Introduction to photoswitches and photopharmacology

Due to its great potential and practical relevance, the field of photopharmacology and the discovery of photochemical switches is rapidly evolving. We are pleased to highlight these recent developments by introducing this shared themed collection of Organic & Biomolecular Chemistry and RSC Medicinal Chemistry, bringing together the latest advances in synthetic techniques, structural design, and medicinal chemistry of photoswitches and photoswitchable drugs.

First, Hashim et al. review the long history of photomedicine, which dates back to the ancient Egyptians (https://doi.org/10.1039/d4md01005a). Modern photomedicine might be considered to have started with the award of the Nobel Prize in 1903 to Finsen for using light in the treatment of lupus. Hashim et al. go on to provide insights into the latest trends, successful strategies, and challenges yet to be met in the field. Having a closer look at one of these developments, Berdnikova and Lvov et al. provide an overview of strategies to photochemically generate thiols, which are of high relevance, for instance, in bioconjugation chemistry, labelling, as well as cellular redox chemistry. Irreversible, light-mediated thiol formation through photo-rearrangements and photocages are discussed alongside examples of reversible formation of thiols via different types of photoswitches (https://doi.org/10.1039/d5ob00191a). While in these examples photoswitches that involve electronic changes in their structures, such as spiropyranes, chromenes, and diarylethenes, have been successfully used to reversibly mask thiols, for photopharmacological applications involving small molecule ligands, photoswitches with a pronounced change in their geometry are dominating.

Especially, azobenzene-based photoswitches have been evolved into powerful light-responsive scaffolds to target different proteins even in a complex cellular context. Specifically, azologization or appending azo-switches onto known ligands, can give access to light-controllable pharmacophores. Tamaoki et al. report the design and testing of a light switchable version of the Wnt agonist BML-284, a molecule that binds to β-catenin and activates the Wnt signalling pathway. The Wnt pathway has been shown to be important for cell differentiation and development, and spatially localized activation is critical. The Z-azo version of the azologized BML-284 ligand can spatially activate Wnt signalling in HEK293T cell monolayers, providing optical control of this fundamental cellular process (https://doi.org/10.1039/d4ob01827c).

Samanta and colleagues describe the development of an azologized Stat3 inhibitor. Stat3 is aberrantly active in many human cancer cells and has been the target of significant drug development efforts. Adding an azophenyl moiety at the para-position of aryl rings in an established Stat3 inhibitor produced a compound that showed light dependent effects on breast cancer cell lines and spheroids (https://doi.org/10.1039/d5md00490j).

Matsuo and Tamaoki et al. then report a p-amino-substituted azobenzene based photopharmacological tool targeting centromere-associated protein E (CENP-E). CENP-E can guide chromosomes from mitotic poles to the cell equatorial plane along the spindle microtubules. Their blue-green light responsive CENP-E inhibitor was able to control chromosome positioning in mitotic cells (https://doi.org/10.1039/d4md00458b).

While classical azobenzene-based photoswitches feature prominently, several articles in this collection highlight the growing interest in azobenzene photoswitches containing heteroaryl units. The presence of one or more heteroatoms in these molecules confers unique light absorption and photoisomerization properties that can be exploited for different applications.

Tamaoki et al. report a novel class of azophotoswitches incorporating various five-membered heteroaryl units from thiazole and isothiazole to thiadiazole and isothiadiazole, that were selected based on DFT calculations to predict maximum absorption wavelengths. A compound containing both thiazole and isothiazole moieties showed longer λ_max (431 nm) than any of the other synthesized compounds, with a decrease in the cis form half-life (2.7 min), confirming that the calculations performed could predict the absorbance maximum and the molecular geometry (https://doi.org/10.1039/d4ob01573h).

Averdunk and Wegner focus on thiophenylazobenzene derivatives since they exhibit a significantly red-shifted absorption band (up to 405 nm) and an almost quantitative E to Z photoisomerization, which are key-features for molecular solar thermal energy storage (MOST) systems. p-Alkoxy azothiophenes were prepared and systematically investigated to establish valuable structure-properties for MOST applications, such as neat solid-state photoisomerisation or photo-induced liquefaction. In the case of methoxy-substituted p-alkoxy azothiophenes, the authors describe an unusual trend on the melting points, contrary to the odd–even effect typical of other systems, with a significant decrease in melting point for every third additional carbon in the alkoxy chain. Photoliquefaction of these thiophenylazobenzene systems could not be achieved, possibly because of reduced molecular mobility in the solid state, the high melting points of the (E)-isomers, short thermal half-lives as well as decomposition (https://doi.org/10.1039/d5ob00506j).

Maiti and Venkataramani et al. describe an azothiazole-based molecular probe comprising H-bonding acceptor sites, such as azo nitrogen and thiazole nitrogen, and a β-naphthol unit, as a potential H-bonding donor. The probe has been designed for sensing multiple analytes of biological importance, including urea, by means of cooperative binding, with the additional feature of spatiotemporal control given by the E/Z isomerization. Although spectroscopic studies of the azothiazole probe reveal the absence of photoisomerization and moderate fluorescence emission, the authors perform qualitative and quantitative detection of ammonia, arginine and lysine, identifying a cost-effective, reusable and versatile chemosensor (https://doi.org/10.1039/d5ob00077g).

These contributions showcase the recent developments in azo-photoswitch design paving the way for the next-generation of tools, sensors, and photopharmacophores. Next to azobenzenes, several other types of photoswitches can be used to generate light-responsive bioactive molecules. In particular, this collection features bioactivity studies using two other types of non-azo-based photoswitches: diarylethenes and spiropyranes.

Sumaru and Uchida et al. present a classical photochromic diarylethene, which, in its closed state, shows dark toxicity by intercalating into the DNA of HeLa cells and loses this ability upon ring-opening under green light irradiation. This reversibility of activation enables the authors to study the exact time needed for the closed form to cause cell death, and also create precise patterns of cell growth by first activating the drug in a larger area by UV-light-mediated ring closing and then irradiating with green light in a micropatterned way (https://doi.org/10.1039/d4ob02087a). Afonin and Komarov et al. use diarylethene as a tool for reversibly switching the conformation of gramicidin S, a natural peptidic antibiotic, which allows for the precise control over the induction of immunogenic cell death. Biological evaluation was carried out in cell monolayers and 3D spheroids, revealing an order of magnitude difference in potency between the closed (more potent) and open isomers, with overall higher activity observed against cancer cells over non-cancerous ones. Both those reports show that photoswitching based on the formation/breaking of bonds is a promising, yet still underexplored design principle in photopharmacology (https://doi.org/10.1039/d5md00075k).

De et al. in turn studied the biological application of a spiropyran switch, which operates through a mixed bond formation/isomerisation mechanism of switching between a closed, neutral isomer and an open, planar, zwitterionic form. The large change of dipole moment that accompanies this transformation is another underexplored process in biomedical applications. In this report, chemical modifications of the spiropyran core were studied for their influence on photochemical behavior and activity as antibiotics on a Gram-positive bacterium Staphylococcus aureus, with the open forms showing overall higher activity (https://doi.org/10.1039/D5OB00033E).

These examples on light-controlling antimicrobial activity, cytotoxicity, anticancer agents, tools targeting proteins in signalling pathways and as parts of the cytoskeleton, illustrate the latest trends in photopharmacophore studies. Such achievements are fostered by an underlying interest in designing and studying photochemical switches. Having observed the diversity and creativity in photoswitch development and the steady progress of photopharmacophores in various applications, we are optimistic that remaining challenges will gradually be addressed, enabling a wider range of structures to be incorporated into compounds for biomedical research. The different aspects covered here illustrate the varied research needed to identify components for future smart medicines. We would like to acknowledge the efforts of the interdisciplinary community reflected in this themed collection and thank the authors who contributed to it.