Spatiotemporal Control of Biology: Synthetic Photochemistry Toolbox with Far-Red and Near-Infrared Light

Abstract

The complex network of naturally occurring biological pathways motivates the development of new synthetic molecules to perturb and/or detect these processes for fundamental research and clinical applications. In this context, photochemical tools have emerged as an approach to control the activity of drug or probe molecules at high temporal and spatial resolutions. Traditional photochemical tools, particularly photolabile protecting groups (photocages) and photoswitches, rely on high-energy UV light that is only applicable to cells or transparent model animals. More recently, such designs have evolved into the visible and near-infrared regions with deeper tissue penetration, enabling photocontrol to study biology in tissue and model animal contexts. This Review highlights recent developments in synthetic far-red and near-infrared photocages and photoswitches and their current and potential applications at the interface of chemistry and biology.

Donor–Acceptor Stenhouse Adduct Displaying Reversible Photoswitching in Water and Neuronal Activity

“…These properties are appealing for photopharmacology, which aims at controlling drug action on demand at selected locations using light, to enable precise responses and reduce unwanted side effects of treatments, or to manipulate specific cell types and neural circuits for investigational purposes. 26,27 Many photoswitchable bioactive molecules have been reported that offer high pharmacological specificity and potency for a diversity of targets, including ion channels [28][29][30] , G protein-coupled receptors [31][32][33] and enzymes [34][35][36][37] . Most are based on aryl azo compounds [38][39][40] , which are difficult to isomerize using orange-red light without introducing substituents that often perturb the pharmacological properties of the original compound.…”

Computational Design, Synthesis, and Photochemistry of Cy7‐PPG, an Efficient NIR‐Activated Photolabile Protecting Group for Therapeutic Applications**

“…However, the synthesis of heptamethine dyes with bulky sp 3 -carbon meso-substituents, such as our target molecule Cy7-PPG, remains challenging (Scheme 1). Unfortunately, our efforts to synthesize a suitable dialdehyde variant 2 b with a fully substituted geminal dimethyl sp 3 -carbon attached to the meso-carbon were unsuccessful.…”

Efficient Discovery of Visible Light-Activated Azoarene Photoswitches with Long Half-Lives Using Active Search

“…This relatively high-energy light (e.g., ultraviolet) may promote undesired side reactions that compete with the isomerization pathway (e.g., electrocyclic ring-closing reactions). UV light can also promote [2 + 2]-dimerizations that alter the structure and function of nucleotides and has a limited (epidermal depth, 0.1 mm) tissue penetration depth, thus limiting the therapeutic potential of photoswitches in photopharmacology . The Z -isomer of azobenzene has a thermal half-life ( t 1/2 ) of 2 days .…”

“…UV light can also promote [2 + 2]dimerizations that alter the structure and function of nucleotides and has a limited (epidermal depth, 0.1 mm) tissue penetration depth, 2 thus limiting the therapeutic potential of photoswitches in photopharmacology. 3 The Z-isomer of azobenzene has a thermal half-life (t 1/2 ) of 2 days. 4 Photoswitches ideally suited for photopharmacology applications feature long absorption wavelengths and long t 1/2 ; unfortunately, the simultaneous optimization of these parameters is challenging and has been empirically observed to compete.…”