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Click-to-Release Reactions for Tertiary Amines and Pyridines
Konrad Chojnacki1, Tori Demuth2, Jenna Faulkner1
1Department of Medicinal Chemistry, College of Pharmacy, 30 S 2000 E, Salt Lake City, Utah 84112, United States.
Journal of the American Chemical Society
|January 15, 2026
Summary
This study introduces novel click-to-release reactions for tertiary amines and pyridines using bioorthogonal chemistry. These new methods expand the scope of functional groups available for spatiotemporal control in drug delivery and chemical biology.
Area of Science:
- Organic Chemistry
- Chemical Biology
- Medicinal Chemistry
Background:
- Click-to-release reactions offer spatiotemporal control for biological processes and drug delivery.
- Current methods have a limited scope of releasable functional groups, excluding many bioactive molecules.
Purpose of the Study:
- To develop new click-to-release strategies for tertiary amines and pyridines.
- To expand the toolbox of bioorthogonal reactions for controlled molecular release.
Main Methods:
- Developed two orthogonal click-to-release strategies utilizing bioorthogonal reactions between isonitriles and tetrazines.
- Employed isocyanopropyl (ICPr) and tetrazylmethyl (TzMe) groups for caging tertiary amines and pyridines.
- Investigated reaction mechanisms through experimental and computational studies.
Main Results:
- Successfully demonstrated click-to-release for tertiary amines and pyridines, expanding functional group compatibility.
- Identified an unexpected release pathway for TzMe groups mediated by tertiary isonitriles.
- Showcased successful application to various bioactive molecules with good stability and demonstrated bioorthogonality in zebrafish embryos.
Conclusions:
- Significantly broadens the range of releasable functional groups in click-to-release chemistry.
- Opens new avenues for applications in chemical biology and targeted drug delivery.
- Provides versatile tools for precise control over molecular release in biological systems.
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