Bioinspired Selenium‐Nitrogen Exchange (SeNEx) Click Chemistry Suitable for Nanomole‐Scale Medicinal Chemistry and Bioconjugation

• Published in: Angewandte Chemie International Edition 2024-04, Vol.63 (15), p.e202318534-n/a
• Main Authors: Hou, Wei, Zhang, Yiyuan, Huang, Fuchao, Chen, Wanting, Gu, Yuang, Wang, Yan, Pang, Jiacheng, Dong, Hewei, Pan, Kangyin, Zhang, Shuning, Ma, Peixiang, Xu, Hongtao
• Format: Article
• Language: English
• Subjects: Alkynes; Alkynes - chemistry; Azides - chemistry; bioconjugation; Chemical reactions; Chemical synthesis; Chemistry; Chemistry, Pharmaceutical - methods; click chemistry; Click Chemistry - methods; Cycloaddition; Cycloaddition Reaction; Exchanging; Functional groups; Libraries; Medical materials; nanomole-scale parallel synthesis; Natural products; Nitrogen; Proteins - chemistry; Ruthenium; Selenium; Selenium-Nitrogen Exchange (SeNEx); selenylation; Sulfur
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202318534

Click chemistry is a powerful molecular assembly strategy for rapid functional discovery. The development of click reactions with new connecting linkage is of great importance for expanding the click chemistry toolbox. We report the first selenium‐nitrogen exchange (SeNEx) click reaction between benzoselenazolones and terminal alkynes (Se−N to Se−C), which is inspired by the biochemical SeNEx between Ebselen and cysteine (Cys) residue (Se−N to Se−S). The formed selenoalkyne connection is readily elaborated, thus endowing this chemistry with multidimensional molecular diversity. Besides, this reaction is modular, predictable, and high‐yielding, features fast kinetics (k2≥14.43 M−1 s−1), excellent functional group compatibility, and works well at miniaturization (nanomole‐scale), opening up many interesting opportunities for organo‐Se synthesis and bioconjugation, as exemplified by sequential click chemistry (coupled with ruthenium‐catalyzed azide‐alkyne cycloaddition (RuAAC) and sulfur‐fluoride exchange (SuFEx)), selenomacrocycle synthesis, nanomole‐scale synthesis of Se‐containing natural product library and DNA‐encoded library (DEL), late‐stage peptide modification and ligation, and multiple functionalization of proteins. These results indicated that SeNEx is a useful strategy for new click chemistry developments, and the established SeNEx chemistry will serve as a transformative platform in multidisciplinary fields such as synthetic chemistry, material science, chemical biology, medical chemistry, and drug discovery. The concept of selenium‐nitrogen exchange (SeNEx) click chemistry is put forward based on the excellent performance of the reaction between benzoselenazolones and terminal alkynes. The reaction exhibits modularity, robustness, mild reaction conditions, and fast kinetics (k2≥14.43 M−1 s−1), and its broad applicability is demonstrated with examples of on‐plate nanomole‐scale parallel synthesis, DNA‐encoded library synthesis, and peptide and protein modification.