of selenium-optimized compounds with demonstrated antitumor efficacy. However, the preparation of these organoselenium compounds, particularly selenoisoquinoline derivatives often necessitates multistep synthetic routes under harsh conditions, including the use of chemical oxidants, transition metal catalysts, or specialized treatments, typically requiring elevated temperatures and prolonged reaction times. Given the environmental concerns and practical limitations of conventional synthetic methods, developing green and efficient approaches for antitumor organoselenium compound synthesis has become imperative. Electrochemical synthesis offers distinct advantages, including mild reaction conditions, a high atom utilization efficiency, and environmental friendliness [2]. Accordingly, it holds vast application potential in the field of drug research and development. The research group of Zhixiong Ruan at Guangzhou Medical University has conducted continuous researches in electrochemical synthetic methodology for drug discovery [3,4].

  Recently, Prof. Zhixiong Ruan’s group has developed an efficient electrochemical approach for the synthesis of selenoheterocyclic compounds for cancer therapy applications (Scheme 1) [5]. These selenoheterocyclic compounds were synthesized under mild conditions without oxidant and catalyst. Based on the mechanistic study, the electrochemical selenoheterocyclic products were formed through seleniumcationic intermediates. Among these synthetic selenoheterocyclic compounds, compounds 4o, 5n and 5o demonstrated promising antitumor effects. These compounds suppressed lung cancer progression by inhibiting the proliferation, migration and invasion of lung cancer cells, suppressing epithelial-mesenchymal transition and inducing cell apoptosis and DNA damage. In addition, compound 5o inhibited tumor growth and metastasis in vivo with a favorable safety profile. What is more, compound 5o was reported to be the first small molecular inhibitor of DEAD-box helicase 10 (DDX10). The marketed selenium-containing drugs such as Sodium Selenite Tablets and Selenious Yeast Capsules are used to treat diseases caused by selenium deficiency, such as Keshan disease, but the anti-tumor efficacy remains uncclear. The clinical candidate drugs for tumor treatment such as methylseleninic acid and selenomethionine are currently undergoing clinical trials. This groundbreaking study not only establishes an efficient synthetic strategy for selenoheterocyclic compounds but also identifies both a promising lead compound and a potential therapeutic target, thereby providing new avenues for antitumor drug development and expanding treatment options for lung cancer.

  Scheme 1

  

  Scheme 1.  Electrochemical synthesis of selenoheterocyclic compounds and the antitumor study.

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  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  CRediT authorship contribution statement

  Zhi-Lin Wu: Writing – original draft. Rong-Nan Yi: Writing – review & editing. Chunlin Zhuang: Supervision.

  Acknowledgment

  Financial support from the Science and Technology Innovation Program of Hunan Province (No. 2022RC4044).

  
  
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     W. Xu, C. Zheng, M. Chen, et al., J. Med. Chem. 68 (2025) 6339–6360. doi: 10.1021/acs.jmedchem.4c02724

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  Scheme 1  Electrochemical synthesis of selenoheterocyclic compounds and the antitumor study.

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