Tetrafluoroaryl azide as an N-terminal capping group for click-to-dissolve diphenylalanine hydrogels

Abstract

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

Synthesis and formulation of self‐immolative PEG‐aryl azide block copolymers and click‐to‐release reactivity with trans‐cyclooctene

“…To complement these alkyl azide-based nanoparticles, we designed a block copolymer with an aryl azide self-immolative linker. Similar to our prodrug and hydrogel strategies, [28][29][30][31][32] the reaction of the aryl azide embedded in the block co-polymer with trans-cyclooctene (TCO) would lead to formation of a triazoline/imine, and eventual self-immolation that would alter the properties of the block copolymer (Figure 1(A)).…”

“…fields. [19][20][21][22][23] While the fastest click-to-release reactions are based on the inverse-electron-demand Diels-Alder reaction, [24][25][26][27] our group is interested in the reactivity of aryl azides and their orthogonality in biological systems so that they can be applied to click-to-release type applications, [28][29][30][31][32] and to the best of our knowledge, there has been no examples of stimuli-responsive nanoparticles that are formulated from block copolymers containing the aryl azide self-immolative linker. Thus, we were interested to see if these types of polymers could be prepared, and second, be used in bioorthogonally-activated stimuli-responsive nanoparticles.…”

“…While the structure of the aryl azide dictates its reactivity, [33][34][35] functionalised aryl azides have relatively high biological stability, with selective reactivity for strained alkenes and alkynes ([3+2]-cycloadditions), [35][36][37] triphenylphosphines (Staudinger reaction), 38 or H 2 S. [39][40][41] We have developed the alkene-azide [3+2]-cycloaddition as a bioorthogonal click-to-release reaction for prodrugs 28,29,32 and hydrogels, 30,31 while others have investigated H 2 S; a gaseous transmitter in the body, as an activation mechanism for aryl azide-containing probes, prodrugs, and materials. [39][40][41] Alkyl azides can also be reduced by H 2 S 42 or glutathione, 43 however, aryl azides are considered more responsive to, and selective toward, alkenes and H 2 S, 44 even in the presence of other endogenous thiol/thiolate species (e.g., glutathione).…”

Fluorescent Hydrogel Producing ZnO for Colorimetric Detection of Glutathione and Cysteine

“…Moreover, it is convenient to operate, cost-effectiveness, and rapid detection. [28] Presently, various nanomaterials including Cu metalloenzyme, [33] Co 3 O 4 , [34] Au, [30] and Carbon Quantum Dots [23] have been reported for Cys and GSH detection through colorimetric method, however, the material preparation is complicated and required rigorous conditions, for example, high temperature and high pressure. Therefore, to prepare novel functional materials at a moderate condition without using toxic solvents and investigate its applications in Cys and GSH detection needed further exploration.…”

“…Thus, it is very urgent to design LMWGs with functional groups to develop hydrogels with prominent mechanical strength and stability for functional applications. [21][22][23][24] Among the 20 amino acids used as building blocks for proteins, the thiolcontaining amino acids, acting as antioxidants and antidotes, participate in biological activities and metabolic processes, which can retain the cellular defense against xenobiotics, gene regulation, and free radicals signal transduction. [25,26] As the only thiol-containing amino acids, cysteine (Cys) contributes biologically in human body by providing a mode for intermolecular cross-linking of proteins using the disulfide bonding to support the secondary structures and functions.…”