Bioorthogonal prodrug activation/decaging strategies need to be selective, rapid and release the drug from the masking group upon activation. The rates of the 1,3-dipolar cycloaddition between a trans-cyclooctene (TCO) and a series of fluorine-substituted azido-PABC self-immolative spacers caging two model drugs, and subsequent release from the 1,2,3-triazoline are reported. As the number of fluorine substituents on the PABC linker increases from one to four, the rate of cycloaddition increases by almost one order of magnitude. Using a combination of fluorescence, H/F NMR, and computational experiments, we have been able to determine how substituents on the PABC ring can influence the degradation rates and also the product distribution of the 1,2,3-triazoline. We have also been able to determine how these substituents influence the rate of imine hydrolysis and 1,6-self-immolation decaging rates of the generated anilines. The NMR and computational studies demonstrate that fluorine substituents on the aromatic ring lower the transition state energy required for converting the triazoline to the imine or aziridine intermediates via extrusion of diatomic nitrogen, and that in the case of a tetrafluoro substituted aromatic ring, it is the imine hydrolysis and 1,6-self-immolation that is rate-limiting. This knowledge further enhances the understanding of factors which influence the stability of triazolines, and enables potential applications of fluorinated aromatics, in particular, perfluorinated aromatics, in synthetic chemistry and sustained-release drug delivery systems.

An alkene–azide 1,3‐dipolar cycloaddition between trans‐cyclooctene (TCO) and an azide‐capped hydrogel that promotes rapid gel dissolution is reported. Using an ultrashort aryl azide‐capped peptide hydrogel (PhePhe), we have demonstrated proof‐of‐concept where upon reaction with TCO, the hydrogel undergoes a gel–sol transition via 1,2,3‐triazoline degradation and 1,6‐self‐immolation of the generated aniline. The potential application of this as a general trigger in sustained drug delivery is demonstrated through release of encapsulated cargo (doxorubicin). Administration of TCO resulted in 87 % of the cargo being released in 10 h, compared to 13–14 % in the control gels. This is the first example of a potential bioorthogonal‐triggered hydrogel dissolution using a traditional click‐type reaction. This type of stimulus could be extended to other aryl azide‐capped hydrogels.

Combinations of aryl azides and trans-cyclooctenes have been studied in a bioorthogonal click-and-release strategy, with two reaction pairings rapidly releasing phenol at micromolar concentrations.

The synthesis of a bioorthogonal-responsive low molecular weight diphenylalanine (PhePhe)-based hydrogel that is capped with a 4-azido-2,3,5,6-tetrafluorobenzyl carbamate self-immolative linker is reported. The hydrogelator (AzF 4 -PhePhe) generates a stable hydrogel at 0.1 wt%, and rapidly reacts with the bioorthogonal reagent trans-cyclooctene (TCO), inducing a gel-to-solution transition. The critical gel concentration is five-fold lower than our previously synthesized non-fluorinated hydrogelator (Az-PhePhe), and the minimum concentration of TCO required for visible gel-to-solution transition in 24 hours is 1 mM. Doxorubicin can be encapsulated in the hydrogel and TCO-triggered dissolution results in 76% and 89% release after 10 and 24 hours, respectively. Compared with our non-substituted aryl azide capping group used for Az-PhePhe, the tetrafluorinated aryl azide group improves the stability of the hydrogel in unbuffered water at a lower critical gel concentration, while improving sensitivity towards the bioorthogonal reagent TCO. rsc.li/rsc-advances 9234 | RSC Adv., 2020, 10, 9234-9244 This journal is Scheme 1 TCO-triggered gel-sol transition of; (a) dipeptide hydrogel using hydrogelator 4-azidobenzyl carbamate-PhePhe 1 (Az-PhePhe; previous work), 12 and (b) dipeptide hydrogel using hydrogelator 4-azidotetrafluorobenzyl carbamate-PhePhe 3 (AzF 4 -PhePhe; this work). This journal isScheme 2 Synthesis of hydrogelator 3 (AzF 4 -PhePhe).This journal is