Design and Synthesis of Iminosydnones for Fast Click and Release Reactions with Cycloalkynes

Abstract

Emerging applications in the field of chemical biology are currently limited by the lack of bioorthogonal reactions allowing both removal and linkage of chemical entities on complex biomolecules. We recently discovered a novel reaction between iminosydnones and strained alkynes leading to two products resulting from ligation and fragmentation of iminosydnones under physiological conditions. We now report the synthesis of a panel of substituted iminosydnones and the structure reactivity relationship between these compounds and strained alkyne partners. This study identified the most relevant substituents, which allow to increase the rate of the transformation and to develop a bifunctional cleavable linker with improved kinetics.

Automated linkage of proteins and payloads producing monodisperse conjugates

“…This trans-tagging reaction is an ideal candidate for this application, since it has a high rate constant (k up to 8.1 M À1 s À1 ) in aqueous buffers and does not interfere with complex biological molecules. 23 A trifunctional molecular construct 1 was thus synthesized, comprising a reactive function for protein conjugation (N-hydroxysuccinimide ester), a bioorthogonal trans-tagging function (iminosydnone), and an affinity tag (biotin). N-hydroxysuccinimide (NHS) ester was selected as the reactive group as it is one of the most widely used functions in bioconjugation.…”

Recent Advances in the Synthesis and Biomedical Applications of Heterocyclic NO-Donors

“…An interaction of sydnone imine hydrochlorides with sulfonyl chlorides in basic media afforded N 6 -sulfonyl iminosydnones 14 which have a great potential in bioorthogonal click-and-release methodology ( Scheme 8 ) [ 38 , 39 ].…”

“…A number of sydnone imine-based ureas and thioureas 17 were prepared by reaction of parent iminosydnones with the corresponding aromatic and aliphatic isocyanates or isothiocyanates ( Scheme 10 ) [ 39 ].…”

Controlled Release of a Micelle Payload via Sequential Enzymatic and Bioorthogonal Reactions in Living Systems

“…We thus designed the amphiphilic structure 5 bearing a hydrophobic aliphatic chain connected to a PEG 750 moiety by an iminosydnone spacer. Surfactant 5 was prepared in seven steps starting from p ‐iodo‐aniline (Figure ) . Physicochemical characterizations proved that 5 self‐assembles in aqueous solutions into micelles M5 of 10 nm size according to DLS analysis.…”