Redox-Activated Substrates for Enhancing Activatable Cyclopropene Bioorthogonal Reactions

Area of Science:

• Chemical Biology
• Bioorthogonal Chemistry
• Organic Synthesis

Background:

• Bioorthogonal chemistry is crucial for chemical biology and clinical applications.
• Designing selective, reactive, and stable bioorthogonal reagents is a key challenge.
• Recent advances include controllable reactivity and click-and-release functionalities.

Purpose of the Study:

• To improve the reactivity of a previously developed controllable cyclopropene-based bioorthogonal ligation.
• To explore new diene reaction partners for cyclopropene reagents.
• To investigate orthogonal activation mechanisms for enhanced bioorthogonal systems.

Main Methods:

• Screening of diene reaction partners for cyclopropene reagents.
• Kinetic analysis of cyclopropene-quinone ligation compared to tetrazine reactions.
• Demonstration of orthogonal activation via caging group removal and redox control.
• Application in live-cell imaging of cell membranes.

Main Results:

• A cyclopropene-quinone pair exhibited a 26-fold increase in reaction rate compared to tetrazine ligations.
• The cyclopropene-quinone reaction demonstrated dual orthogonal activation mechanisms.
• The system was successfully employed for imaging fixed cell membranes.

Conclusions:

• The cyclopropene-quinone ligation offers significantly enhanced reactivity for bioorthogonal applications.
• Orthogonal activation strategies provide versatile control over bioorthogonal reactions.
• This system shows promise as a bioimaging tool for cellular labeling.