Multifluorinated Aryl Azides for the Development of Improved H₂S Probes, and Fast Strain‐promoted Azide‐Alkyne Cycloaddition and Staudinger Reactions

Abstract

The development of advanced bioorthogonal reactions for detection and labeling of biomolecules is significant in chemical biology. Recently, researchers have found that multifluorinated aryl azides hold great potential for the development of improved bioorthogonal reactions. The fluorine atom can be a perfect substituent group because of its properties of excellent electronegativity and small steric hindrance. In this Minireview, we discuss recent developments of improved hydrogen sulfide (H 2 S) fluorescence probes, fast strain-promoted azide-alkyne cycloaddition (SPAAC) and nonhydrolysis Staudinger reactions based on the use of multifluorinated aryl azides. Additionally, kinetic studies and biological applications of these reactions are also presented. 2 3 4 5 6 7 8

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

“…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). 45 Examples of alkyl azide block copolymers used in polymeric drug delivery systems have been reported by Yan 42 and Stang, 43 whereby the alkyl azide is reduced by H 2 S and glutathione, respectively.…”

Bioorthogonal Reactions of Triarylphosphines and Related Analogues

“…99,105 Building on the success of bis-halogenated aryl azides, perfluorinated probes were investigated for fast bioorthogonal ligation. 107 Perfluoroaryl azide groups are widely used in chemical biology for modulating amino acid polarities, cycloaddition reactions, and photo-cross-linking. 108,109 These perfluorinated reagents also react readily with triarylphosphines to form iminophosphorane products.…”

“…358 Trialkylphosphine nucleophiles reacted with coumarin dyes via conjugate addition to quench fluorophore emission (106, Figure 42B). Under blue light illumination, the phosphine groups were photochemically released from the coumarin scaffold (107). The liberated phosphines then reduced disulfide bonds in endogenous proteins to simulate reductive stress.…”

Synthesis of Azaylide‐Based Amphiphiles by the Staudinger Reaction

“…Taking advantage of this hydrolysis, the Staudinger reaction has been employed in the biochemical field, [19–22] as initiated by Bertozzi and co‐workers [23] . Recently, Yan, [24] Xi, [25] Yoshida, and Hosoya [26] reported the “non‐hydrolysis” Staudinger reaction for biolabeling, in which halogen atoms on the aryl azide significantly improve the hydrolytic stability of azaylide [27, 28] . This unusual stability prompted us to utilize the azaylide formation for various supramolecular materials in water.…”

“…[23] Recently, Yan, [24] Xi, [25] Yoshida, and Hosoya [26] reported the "non-hydrolysis" Staudinger reaction for biolabeling, in which halogen atoms on the aryl azide significantly improve the hydrolytic stability of azaylide. [27,28] This unusual stability prompted us to utilize the azaylide formation for various supramolecular materials in water. The advantages of this method are: (i) a variety of trisubstituted phosphine compounds are commercially available [29] and reported, [30] and (ii) their triaryl moieties can be utilized for hydrophobic parts directly.…”