Arnaut Pierre, Pozsoni Nestor Bracho, Bondar Denys, Lippmann Petra, Boschuk Susanne, Semenyuta Ivan, Bhandary Subhrajyoti, Van Hecke Kristof, Karpichev Yevgen, Cavarzerani Enrico, Canzonieri Vincenzo, Rizzolio Flavio, Scattolin Thomas, Vougioukalakis Georgios C, Ott Ingo, Tzouras Nikolaos V, Nolan Steven P
Department of Chemistry and Centre for Sustainable Chemistry, Ghent University Ghent Belgium
Department of Chemistry and Biotechnology, Tallinn University of Technology, School of Science Tallinn Estonia.
Chem Sci. 2025 Aug 19. doi: 10.1039/d5sc04490a.
Two distinct synthetic pathways are disclosed that lead to new gold-selenolato complexes, stabilized by N-heterocyclic carbenes (NHCs). The weak base route can provide facile access to phenylselenolate complexes of gold, using both NHC and phopshine ligands. In addition, the pathway based on the carbometallation of elemental selenium enables the construction of a more diverse library of products, based on substituted aryl-selenide fragments whose selenol congeners are not commercially available. Biological studies performed on human cancer cell lines (A-549, H-T29, and MCF-7) and mammal healthy cell lines (Vero-E6) reveal that a selection of these complexes exhibit cytotoxic activity and are selective towards cancerous cells. experiments confirmed that our lead candidate is indeed a TrxR inhibitor. Finally, this complex showed strong cytotoxic activity even in advanced biological models, including patient-derived 3D tumor organoids. Noteworthily, it remained effective in both colon cancer and HGSOC organoids, even in patients resistant to standard chemotherapy agents.
公开了两条不同的合成途径，可生成由N-杂环卡宾（NHCs）稳定的新型金-硒醇盐配合物。弱碱途径可以使用NHC和膦配体轻松获得金的苯硒醇盐配合物。此外，基于元素硒的碳金属化途径能够构建更多样化的产物库，这些产物基于取代芳基硒化物片段，其硒醇类似物无法通过商业途径获得。对人类癌细胞系（A-549、H-T29和MCF-7）和哺乳动物健康细胞系（Vero-E6）进行的生物学研究表明，这些配合物中的一部分表现出细胞毒性活性，并且对癌细胞具有选择性。实验证实，我们的主要候选物确实是一种硫氧还蛋白还原酶（TrxR）抑制剂。最后，即使在包括患者来源的3D肿瘤类器官在内的先进生物学模型中，这种配合物也显示出强大的细胞毒性活性。值得注意的是，即使在对标准化疗药物耐药的患者中，它在结肠癌和高级别浆液性卵巢癌（HGSOC）类器官中均保持有效。
