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Control of Tetrazine Bioorthogonal Reactivity by Rotaxanation.
Carlos Fumero-Medina1, Yaiza Pérez-Pérez1, Lidia A Pérez-Márquez2
1Instituto de Productos Naturales y Agrobiología (IPNA), Consejo Superior de Investigaciones Científicas (CSIC), Avda. Astrofísico Fco. Sánchez 3, La Laguna, Tenerife, 38206, Spain.
Angewandte Chemie (International Ed. in English)
|September 22, 2025
Summary
Rotaxanation controls tetrazine reactions. Stimulus-triggered mechanical bond disassembly activates the inverse electron demand Diels-Alder (IEDDA) reaction, enabling bioorthogonal chemistry in live cells.
Area of Science:
- Supramolecular Chemistry
- Bioorthogonal Chemistry
- Organic Synthesis
Background:
- Tetrazine-mediated inverse electron demand Diels-Alder (IEDDA) reactions are crucial bioorthogonal tools.
- Controlling the kinetics and spatial activation of IEDDA reactions remains a challenge.
Purpose of the Study:
- To investigate rotaxanation as a method for controlling tetrazine-mediated IEDDA reactions.
- To demonstrate stimulus-responsive activation of IEDDA reactions using rotaxanes.
- To achieve controlled IEDDA reactions in live cellular environments.
Main Methods:
- Synthesis of tetrazine rotaxanes using crown ether templating and nucleophilic aromatic substitution.
- Kinetic studies comparing rotaxanes with their linear counterparts.
- Development of a β-galactosidase-sensitive tetrazine rotaxane for cellular experiments.
- Monitoring fluorescence changes to confirm IEDDA reaction progress.
Main Results:
- Tetrazine rotaxanes were synthesized in high yield.
- The kinetics of the IEDDA reaction with rotaxanes were slower than with linear threads.
- Disassembly of the rotaxane's mechanical bond, triggered by a specific stimulus, activated the IEDDA reaction.
- Controlled IEDDA and fluorescence generation were achieved in live cells via enzymatic digestion of the rotaxane.
Conclusions:
- Rotaxanation provides an effective strategy for controlling tetrazine-mediated IEDDA reactions.
- Mechanical bond disassembly serves as a trigger for activating IEDDA bioorthogonal chemistry.
- This approach enables spatiotemporal control of IEDDA reactions within living cells, opening new avenues for biological imaging and drug delivery.
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