Azido-PEG16-NHS ester

Azido-PEG16-NHS ester is a bifunctional polyethylene glycol (PEG) linker designed for assembling PROTACs through orthogonal chemistries. The NHS ester enables efficient coupling to primary amines on targeting ligands, while the azide handle supports subsequent bioorthogonal conjugation (e.g., via azide–alkyne cycloaddition). Its PEG-based architecture provides conformational flexibility and improved solubility, helping maintain effective ternary complex formation. Detailed structural and reactivity considerations are provided below.

Structure: The linker contains a PEG chain terminating in an N-hydroxysuccinimide ester and an azide functional group. It features an NHS-activated carboxylate for acyl transfer, ether linkages within the PEG backbone, and an azide moiety suitable for click-type reactions. Overall, it is typically water-compatible and highly polar.

Reactivity: The NHS ester reacts with primary amines under mild, aqueous or mixed aqueous buffer conditions to form stable amide bonds, commonly using bases such as bicarbonate or carbonate to promote nucleophilic acyl substitution. The azide group is retained for later conjugation, typically using copper(I)-catalyzed or copper-free azide–alkyne cycloaddition depending on compatibility with sensitive ligands. Reaction design should minimize conditions that degrade NHS esters or quench azides.