The Sulfo-Click Reaction: Expanding the Toolbox for Bioconjugation and Medicinal Chemistry

Abstract

The sulfo-click reaction, which relies on the chemoselective coupling of sulfonyl azides with thioacids to yield Nacylsulfonamides, has emerged as a powerful and versatile transformation in synthetic chemistry and bioconjugation. Its high efficiency, operational simplicity, and compatibility with mild conditions and diverse functional groups have enabled broad applications in both chemical biology and medicinal chemistry. Notably, this reaction supports site-selective bioconjugation in aqueous media and is well suited to complex biomolecular systems, facilitating the preparation of functionalized bioconjugates. In addition, the resulting N-acylsulfonamide motif has attracted significant interest in drug design as a metabolically stable bioisostere of carboxylic acids and phosphates. In this review, we summarize the development of the sulfo-click reaction, discuss its mechanistic features and reaction scope, and highlight recent advances and emerging applications, underscoring its value as a modular and reliable platform for both fundamental and applied research.