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.

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.

Publication History

Article published online:
17 March 2023