Tuning activation and self-immolative properties of the bioorthogonal alkene–azide click-and-release strategy

Abstract

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

Mechanisms and Substituent Effects of Metal-Free Bioorthogonal Reactions

“… Indeed, the LUMO-lowering effect of fluorines on the phenylazide group decreased the energy gap to TCO’s HOMO, which translated into a faster reaction . In a PBS:MeCN (18:1) solution, 26 (Figure b) reacted with a highly strained cis-dioxolane-fused trans- cyclooctene ( 29 , Figure c) at a bimolecular rate of 4.9 M –1 s –1 . However, the fluorines deterred the rate of elimination by stabilizing the intermediates .…”

“…In a PBS:MeCN (18:1) solution, 26 (Figure b) reacted with a highly strained cis-dioxolane-fused trans- cyclooctene ( 29 , Figure c) at a bimolecular rate of 4.9 M –1 s –1 . However, the fluorines deterred the rate of elimination by stabilizing the intermediates . PABC-type linkers have shown to benefit from a faster release when containing a benzylic methyl substituent because of the stabilization of the buildup of positive charge in the transition state. ,, With the combination of aryl azide 27 (Figure b), Gamble et al achieved rapid bimolecular kinetics and release from tetrafluorobenzyloxy type linkers within an hour ( t 1/2 = 54 min) and maximum release (94%) after 146 min …”

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).…”