Molecular Photoswitches Research Articles

Hemipiperazines as peptide-derived molecular photoswitches with low-nanomolar cytotoxicity

Molecular photoswitches transform light energy into reversible structural changes. Their combination with known pharmacophores often allows for photomodulation of the biological activity. The effort to apply such compounds in photopharmacology as light-activated pro-drugs is, however, hampered by serious activity reduction upon pharmacophore modifications, or limited biostability. Here we report that a potent antimitotic agent plinabulin and its derivatives demonstrate up to 56-fold reversible activity photomodulation. Alternatively, irreversible photoactivation with cyan light can enhance the cytotoxicity up to three orders of magnitude—all without compromising the original activity level, as the original pharmacophore structure is unchanged. This occurs due to the presence of a peptide-derived photoswitchable motif hemipiperazine inside the plinabulin scaffold. Furthermore, we systematically describe photochromism of these thermally stable and biocompatible hemipiperazines, as well as a photoswitchable fluorophore derived from plinabulin. The latter may further expand the applicability of hemipiperazine photochromism towards super-resolution microscopy.

Enhanced Sampling Aided Design of Molecular Photoswitches.

Advances in the evolving field of atomistic simulations promise important insights for the design and fundamental understanding of novel molecular photoswitches. Here, we use state-of-the-art enhanced simulation techniques to unravel the complex, multistep chemistry of donor-acceptor Stenhouse adducts (DASAs). Our reaction discovery workflow consists of enhanced sampling for efficient chemical space exploration, refinement of newly observed pathways with more accurate ab initio electronic structure calculations, and structural modifications to introduce design principles within future generations of DASAs. We showcase our discovery workflow by not only recovering the full photoswitching mechanism of DASA but also predicting a plethora of new plausible thermal pathways and suggesting a way for their experimental validation. Furthermore, we illustrate the tunability of these newly discovered reactions, leading to a potential avenue for controlling DASA dynamics through multiple external stimuli. Overall, these insights could offer alternative routes to increase the efficiency and control of DASA's photoswitching mechanism, providing new elements to design more complex light-responsive materials.

Heterocyclic Hemithioindigos: Highly Advantageous Properties as Molecular Photoswitches.

A survey of heterocyclic hemithioindigo photoswitches is presented identifying a number of structural motives with outstanding property profiles. The highly sought-after combination of pronounced color change, quantitative switching in both directions, exceptional high quantum yields, and tunable high thermal stability of metastable states can be realized with 4-imidazole, 2-pyrrole, and 3-indole-based derivatives. In the former, an unusual preorganization using isomer selective chalcogen- and hydrogen bonding allows to precisely control geometry changes and tautomerism upon switching. Heterocyclic hemithioindigos thus represent highly promising photoswitches with advanced capabilities that will be of great value to anyone interested in establishing defined and reversible control at the molecular level.

The competitive mechanism between photoisomerization and excited state intramolecular proton transfer process of 2′-Hydroxychalcone system

The photoisomerization and excited state intramolecular proton transfer (ESIPT) are the most common processes in molecular photoswitches. Their coexistence and competing relationship in molecules usually make the deactivation process of the molecules become complex. In the current work, we study the underlying deactivation mechanism of trans-form 2′-hydroxychalcone (2′HC), which possesses both photoisomerization and ESIPT in the excited state, by combining high-level electronic structure calculations and on-the-fly surface hopping dynamics simulations. Four minimum energy conical intersections (MECIs) are found to be involved in the whole deactivation process. Following excitation to the S3 state of the most stable trans-enol tautomer, a strong coupling from the ππ* onto the nπ* state facilitates the ultrafast S3/S1 internal conversion process through an intricate conical intersection seam among S1, S2 and S3 state. The subsequent S1 to S0 state relaxation pathway is divided into two branches. The first process is initiated by twisting motion of C8─C9 bridging bond, which decays directly to the ground state via enol MECI. The other one is triggered by an ultrafast ESIPT process firstly and followed by twisting motion of the C1─C7 bond, leading the system funnel to the ground state by a keto type MECI, and finally generates the precursor of coloured flavanone. The proposed S3→(S2) S1 → S0 two step decay pattern is consistent with previous experimental observations. At the molecular microscopic level, the CO bond alternation motion plays a vital role in the whole relaxation process. Our results indicate that further practical application of 2′HC as molecular photoswitches can be achieved by modifying the molecular structure to enhance the ESIPT process.

Peptide-Based Low Molecular Weight Photosensitive Supramolecular Gelators.

Over the last couple of decades, stimuli-responsive supramolecular gels comprising synthetic short peptides as building blocks have been explored for various biological and material applications. Though a wide range of stimuli has been tested depending on the structure of the peptides, light as a stimulus has attracted extensive attention due to its non-invasive, non-contaminant, and remotely controllable nature, precise spatial and temporal resolution, and wavelength tunability. The integration of molecular photo-switch and low-molecular-weight synthetic peptides may thus provide access to supramolecular self-assembled systems, notably supramolecular gels, which may be used to create dynamic, light-responsive “smart” materials with a variety of structures and functions. This short review summarizes the recent advancement in the area of light-sensitive peptide gelation. At first, a glimpse of commonly used molecular photo-switches is given, followed by a detailed description of their incorporation into peptide sequences to design light-responsive peptide gels and the mechanism of their action. Finally, the challenges and future perspectives for developing next-generation photo-responsive gels and materials are outlined.

Reversible, Red-Shifted Photoisomerization in Protonated Azobenzenes.

Azobenzenes are among the best-studied molecular photoswitches and play a key role in the search for red-shifted photoresponsive materials for extended applications. Currently, most approaches deal with aromatic substitution patterns to achieve visible light application, on occasion paired with protonation to yield red-shifted absorption of the azonium species. Appropriate substitution patterns are essential to stabilize the latter approach, as conventional acids are known to induce a fast Z- to E-conversion. Here, we show that steady-state protonation of the azo-bridge instead is possible in simple azobenzenes when the pKa of the acid is low enough, yielding both the Z- and E-azonium as supported by UV–vis- and 1H NMR spectroscopy as well as density functional theory calculations. Moreover, the steady-state protonation of para-methoxyazobenzene, specifically, yields photoisomerizable azonium ions in which the direction of switching is essentially reversed, that is, visible light produces the out-of-equilibrium Z-azonium. Although the current conditions render the visible light photoswitch unsuitable for in vivo and material application, the demonstrated understanding of simple azobenzenes paves the way for a great range of further work on this already widely studied photoswitch.

Multiscale simulation unravels the light-regulated reversible inhibition of dihydrofolate reductase by phototrexate.

Molecular photoswitches are widely used in photopharmacology, where the biomolecular functions are photo-controlled reversibly with high spatiotemporal precision. Despite the success of this field, it remains elusive how the protein environment modulates the photochemical properties of photoswitches. Understanding this fundamental question is critical for designing more effective light-regulated drugs with mitigated side effects. In our recent work, we employed first-principles non-adiabatic dynamics simulations to probe the effects of protein on the trans to cis photoisomerization of phototrexate (PTX), a photochromic analog of the anticancer therapeutic methotrexate that inhibits the target enzyme dihydrofolate reductase (DHFR). Building upon this study, in this work, we employ multiscale simulations to unravel the full photocycle underlying the light-regulated reversible inhibition of DHFR by PTX, which remains elusive until now. First-principles non-adiabatic dynamics simulations reveal that the cis to trans photoisomerization quantum yield is hindered in the protein due to backward isomerization on the ground-state following non-adiabatic transition, which arises from the favorable binding of the cis isomer with the protein. However, free energy simulations indicate that cis to trans photoisomerization significantly decreases the binding affinity of the PTX. Thus, the cis to trans photoisomerization most likely precedes the ligand unbinding from the protein. We propose the most probable photocycle of the PTX-DHFR system. Our comprehensive simulations highlight the trade-offs among the binding affinity, photoisomerization quantum yield, and the thermal stability of the ligand's different isomeric forms. As such, our work reveals new design principles of light-regulated drugs in photopharmacology.

Mechanism of the Aza-Piancatelli Reaction: Scope and Limitations of Furan Substitution in Donor-Acceptor Stenhouse Adduct Synthesis.

The aza-Piancatelli reaction has been widely used to synthesize donor–acceptor Stenhouse adducts (DASAs), a new class of molecular photoswitches with unique properties. However, the substitution pattern of furan cores has been limited to position 3, as 3,4-disubstituted furans remain unreactive. Herein, we explore the aza-Piancatelli reaction mechanism using density functional theory (DFT) calculations to understand the influence of the different substituents on the reactivity. We found that all the reaction pathways are kinetically accessible, but the driving force of the reaction is lost in disubstituted furans due to the loss of conjugation in the DASA products. Finally, a simple model is proposed to guide the design of synthetic routes using this reaction.

Stepping Out of the Blue: From Visible to Near‐IR Triggered Photoswitches

AbstractLight offers unique opportunities for controlling the activity of materials and biosystems with high spatiotemporal resolution. Molecular photoswitches are chromophores that undergo reversible isomerization between different states upon irradiation with light, allowing a convenient means to control their influence over the system of interest. However, a significant limitation of classical photoswitches is the requirement to initiate the switching in one or both directions using deleterious UV light with poor tissue penetration. Red‐shifted photoswitches are hence in high demand and have attracted keen recent research interest. In this Review, we highlight recent progress towards the development of visible‐ and NIR‐activated photoswitches characterized by distinct photochromic reaction mechanisms. We hope to inspire further endeavors in this field, allowing the full potential of these tools in biotechnology and materials chemistry applications to be realized.

Stepping Out of the Blue: From Visible to Near-IR Triggered Photoswitches.

Light offers unique opportunities for controlling the activity of materials and biosystems with high spatiotemporal resolution. Molecular photoswitches are chromophores that undergo reversible isomerization between different states upon irradiation with light, allowing a convenient means to control their influence over the system of interest. However, a significant limitation of classical photoswitches is the requirement to initiate the switching in one or both directions using deleterious UV light with poor tissue penetration. Red-shifted photoswitches are hence in high demand and have attracted keen recent research interest. In this Review, we highlight recent progress towards the development of visible- and NIR-activated photoswitches characterized by distinct photochromic reaction mechanisms. We hope to inspire further endeavors in this field, allowing the full potential of these tools in biotechnology and materials chemistry applications to be realized.

A multi-stage single photochrome system for controlled photoswitching responses.

The ability of molecular photoswitches to convert on/off responses into large macroscale property change is fundamental to light-responsive materials. However, moving beyond simple binary responses necessitates the introduction of new elements that control the chemistry of the photoswitching process at the molecular scale. To achieve this goal, we designed, synthesized and developed a single photochrome, based on a modified donor-acceptor Stenhouse adduct (DASA), capable of independently addressing multiple molecular states. The multi-stage photoswitch enables complex switching phenomena. To demonstrate this, we show spatial control of the transformation of a three-stage photoswitch by tuning the population of intermediates along the multi-step reaction pathway of the DASAs without interfering with either the first or final stage. This allows for a photonic three-stage logic gate where the secondary wavelength solely negates the input of the primary wavelength. These results provide a new strategy to move beyond traditional on/off binary photochromic systems and enable the design of future molecular logic systems.

Visible Light-Driven Alkyne-Grafted Ethylene-Bridged Azobenzene Chromophores for Photothermal Utilization.

Molecular photoswitches are considered to be important candidates in the field of solar energy storage due to their sensitive and reversible bidirectional optical response. Nevertheless, it is still a daunting challenge to design a molecular photoswitch to improve the low solar spectrum utilization and quantum yields while achieving charging and discharging of heat without solvent assistance. Herein, a series of visible-light-driven ethylene-bridged azobenzene (b-Azo) chromophores with different alkyne substituents which can undergo isomerization reactions promoted in both directions by visible light are reported. Their visible light responsiveness improves their solar spectrum utilization while also having high quantum yields. In addition, as the compounds are liquids, there is no need to dissolve the compounds in order to exploit this switching. The photoisomerization of b-Azo can be adjusted by alkyne-related substituents, and hexyne-substituted b-Azo is able to store and release photothermal energy with a high density of 106.1 J·g−1, and can achieve a temperature increase of 1.8 °C at a low temperature of −1 °C.

The effect of temperature on the photoacidity of merocyanine photoacids in water

Merocyanine photoacids are molecular photoswitches that can be used to regulate acid-base reactions reversibly. Despite their growing impact across multiple research areas including materials science and nanotechnology, the effect of temperature on their functioning in aqueous environments has not yet been explored. Here we employ variable-temperature pH and UV-Vis analyses to rationalize their temperature-dependent (photo)chemical behaviors in water, showing that their photoacidity is inversely proportional to the temperature (by ca. −0.01 pK/°C).

Cover Feature: Smart Photochromic Materials Triggered with Visible Light (Eur. J. Org. Chem. 19/2022)

The Cover Feature illustrates stimuli-responsive materials triggered with visible light. Molecular photoswitches that reversibly change their molecular properties upon visible illumination can be incorporated into various materials and elicit macroscopic light-triggered effects. Applications span from solar energy conversion to biocompatible drug-releasing compositions. More information can be found in the Review by A.-L. Leistner and Z. L. Pianowski.

Fluorescence photoswitch of stiff-stilbene derivatives for anti-counterfeiting

Precise improvement of photo-isomerized reaction of molecular photoswitches is a greatly meaningful research topic for the fabrication of high-performance smart materials. Herein, a series of stiff-stilbene derivatives with substituents of different electronic effects were designed and prepared handily through Suzuki coupling reaction. Through studying their photoisomerization properties, we disclosed the influence law of electronic effect on photoisomerization properties of stiff-stilbenes that strong electron-donating and electron-deficient groups located in the counterposition of stiff-stilbenes on the benzene ring were not conducive to photochromism performance of stiff-stilbene skeleton. The (E)-form of these stiff-stilbenes, a new class of fluorescence dyes, showed good photoluminescence performance, and dramatically stronger than their (Z)-isomers. Importantly, we witnessed a fascinating photo-modulating fluorescence behavior for these molecular photoswitches, which were further applied in high-secrecy-level anti-counterfeiting. The study provided a reference for the design of excellent molecular photoswitches with purpose and precision and the development of new intelligent optical materials.

Effects of Enzyme-Ligand Interactions on the Photoisomerization of a Light-Regulated Chemotherapeutic Drug.

Molecular photoswitches permit using light to control protein activity with high spatiotemporal resolutions, thereby alleviating the side effects of conventional chemotherapy. However, due to the challenges in probing ultrafast photoisomerization reactions in biological environments, it remains elusive how the protein influences the photochemistry of the photoswitches, which hampers the rational design of light-regulated therapeutics. To overcome this challenge, we employed first-principles nonadiabatic dynamics simulations to characterize the photodynamics of the phototrexate (PTX), a recently developed photoswitchable anticancer chemotherapeutic that reversibly inhibits its target enzyme dihydrofolate reductase (DHFR). Our simulations show that the protein environment impedes the trans to cis photoisomerization of the PTX. The confinement in the ligand-binding cavity slows down the isomerization kinetics and quantum yield of the photoswitch by reshaping its conical intersection, increasing its excited-state free-energy barrier and quenching its local density fluctuations. Also, the protein environment results in a suboptimal binding mode of the photoproduct that needs to undergo large structural rearrangement to effectively inhibit the enzyme. Therefore, we predict that the PTX's trans → cis photoisomerization in solution precedes its binding with the protein, despite the favorable binding energy of the trans isomer. Our findings highlight the importance of the protein environment on the photochemical reactions of the molecular photoswitches. As such, our work represents an important step toward the rational design of light-regulated drugs in photopharmacology.

Smart Photochromic Materials Triggered with Visible Light

AbstractMolecular photoswitches reversibly convert the energy of light into a variety of structural changes at the molecular level. They can be integrated into smart materials with broad range of applicability. While most photochromic systems require UV light for activation, application of photoswitches operational entirely within the visible or NIR range of light brings considerable benefits, such as biocompatibility, better light penetration through the material, propelling with sunlight, or a possibility to design dual systems that are mutually activated with UV or visible light frequencies for two distinct functions. In this Review, we discuss the most relevant classes of molecular photoswitches, and demonstrate a selection of photochromic polymers, gels, porous materials, surfaces, energy‐storing materials and other systems triggered with visible light.

Hypothesis-Driven, Structure-Based Design in Photopharmacology: The Case of eDHFR Inhibitors.

Photopharmacology uses light to regulate the biological activity of drugs. This precise control is obtained through the incorporation of molecular photoswitches into bioactive molecules. A major challenge for photopharmacology is the rational design of photoswitchable drugs that show light-induced activation. Computer-aided drug design is an attractive approach toward more effective, targeted design. Herein, we critically evaluated different structure-based approaches for photopharmacology with Escherichia coli dihydrofolate reductase (eDHFR) as a case study. Through the iterative examination of our hypotheses, we progressively tuned the design of azobenzene-based, photoswitchable eDHFR inhibitors in five design–make–switch–test–analyze cycles. Targeting a hydrophobic subpocket of the enzyme and a specific salt bridge only with the thermally metastable cis-isomer emerged as the most promising design strategy. We identified three inhibitors that could be activated upon irradiation and reached potencies in the low-nanomolar range. Above all, this systematic study provided valuable insights for future endeavors toward rational photopharmacology.

Digital photoprogramming of liquid-crystal superstructures featuring intrinsic chiral photoswitches

Dynamic patterning of soft materials in a fully reversible and programmable manner with light enables applications in anti-counterfeiting, displays and labelling technology. However, this is a formidable challenge due to the lack of suitable chiral molecular photoswitches. Here, we report the development of a unique intrinsic chiral photoswitch with broad chirality modulation to achieve digitally controllable, selectable and extractable multiple stable reflection states. An anti-counterfeiting technique, embedded with diverse microstructures, featuring colour-tunability, erasability, reversibility, multi-stability and viewing-angle dependency of pre-recorded patterns, is established with these photoresponsive superstructures. This strategy allows dynamic helical transformation from the molecular and supramolecular to the macroscopic level using light-activated intrinsic chirality, demonstrating the practicality of photoprogramming photonics.

Hemithioindigo-Based Trioxobicyclononadiene: 3D Multiswitching of Electronic and Geometric Properties.

Molecular photoswitches that offer simultaneous precise control over geometrical and electronic changes are rare yet highly sought tools for the development of responsive nanosystems. Here we present such an advantageous combination of property control within a novel multiphotoswitch architecture. Hemithioindigo-based trioxobicyclononadiene (HTI-TOND) offers a rigid three-dimensional molecular structure that undergoes different exotic rearrangement reactions upon photochemical and thermal signaling. Three to four different states with distinct geometric and electronic properties can be accessed reversibly in high yields within this molecular framework. Thus, a highly promising and unique switching tool has become available to instill the next level of addressability at the smallest scales.