DBCO-NHCO-PEG13-NHS ester

This DBCO-NHCO-PEG13-NHS ester is a bifunctional PEG-based linker designed for efficient PROTAC assembly by enabling orthogonal conjugation. The DBCO moiety supports rapid, copper-free click coupling with azide-bearing partners, while the NHS ester facilitates amide bond formation with primary amines on ligands or protein-targeting scaffolds. Together, these features improve modular synthesis, yield reproducibility, and flexibility in tuning linker placement for targeted protein degradation workflows. Detailed structural and reactivity guidance is provided below.

Structure: The linker combines a cyclooctyne (DBCO) core with a carbamate-linked PEG spacer terminating in an N-hydroxysuccinimide (NHS) ester. It contains stable amide/carbamate functionalities, an activated succinimidyl ester for acyl transfer, and an ether-rich PEG segment that enhances solubility and conformational flexibility.

Reactivity: The NHS ester reacts with primary amines via nucleophilic acyl substitution to form stable amide bonds, typically under mildly basic aqueous or mixed solvent conditions compatible with amine-containing ligands. The DBCO group undergoes strain-promoted azide–alkyne cycloaddition (SPAAC) with azides under copper-free conditions. Sequential coupling strategies are commonly used to preserve orthogonality and minimize cross-reactivity between functional handles.