Photo-Triggered Click Chemistry for Biological Applications

Abstract

In the last decade and a half, numerous bioorthogonal reactions have been developed with a goal to study biological processes in their native environment, i.e., in living cells and animals. Among them, the photo-triggered reactions offer several unique advantages including operational simplicity with the use of light rather than toxic metal catalysts and ligands, and exceptional spatiotemporal control through the application of an appropriate light source with pre-selected wavelength, light intensity and exposure time. While the photoinduced reactions have been studied extensively in materials research, e.g., on macromolecular surface, the adaptation of these reactions for chemical biology applications is still in its infancy. In this chapter, we review the recent efforts in the discovery and optimization the photo-triggered bioorthogonal reactions, with a focus on those that have shown broad utility in biological systems. We discuss in each cases the chemical and mechanistic background, the kinetics of the reactions and the biological applicability together with the limiting factors.

Keywords: Azirine; Bioorthogonal reaction; Cyclopropenone; Hetero Diels–Alder reaction; Nitrile imine; Photo-triggered reaction; Photoclick; Tetrazole; o-Naphthoquinone methide; o-Quinodimethanes.

Fig. 1

Fluorescent imaging of microtubules in CHO cells using 405 nm photoactivatable tetrazole 55 in the presence or in the absence of a fumarate-modified docetaxel 56. The rectangle area were illuminated with the 405-nm laser for the indicated time

Fig. 2

Structure of 2PE photoactivatable tetrazoles (top) and fluorescent imaging of microtubules in CHO cells (bottom) using tetrazole 59 in the presence or in the absence of a fumarate-modified docetaxel 56. The rectangle area were illuminated with the 700-nm femtosecond pulsed laser for the indicated time

Fig. 3

a Hydrogel formation with the tetrazole-based photoclick reaction. b The collapse of hydrogels induced by intramolecular photoclick reaction

Scheme 1

Photo-triggered generation of reactive intermediates

Scheme 2

a Strategy based on photoactivation of the precursor to generate a highly reactive and unstable species. b Strategy based the removal of a photo-protecting group

Scheme 3

Summary of photo-triggered cycloaddition reactions useful in biological applications. a Reactions between alkenes and photochemically generated 1,3-dipoles or 1,3-dienes. b SPAAC between photoprotected cyclooctynes and azides

Scheme 4

Plausible mechanistic pathways for the generation of nitrile imine and its reactions in the chloride-containing aqueous medium. The photoinduced tetrazole ring rupture followed by cycloaddition with alkenes are colored in blue

Scheme 5

Synthesis of N-aryltetrazoles

Scheme 6

Reaction of biaryltetrazoles with various dipolarophiles in the photoinduced cycloaddition reaction: a first study, b optimizing the photoactivation wavelength

Scheme 7

Tetrazoles with the extended π-systems

Scheme 8

Strategies for site selective protein modifications via photo-triggered tetrazole-alkene cycloaddition reaction: a modification of native residues, b genetic encoding of tetrazole amino acids, and c genetic encoding of alkene amino acids

Scheme 9

Tetrazole-based turn-on fluorescent probes for imaging microtubules in live cells

Scheme 10

Photo-triggered reactions of azirines and alkenes or alcohols

Scheme 11

Selective modification of an azirine-containing lysozyme by a PEG-modified fumarate via a photo-triggered cycloaddition reaction

Scheme 12

Photoactivation of NQMP to generate oNQM, which then reacts with vinyl (thio)ether

Scheme 13

Substrate scope of the alkene dienophiles in the photo-triggered cycloaddition reaction; product was formed only with ethyl vinyl ether

Scheme 14

Reactions between NQM and the electron-rich alkenes or thiol

Scheme 15

Exploiting the reversibility: capture with oNMQs and release through photolysis or hydrolysis

Scheme 16

Mechanism of the photo-triggered isomerization and hetero Diels–Alder reaction of o-methyl phenyl ketones and aldehydes

Scheme 17

Photo-triggered hetero Diels–Alder reaction with FMP

Scheme 18

Synthesis and photodecarbonylation of dibenzocyclopropenones.