There has been significant interest in the methodologies of controlled release for a diverse range of applications spanning drug delivery, biological and chemical sensors, and diagnostics. The advancement in novel substrate-polymer coupling moieties has led to the discovery of selfimmolative linkers. This new class of linker has gained popularity in recent years in polymeric release technology as a result of stable bond formation between protecting-and leaving groups, which becomes labile upon activation, leading to the rapid disassembly of the parent polymer. This ability has prompted numerous studies into the design and development of self-immolative linkers and the kinetics surrounding their disassembly. This review details the main concepts that underpin self-immolative linker technologies that feature in polymeric or dendritic conjugate systems and outlines the chemistries of amplified self-immolative elimination. 65 For the purpose of clarity, a colour scheme has been adopted to highlight trigger (blue), self-immolative linker (green) and reporter (red) moieties.

A range of carbamate functionalized 1,4-disubstituted triazoles featuring a base sensitive trigger residue, plus a model aromatic amine reporter group, were prepared via copper(i) catalysed azide-alkyne cycloaddition and evaluated for their self-immolative characteristics. This study revealed a clear structure-reactivity relationship, via Hammett analysis, between the structure of the 1,4-disubstituted triazole and the rate of self-immolative release of the amine reporter group, thus demonstrating that under basic conditions this type of triazole derivative has the potential to be employed in a range of chemical release systems.

The applications of bioconjugation chemistry are rapidly expanding, and the addition of new strategies to the bioconjugation and ligation toolbox will further advance progress in this field. Herein, we present a detailed study of the Diels–Alder cycloaddition (DAC) reaction between pentafulvenes and maleimides in aqueous solutions and investigate the reaction as an emerging bioconjugation strategy. The DAC reactions were found to proceed efficiently, quantitatively yielding cycloadducts with reaction rates ranging up to ∼0.7 M–1 s–1 for a series of maleimides, including maleimide-derivatized peptides and proteins. The absence of cross-reactivity of the pentafulvene with a large panel of functional (bio)­molecules and biological media further demonstrated the bioorthogonality of this approach. The utility of the DAC reaction for bioorthogonal bioconjugation applications was further demonstrated in the presence of biological media and proteins, as well as through protein derivatization and labeling, which was comparable to the widely employed sulfhydryl–maleimide coupling chemistry.