Azido-PEG6-NHS ester

Azido-PEG6-NHS ester is a bifunctional polyethylene glycol linker designed for constructing PROTACs and related targeted protein degradation conjugates. It couples an NHS-activated ester for efficient amide-bond formation with an azide handle for subsequent bioorthogonal ligation, enabling modular assembly of ternary or multicomponent degraders. Its PEG-based spacer improves aqueous compatibility and can help tune linker flexibility, while orthogonal reactivity supports sequential, controlled conjugation workflows. Detailed structural and reactivity considerations are provided below.

Structure: The molecule contains a PEG-based hydrophilic chain terminating in an NHS ester and a terminal azide group. It features an activated carboxylate for nucleophilic acyl substitution and an azide functionality suitable for click-type transformations. The ether-rich backbone confers flexibility and improved solubility in aqueous media.

Reactivity: The NHS ester reacts with primary amines to form stable amide bonds via nucleophilic acyl substitution, typically under mildly basic conditions in aqueous or mixed aqueous/organic solvents. The azide group is commonly preserved for orthogonal conjugation, including copper-catalyzed azide–alkyne cycloaddition or strain-promoted azide–alkyne cycloaddition, depending on the partner and desired biocompatibility. To maintain reactivity, avoid strong nucleophiles that can hydrolyze the NHS ester and minimize prolonged exposure to water before coupling.