Facile Nitrone Synthesis Enables Bioorthogonal Payload Delivery

Keywords

bioorthogonal bond cleavage - nitrone cycloaddition - cyclooctynes

Significance

Bioorthogonal bond-cleavage chemistry is a powerful modality for targeted payload delivery. Established reactant systems that enable this approach include tetrazines in partner with cyclooctynes or trans-cyclooctenes. The authors report a new entry to this field by showing that electron-deficient nitrones serve as efficient cycloaddition partners with cyclooctynes, selectively and efficiently releasing payloads through a cycloaddition/elimination cascade.

Comment

Key to evaluating this bioorthogonal click-release approach was the novel nitrone synthesis from the corresponding α-haloaryl ketone. Substitution at the α-carbon with N-methylhydroxylamine followed by aerobic oxidation under ambient conditions permitted access to a diverse array of nitrone triggers. Upon reaction with cyclooctyne prodrug, a regioselective nitrone dipolar cycloaddition/elimination cascade releases the drug payload. In vivo biological testing in mice with a nitrone and doxorubicin-cyclooctyne derivative showed that off-target accumulation of doxorubicin was decreased relative to the free doxorubicin group. 

Publication History

Article published online:
26 November 2025