Isonitrile-responsive and bioorthogonally removable tetrazine protecting groups
Julian Tu1, Dennis Svatunek2, Saba Parvez3
1Department of Medicinal Chemistry , College of Pharmacy , University of Utah , Salt Lake City , 84112 , USA .
Chemical Science
|February 29, 2020
Summary
New tetrazines are rapidly removed by isonitriles under mild conditions, acting as effective protecting groups. This bioorthogonal chemistry is compatible with biological systems and enables multiplexed molecular release.
Area of Science:
- Chemical Biology
- Organic Chemistry
- Biomolecular Chemistry
Background:
- In vivo compatible reactions are crucial for chemical biology and pharmaceutical applications.
- Developing novel bioorthogonal reactions expands the toolkit for manipulating molecules in biological systems.
Purpose of the Study:
- To report novel tetrazine derivatives that can be removed by isonitriles under mild conditions.
- To evaluate the utility of these tetrazines as protecting groups for amines and phenols.
- To demonstrate the compatibility and application of this chemistry in biological environments.
Main Methods:
- Synthesis of tetrazylmethyl derivatives.
- Isonitrile-induced deprotection studies under various conditions.
- NMR and computational studies to elucidate reaction mechanisms.
- Cytotoxicity experiments and fluorophore release studies in proteins and zebrafish embryos.
Main Results:
- Tetrazylmethyl derivatives serve as efficient protecting groups for amines and phenols.
- Isonitrile-induced removal is rapid, near-quantitative, and accelerated by (trimethylsilyl)methyl isocyanide.
- The reaction mechanism involves an imine-tautomerization step, influenced by Si-C bond cleavage.
- Demonstrated compatibility with biomacromolecules, cellular environments, and living organisms.
- Successful multiplexed fluorophore release in vertebrates using combined tetrazine chemistries.
Conclusions:
- Tetrazylmethyl derivatives offer a versatile and bioorthogonal method for protecting and releasing molecules.
- This chemistry is suitable for applications in complex biological systems, including in vivo.
- The findings open new avenues for multiplexed release strategies in chemical biology and drug delivery.
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