SuFEx chemistry for nucleosides, nucleotides, and nucleic acids

Abstract

Sulfur(VI) fluoride exchange (SuFEx) reactions were introduced as next-generation click transformations that form robust sulfur(VI)-based linkages under mild conditions. Their defining feature is the unusual behaviour of the S–F bond: it is thermodynamically stable, yet can be selectively substituted when a suitable nucleophile is properly positioned. This balance has made SuFEx a valuable platform in chemical biology, enabling novel covalent probes, inhibitors and conjugation strategies in complex aqueous environments. In contrast, SuFEx applications to nucleosides, nucleotides and nucleic acids remain comparatively scarce and are only now beginning to mature. Progress has been limited by scaffold-specific synthetic and workflow constraints, including the scarcity of broadly enabling methodological studies and limited compatibility with standard oligonucleotide workflows. Even so, recent reports show that these barriers can be overcome in selected settings and that SuFEx can be translated into functional nucleic-acid constructs. This review summarises current advances with a focus on concepts and practical design rules. The first part is chemistry-centered: it compares the most successful strategies for installing sulfur(VI)–fluoride electrophiles on nucleoside, nucleotide, and oligonucleotide frameworks, and discusses reagent choices, linker designs and warhead positioning. The second part focuses on applications, outlining how these synthetic advances are turned into chemical biology tools where proximity effects convert reversible recognition into durable capture. We conclude by highlighting key bottlenecks and the most promising opportunities for progress.