Exploring Chalcogen Connection in Glutathione Trichalcogenides via ¹H-Detected ⁷⁷Se/¹²⁵Te NMR

Le résumé fourni par la source

Trichalcogenides with linearly catenated chalcogen atoms (S, Se, and Te), exemplified by glutathione trisulfide, are increasingly recognized as key regulators of biological redox processes. However, their robust structural characterization remains limited because the NMR-active sulfur isotope (³³S, I = 3/2) is low-abundance and quadrupolar. The examination of chalcogen connection in heterologous trichalcogenides remains highly challenging. Recent studies have examined ⁷⁷Se and ¹²⁵Te as replacements for sulfur and applied ⁷⁷Se/¹²⁵Te NMR in biomolecules. In this study, we report the in situ synthesis of heterologous trichalcogenides of glutathione disulfide (GS-SG) by inserting a single chalcogen atom into a disulfide bond using chalcogen donors in a conventional NMR tube. The NMR-active isotopes ⁷⁷Se and ¹²⁵Te (I = 1/2) provide broad chemical-shift ranges and high sensitivity to structural and dynamic changes, enabling multinuclear NMR. ¹H DOSY and quantitative ¹H NMR confirm a single major species (>95% by NMR) and ¹H-detected ⁷⁷Se/¹²⁵Te heteronuclear multiple-bond correlation experiments demonstrate long-range coherence transfers. Heavy chalcogen insertion causes greater structural perturbation, making Se more suitable than Te. Density functional theory calculation revealed a smaller highest occupied molecular orbital–lowest unoccupied molecular orbital gap for GS-Te-SG, indicating its lower thermodynamic stability than GS-Se-SG. Consistent results were observed in the cystine-based experiments. To the best of our knowledge, for the first time, this study demonstrated that Se or Te can be inserted into the central site of disulfide bonding. In the biological assays, glutathione derivatives incorporating heavier chalcogens exhibit antiradical activities. This in situ synthetic and analytical framework expands the chemical space of biologically relevant chalcogenides.

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