Unexpected Cyclization Product Discovery from the Photoinduced Bioconjugation Chemistry between Tetrazole and Amine

Bioconjugation chemistry has emerged as a powerful tool for the modification of diverse biomolecules under mild conditions. Tetrazole, initially proposed as a bioorthogonal photoclick handle for 1,3-dipolar cyclization with alkenes, was later demonstrated to possess broader photoreactivity with carb...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2024-01, Vol.146 (3), p.2122-2131
Main Authors: Zhang, Juan, Liu, Jinlu, Li, Xianfeng, Ju, Yunzhu, Li, Yangfeng, Zhang, Gong, Li, Yizhou
Format: Article
Language:English
Subjects:
Amines - chemistry
Click Chemistry
Cyclization
DNA
Proteins - chemistry
Tetrazoles - chemistry
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Summary:Bioconjugation chemistry has emerged as a powerful tool for the modification of diverse biomolecules under mild conditions. Tetrazole, initially proposed as a bioorthogonal photoclick handle for 1,3-dipolar cyclization with alkenes, was later demonstrated to possess broader photoreactivity with carboxylic acids, serving as a versatile bioconjugation and photoaffinity labeling probe. In this study, we unexpectedly discovered and validated the photoreactivity between tetrazole and primary amine to afford a new 1,2,4-triazole cyclization product. Given the significance of functionalized N-heterocycles in medicinal chemistry, we successfully harnessed the serendipitously discovered reaction to synthesize both pharmacologically relevant DNA-encoded chemical libraries (DELs) and small molecule compounds bearing 1,2,4-triazole scaffolds. Furthermore, the mild reaction conditions and stable 1,2,4-triazole linkage found broad application in photoinduced bioconjugation scenarios, spanning from intramolecular peptide macrocyclization and templated DNA reaction cross-linking to intermolecular photoaffinity labeling of proteins. Triazole cross-linking products on lysine side chains were identified in tetrazole-labeled proteins, refining the comprehensive understanding of the photo-cross-linking profiles of tetrazole-based probes. Altogether, this tetrazole-amine bioconjugation expands the current bioconjugation toolbox and creates new possibilities at the interface of medicinal chemistry and chemical biology.
ISSN:0002-7863
1520-5126
1520-5126
DOI:10.1021/jacs.3c11574