Dithienylethene-Based Photoswitchable Phosphines for the Palladium-Catalyzed Stille Coupling Reaction.

Homogeneous transition metal catalysis is a constantly developing field in chemical sciences. A growing interest in this area is photoswitchable catalysis, which pursues in situ modulation of catalyst activity through noninvasive light irradiation. Phosphorus ligands are excellent targets to accomplish this goal by introducing photoswitchable moieties; however, only a limited number of examples have been reported so far. In this work, we have developed a series of palladium complexes capable of catalyzing the Stille coupling reaction that contain photoisomerizable phosphine ligands based on dithienylethene switches. Incorporation of electron-withdrawing substituents into these dithienylethene moieties allows variation of the electron density on the phosphorus atom of the ligands upon light irradiation, which in turn leads to a modulation of the catalytic properties of the formed complexes and their activity in a model Stille coupling reaction. These results are supported by theoretical computations, which show that the energy barriers for the rate-determining steps of the catalytic cycle decrease when the photoswitchable phosphine ligands are converted to their closed state.

Amplified photomodulation of a bis(dithienylethene)-substituted phosphine.

Phosphine ligands play a crucial role in homogeneous catalysis, allowing fine-tuning of the catalytic activity of various metals by modifying their structure. An ultimate challenge in this field is to reach controlled modulation of catalysis in situ, for which the development of phosphines capable of photoswitching between states with differential electronic properties has been proposed. To magnify this light-induced behavior, in this work we describe a novel phosphine ligand incorporating two dithienylethene photoswitchable moieties tethered to the same phosphorus atom. Double photoisomerization was observed for this ligand, which remains unhindered upon gold(I) complexation. As a result, the preparation of a fully ring-closed phosphine isomer was accomplished, for which amplified variation of phosphorus electron density was verified both experimentally and by computational calculations. Accordingly, the presented molecular design based on multiphotochromic phosphines could open new ways for preparing enhanced photoswitchable catalytic systems.

Three-Photon Infrared Stimulation of Endogenous Neuroreceptors in Vivo.

To interrogate neural circuits and crack their codes, in vivo brain activity imaging must be combined with spatiotemporally precise stimulation in three dimensions using genetic or pharmacological specificity. This challenge requires deep penetration and focusing as provided by infrared light and multiphoton excitation, and has promoted two-photon photopharmacology and optogenetics. However, three-photon brain stimulation in vivo remains to be demonstrated. We report the regulation of neuronal activity in zebrafish larvae by three-photon excitation of a photoswitchable muscarinic agonist at 50 pM, a billion-fold lower concentration than used for uncaging, and with mid-infrared light of 1560 nm, the longest reported photoswitch wavelength. Robust, physiologically relevant photoresponses allow modulating brain activity in wild-type animals with spatiotemporal and pharmacological precision. Computational calculations predict that azobenzene-based ligands have high three-photon absorption cross-section and can be used directly with pulsed infrared light. The expansion of three-photon pharmacology will deeply impact basic neurobiology and neuromodulation phototherapies.

Spiropyran-based chromic hydrogels for CO2 absorption and detection.

By enabling rapid, cost-effective, user-friendly and in situ detection of carbon dioxide, colorimetric CO2 sensors are of relevance for a variety of fields. However, it still remains a challenge the development of optical chemosensors for CO2 that combine high sensitivity, selectivity and reusability with facile integration into solid materials. Herein we pursued this goal by preparing hydrogels functionalized with spiropyrans, a well-known class of molecular switches that undergo different color changes upon application of light and acid stimuli. By varying the nature of the substituents of the spiropyran core, different acidochromic responses are obtained in aqueous media that allow discriminating CO2 from other acid gases (e.g., HCl). Interestingly, this behavior can be transferred to functional solid materials by synthesizing polymerizable spiropyran derivatives, which are used to prepare hydrogels. These materials preserve the acidochromic properties of the incorporated spiropyrans, thus leading to selective, reversible and quantifiable color changes upon exposure to different CO2 amounts. In addition, CO2 desorption and, therefore, recovery of the initial state of the chemosensor is favored by irradiation with visible light. This makes spiropyran-based chromic hydrogels promising systems for the colorimetric monitorization of carbon dioxide in a diversity of applications.

Remote local photoactivation of morphine produces analgesia without opioid-related adverse effects.

BACKGROUND AND PURPOSE: Opioid-based drugs are the gold standard medicines for pain relief. However, tolerance and several side effects (i.e. constipation and dependence) may occur upon chronic opioid administration. Photopharmacology is a promising approach to improve the benefit/risk profiles of these drugs. Thus, opioids can be locally activated with high spatiotemporal resolution, potentially minimizing systemic-mediated adverse effects. Here, we aimed at developing a morphine photo-derivative (photocaged morphine), which can be activated upon light irradiation both in vitro and in vivo. EXPERIMENTAL APPROACH: Light-dependent activity of pc-morphine was assessed in cell-based assays (intracellular calcium accumulation and electrophysiology) and in mice (formalin animal model of pain). In addition, tolerance, constipation and dependence were investigated in vivo using experimental paradigms. KEY RESULTS: In mice, pc-morphine was able to elicit antinociceptive effects, both using external light-irradiation (hind paw) and spinal cord implanted fibre-optics. In addition, remote morphine photoactivation was devoid of common systemic opioid-related undesired effects, namely, constipation, tolerance to the analgesic effects, rewarding effects and naloxone-induced withdrawal. CONCLUSION AND IMPLICATIONS: Light-dependent opioid-based drugs may allow effective analgesia without the occurrence of tolerance or the associated and severe opioid-related undesired effects. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.

Reversible Photocontrol of Dopaminergic Transmission in Wild-Type Animals.

Understanding the dopaminergic system is a priority in neurobiology and neuropharmacology. Dopamine receptors are involved in the modulation of fundamental physiological functions, and dysregulation of dopaminergic transmission is associated with major neurological disorders. However, the available tools to dissect the endogenous dopaminergic circuits have limited specificity, reversibility, resolution, or require genetic manipulation. Here, we introduce azodopa, a novel photoswitchable ligand that enables reversible spatiotemporal control of dopaminergic transmission. We demonstrate that azodopa activates D1-like receptors in vitro in a light-dependent manner. Moreover, it enables reversibly photocontrolling zebrafish motility on a timescale of seconds and allows separating the retinal component of dopaminergic neurotransmission. Azodopa increases the overall neural activity in the cortex of anesthetized mice and displays illumination-dependent activity in individual cells. Azodopa is the first photoswitchable dopamine agonist with demonstrated efficacy in wild-type animals and opens the way to remotely controlling dopaminergic neurotransmission for fundamental and therapeutic purposes.

Fast Photoswitchable Molecular Prosthetics Control Neuronal Activity in the Cochlea.

Artificial control of neuronal activity enables the study of neural circuits and restoration of neural functions. Direct, rapid, and sustained photocontrol of intact neurons could overcome the limitations of established electrical stimulation such as poor selectivity. We have developed fast photoswitchable ligands of glutamate receptors (GluRs) to enable neuronal control in the auditory system. The new photoswitchable ligands induced photocurrents in untransfected neurons upon covalently tethering to endogenous GluRs and activating them reversibly with visible light pulses of a few milliseconds. As a proof of concept of these molecular prostheses, we applied them to the ultrafast synapses of auditory neurons of the cochlea that encode sound and provide auditory input to the brain. This drug-based method afforded the optical stimulation of auditory neurons of adult gerbils at hundreds of hertz without genetic manipulation that would be required for their optogenetic control. This indicates that the new photoswitchable ligands are also applicable to the spatiotemporal control of fast spiking interneurons in the brain.

Synthesis and In Vitro Studies of Photoactivatable Semisquaraine-type Pt(II) Complexes.

The synthesis, full characterization, photochemical properties, and cytotoxic activity toward cisplatin-resistant cancer cell lines of new semisquaraine-type Pt(II) complexes are presented. The synthesis of eight semisquaraine-type ligands has been carried out by means of an innovative, straightforward methodology. A thorough structural NMR and X-ray diffraction analysis of the new ligands and complexes has been done. Density functional theory calculations have allowed to assign the trans configuration of the platinum center. Through the structural modification of the ligands, it has been possible to synthesize some complexes, which have turned out to be photoactive at wavelengths that allow their activation in cell cultures and, importantly, two of them show remarkable solubility in biological media. Photodegradation processes have been studied in depth, including the structural identification of photoproducts, thus justifying the changes observed after irradiation. From biological assessment, complexes C7 and C8 have been demonstrated to behave as promising photoactivatable compounds in the assayed cancer cell lines. Upon photoactivation, both complexes are capable of inducing a higher cytotoxic effect on the tested cells compared with nonphotoactivated compounds. Among the observed results, it is remarkable to note that C7 showed a PI > 50 in HeLa cells, and C8 showed a PI > 40 in A2780 cells, being also effective over cisplatin-resistant A2780cis cells (PI = 7 and PI = 4, respectively). The mechanism of action of these complexes has been studied, revealing that these photoactivated platinum complexes would actually present a combined mode of action, a therapeutically potential advantage.

Thermoresponsive multicolor-emissive materials based on solid lipid nanoparticles.

Despite the recent advances in the field of thermofluorochromism, the fabrication of thermoresponsive multicolor-emissive materials in a simple, low-cost and versatile manner still remains a challenge. Herein we accomplish this goal by expanding the concept of matrix-induced thermofluorochromism, where a sudden two-state variation of dyes' emission is promoted by the solid-liquid transition of a surrounding phase change material (e.g., paraffins). We demonstrate that this behavior can be transferred to the nanoscale by the synthesis of dye-loaded solid lipid nanoparticles, different types of which can then be combined into a single platform to obtain multicolor thermofluorochromism using a single type of emitter. Because of the reduced dimensions of these particles, they can be utilized to prepare transparent nanocomposites and inkjet-printed patterns showing complex thermoresponsive luminescence signals and applications ranging from smart displays to thermal sensing and high-security anti-counterfeiting.

Optical control of adenosine A3 receptor function in psoriasis.

Psoriasis is a chronic and relapsing inflammatory skin disease lacking a cure that affects approximately 2% of the population. Defective keratinocyte proliferation and differentiation, and aberrant immune responses are major factors in its pathogenesis. Available treatments for moderate to severe psoriasis are directed to immune system causing systemic immunosuppression over time, and thus concomitant serious side effects (i.e. infections and cancer) may appear. In recent years, the Gi protein-coupled A3 receptor (A3R) for adenosine has been suggested as a novel and very promising therapeutic target for psoriasis. Accordingly, selective, and high affinity A3R agonists are known to induce robust anti-inflammatory effects in animal models of autoimmune inflammatory diseases. Here, we demonstrated the efficacy of a selective A3R agonist, namely MRS5698, in preventing the psoriatic-like phenotype in the IL-23 mouse model of psoriasis. Subsequently, we photocaged this molecule with a coumarin moiety to yield the first photosensitive A3R agonist, MRS7344, which in photopharmacological experiments prevented the psoriatic-like phenotype in the IL-23 animal model. Thus, we have demonstrated the feasibility of using a non-invasive, site-specific, light-directed approach to psoriasis treatment.

Solid Multiresponsive Materials Based on Nitrospiropyran-Doped Ionogels.

The application of molecular switches for the fabrication of multistimuli-responsive chromic materials and devices still remains a challenge because of the restrictions imposed by the supporting solid matrices where these compounds must be incorporated: they often critically affect the chromic response as well as limit the type and nature of external stimuli that can be applied. In this work, we propose the use of ionogels to overcome these constraints, as they provide a soft, fluidic, transparent, thermally stable, and ionic-conductive environment where molecular switches preserve their solution-like properties and can be exposed to a number of different stimuli. By exploiting this strategy, we herein pioneer the preparation of nitrospiropyran-based materials using a single solid platform that exhibit optimal photo-, halo-, thermo-, and electrochromic switching behaviors.

Dual-Wavelength Gated oxo-Diels-Alder Photoligation.

The control of chemical functionalization with orthogonal light stimuli paves the way toward manipulating materials with unprecedented spatiotemporal resolution. To reach this goal, we herein introduce a photochemical reaction system that enables two-color control of covalent ligation via an oxo-Diels-Alder cycloaddition between two separate light-responsive molecular entities: a UV-activated photocaged diene based on ortho-quinodimethanes and a carbonyl dienophile appended to a diarylethene photoswitch, whose reactivity can be modulated upon illumination with UV and visible light.

Reversibly Switchable Fluorescent Molecular Systems Based on Metallacarborane-Perylenediimide Conjugates.

Icosahedral metallacarboranes are θ-shaped anionic molecules in which two icosahedra share one vertex that is a metal center. The most remarkable of these compounds is the anionic cobalt-based metallacarborane [Co(C2 B9 H11 )2 ]- , whose oxidation-reduction processes occur via an outer sphere electron process. This, along with its low density negative charge, makes [Co(C2 B9 H11 )2 ]- very appealing to participate in electron-transfer processes. In this work, [Co(C2 B9 H11 )2 ]- is tethered to a perylenediimide dye to produce the first examples of switchable luminescent molecules and materials based on metallacarboranes. In particular, the electronic communication of [Co(C2 B9 H11 )2 ]- with the appended chromophore unit in these compounds can be regulated upon application of redox stimuli, which allows the reversible modulation of the emitted fluorescence. As such, they behave as electrochemically-controlled fluorescent molecular switches in solution, which surpass the performance of previous systems based on conjugates of perylendiimides with ferrocene. Remarkably, they can form gels by treatment with appropriate mixtures of organic solvents, which result from the self-assembly of the cobaltabisdicarbollide-perylendiimide conjugates into 1D nanostructures. The interplay between dye π-stacking and metallacarborane electronic and steric interactions ultimately governs the supramolecular arrangement in these materials, which for one of the compounds prepared allows preserving the luminescent behavior in the gel state.

Adrenergic Modulation With Photochromic Ligands.

Adrenoceptors are ubiquitous and mediate important autonomic functions as well as modulating arousal, cognition, and pain on a central level. Understanding these physiological processes and their underlying neural circuits requires manipulating adrenergic neurotransmission with high spatio-temporal precision. Here we present a first generation of photochromic ligands (adrenoswitches) obtained via azologization of a class of cyclic amidines related to the known ligand clonidine. Their pharmacology, photochromism, bioavailability, and lack of toxicity allow for broad biological applications, as demonstrated by controlling locomotion in zebrafish and pupillary responses in mice.

Correction: Photoswitchable dynasore analogs to control endocytosis with light.

[This corrects the article DOI: 10.1039/D0SC03820B.].

An all-photonic full color RGB system based on molecular photoswitches.

On-command changes in the emission color of functional materials is a sought-after property in many contexts. Of particular interest are systems using light as the external trigger to induce the color changes. Here we report on a tri-component cocktail consisting of a fluorescent donor molecule and two photochromic acceptor molecules encapsulated in polymer micelles and we show that the color of the emitted fluorescence can be continuously changed from blue-to-green and from blue-to-red upon selective light-induced isomerization of the photochromic acceptors to the fluorescent forms. Interestingly, isomerization of both acceptors to different degrees allows for the generation of all emission colors within the red-green-blue (RGB) color system. The function relies on orthogonally controlled FRET reactions between the blue emitting donor and the green and red emitting acceptors, respectively.

Synthetic Photoswitchable Neurotransmitters Based on Bridged Azobenzenes.

Photoswitchable neurotransmitters of ionotropic kainate receptors were synthesized by tethering a glutamate moiety to disubstituted C2-bridged azobenzenes, which were prepared through a novel methodology that allows access to diazocines with higher yields and versatility. Because of the singular properties of these photochromes, photoisomerizable compounds were obtained with larger thermal stability for their inert cis isomer than for their biologically activity trans state. This enabled selective neuronal firing upon irradiation without background activity in the dark.

Color-Tunable White-Light-Emitting Materials Based on Liquid-Filled Capsules and Thermally Responsive Dyes.

Color-tunable white-light-emitting materials are currently attracting much attention because of their potential applications in artificial lighting, sensing, and imaging. However, preparation of these systems from organic emitters is often cumbersome due to the interchromophoric interactions occurring upon solvent drying in the final solid materials, which can be hardly predicted and may lead to detrimental effects. To circumvent these obstacles, we have developed a new fabrication methodology that relies on dye encapsulation within liquid-filled capsules, thus enabling direct transfer of the luminescent properties from solution to the solid state and as such, rational design of miniaturized white-light-emitting materials. By introducing a thermally responsive chromophore into the capsules, these materials are further endowed with color tunability, which does not only allow ample modulation of the emitted color but also facilitate external fine control of the system so as to ensure precise realization of white light at the desired temperature and excitation wavelength.

Solid Materials with Tunable Reverse Photochromism.

Herein, we report a novel, straightforward, and universal strategy to achieve solid materials with highly tunable reverse photochromism. This was accomplished by means of commercially available spiropyran dyes, which can produce different types of stable merocyanine states (i.e., nonprotonated and protonated forms) displaying distinct reverse photochromic properties (i.e., colors and coloration rates). To finely control the concentration ratio of these species and, as such, tailor the optical performance of the photochromes, we exploited their differential interaction with surrounding media of distinctive nature (i.e., nonvolatile protic and aprotic polar solvents). In this way, solutions displaying different photochromic responses were prepared for individual spiropyrans without requiring chemical derivatization, an approach that can be generalized to other spiro dyes with distinct acid-base properties. To transfer this behavior to the solid state, core-shell capsules of these solutions were prepared, which were then used as ink materials for the fabrication of flexible polymeric films with unprecedented tunability of their photochromic properties that can be employed as rewritable multicolored devices.

Rationally designed azobenzene photoswitches for efficient two-photon neuronal excitation.

Manipulation of neuronal activity using two-photon excitation of azobenzene photoswitches with near-infrared light has been recently demonstrated, but their practical use in neuronal tissue to photostimulate individual neurons with three-dimensional precision has been hampered by firstly, the low efficacy and reliability of NIR-induced azobenzene photoisomerization compared to one-photon excitation, and secondly, the short cis state lifetime of the two-photon responsive azo switches. Here we report the rational design based on theoretical calculations and the synthesis of azobenzene photoswitches endowed with both high two-photon absorption cross section and slow thermal back-isomerization. These compounds provide optimized and sustained two-photon neuronal stimulation both in light-scattering brain tissue and in Caenorhabditis elegans nematodes, displaying photoresponse intensities that are comparable to those achieved under one-photon excitation. This finding opens the way to use both genetically targeted and pharmacologically selective azobenzene photoswitches to dissect intact neuronal circuits in three dimensions.