SuFEx chemistry for nucleosides, nucleotides, and nucleic acids

Area of Science:

• Chemical Biology
• Organic Chemistry
• Nucleic Acid Chemistry

Background:

• Sulfur(vi) fluoride exchange (SuFEx) reactions offer robust linkages under mild conditions.
• The unique S-F bond in SuFEx is stable yet reactive, making it valuable for chemical biology applications.
• SuFEx applications in nucleosides, nucleotides, and nucleic acids are emerging but face synthetic and workflow challenges.

Purpose of the Study:

• To review recent advances in SuFEx chemistry applied to nucleic acids.
• To provide practical design rules for SuFEx implementation in oligonucleotide workflows.
• To highlight applications of SuFEx-modified nucleic acids in chemical biology.

Main Methods:

• Comparison of strategies for installing sulfur(vi)-fluoride electrophiles on nucleoside, nucleotide, and oligonucleotide frameworks.
• Discussion of reagent choices, linker designs, and electrophile positioning.
• Analysis of how synthetic advances translate into chemical biology tools.

Main Results:

• SuFEx can be successfully applied to nucleic acid frameworks, overcoming previous synthetic and workflow constraints.
• Established design rules facilitate the development of functional nucleic acid constructs using SuFEx.
• SuFEx enables the creation of covalent probes and inhibitors for chemical biology.

Conclusions:

• SuFEx chemistry is a maturing field for nucleic acid modification with significant potential in chemical biology.
• Key bottlenecks include scaffold-specific synthesis and workflow integration.
• Promising opportunities lie in developing broadly enabling methodologies and expanding applications.