Bioorthogonal “Click-and-Release” of Iminosydnones to Give Water-Stable Isocyanates

Key words

bioorthogonal click-and-release - drug delivery - iminosydnones - isocyanates

Significance

Bioorthogonal click-and-release is one strategy for targeted drug delivery. For this method to be effective, high reaction rates are required. Taran and co-workers demonstrate that alkyl and aryl iminosydnones (referring to the substituent on the exocyclic imine nitrogen atom), which were never previously synthesized, have high rates (>100 M^–1s^–1) of click-and-release with cycloalkynes. This releases alkyl or aryl isocyanates respectively, which can subsequently react with intracellular thiol­ nucleophiles. The initial [3+2] cycloaddition only occurs in the neutral 1,3-dipole form of the iminosydnone. With pK _a values near neutrality (pK _a[alkyl] ~ 8.5, pK _a[aryl] ~ 6.5) these iminosydnones offer an inherent mechanism of rate control based on pK _a vs intracellular pH.

 

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Comment

Prior to this work, only iminosydnones with electron-withdrawing substituents on the exocyclic nitrogen atom had been investigated. These have low rates of addition to cycloalkynes. Furthermore, upon click-and-release, the resulting isocyanate would be too electrophilic to be captured by an endogenous nucleophile before undergoing hydrolysis. By developing syntheses of alkyl and aryl iminosydnones, Taran and co-workers have introduced a method for the intracellular delivery of isocyanates that can be captured by biochemical nucleophiles of interest, such as cysteine residues in glutathione or human serum albumin.

 

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Publication History

Article published online:
17 March 2023