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Abstract Light-driven rotary molecular motors are among the most promising classes of responsive molecular machines and take advantage of their intrinsic chirality which governs unidirectional rotation. As a consequence of their dynamic function, they receive considerable interest in the areas of supramolecular chemistry, asymmetric catalysis and responsive materials. Among the emerging classes of responsive photochromic molecules, multistate first-generation molecular motors driven by benign visible light remain unexplored, which limits the exploitation of the full potential of these mechanical light-powered systems. Herein, we describe a series of all-visible-light-driven first-generation molecular motors based on the salicylidene Schiff base functionality. Remarkable redshifts up to 100 nm in absorption are achieved compared to conventional first-generation motor structures. Taking advantage of all-visible-light-driven multistate motor scaffolds, adaptive behaviour is found as well, and potential application in multistate photoluminescence is demonstrated. These functional visible-light-responsive motors will likely stimulate the design and synthesis of more sophisticated nanomachinery with a myriad of future applications in powering dynamic systems.

Abstract Photoisomerization and photoluminescence are two distinct energy dissipation pathways in light‐driven molecular motors. The photoisomerization properties of discrete molecular motors have been well established in solution, but their photoluminescent properties have been rarely reported—especially in aggregates. Here, it is shown that an overcrowded alkene‐based molecular motor exhibits distinct dynamic properties in solution and aggregate states, for example, gel and solid states. Despite the poor emissive properties of molecular motors in solution, a bright emission is observed in the aggregate states, including in gel and the crystalline solid. The emission wavelength is highly dependent on the nature of the supramolecular packing and order in the aggregates. As a result, the fluorescent color can be readily tuned reversibly via mechanical grinding and vapor fuming, which provides a new platform for developing multi‐stimuli functional materials.

Abstract Converting elementary sulfur into sulfur-rich polymers provides a sustainable strategy to replace fossil-fuel-based plastics. However, the low ring strain of eight-membered rings, i.e., S8 monomers, compromises their ring-opening polymerization (ROP) due to lack of an enthalpic driving force and as a consequence, poly(sulfur) is inherently unstable. Here we report that copolymerization with cyclic disulfides, e.g., 1,2-dithiolanes, can enable a simple and energy-saving way to convert elementary sulfur into sulfur-rich thermoplastics. The key strategy is to combine two types of ROP—both mediated by disulfide bond exchange—to tackle the thermodynamic instability of poly(sulfur). Meanwhile, the readily modifiable sidechain of the cyclic disulfides provides chemical space to engineer the mechanical properties and dynamic functions over a large range, e.g., self-repairing ability and degradability. Thus, this simple and robust system is expected to be a starting point for the organic transformation of inorganic sulfur toward sulfur-rich functional and green plastics.

Abstract In the past two decades, the research and development of light-triggered molecular machines have mainly focused on developing molecular devices at the nanoscale. A key scientific issue in the field is how to amplify the controlled motion of molecules at the nanoscale along multiple length scales, such as the mesoscopic or the macroscopic scale, or in a more practical perspective, how to convert molecular motion into changes of properties of a macroscopic material. Light-driven molecular motors are able to perform repetitive unidirectional rotation upon irradiation, which offers unique opportunities for responsive macroscopic systems. With several reviews that focus on the design, synthesis and operation of the motors at the nanoscale, photo-responsive macroscopic materials based on light-driven molecular motors have not been comprehensively summarized. In the present review, we first discuss the strategy of confining absolute molecular rotation into relative rotation by grafting motors on surfaces. Secondly, examples of self-assemble motors in supramolecular polymers with high internal order are illustrated. Moreover, we will focus on building of motors in a covalently linked system such as polymeric gels and polymeric liquid crystals to generate complex responsive functions. Finally, a perspective toward future developments and opportunities is given. This review helps us getting a more and more clear picture and understanding on how complex movement can be programmed in light-responsive systems and how man-made adaptive materials can be invented, which can serve as an important guideline for further design of complex and advanced responsive materials.

Abstract In recent years, the use of light to selectively and precisely activate drugs has been developed along the fundamental concepts of photopharmacology. One of the key methods in this field relies on transiently silencing the drug activity with photocleavable protecting groups (PPGs). To effectively utilize light‐activated drugs in future medical applications, physicians will require a reliable method to assess whether light penetrates deep enough into the tissues to activate the photoresponsive theragnostic agents. Here, we describe the development and evaluation of magnetic resonance (MR) imaging agents that allow for the detection of light penetration and drug activation in the tissues using non‐invasive whole‐body magnetic resonance imaging (MRI) and chemical exchange saturation transfer (CEST)‐MRI modalities. The approach relies on the use of PPG‐protected MR contrast agents, which upon irradiation with light change their imaging signal. A Gadolinium(III)‐based MRI contrast agent is presented that undergoes a significant change in relaxivity (25%) upon uncaging, providing a reliable indicator of light‐induced cargo release. Additionally, we introduce the first light‐responsive CEST‐MRI imaging agent, enabling positive signal enhancement (off‐to‐on) upon light activation, offering a novel approach to visualize the activation of photoactive agents in living tissues. This research provides a proof‐of‐principle for the non‐invasive, whole‐body imaging of light penetration and drug activation with high temporal resolution characteristic of MR methods.

Abstract Developing dynamic chemistry for polymeric materials offers chemical solutions to solve key problems associated with current plastics. Mechanical performance and dynamic function are equally important in material design because the former determines the application scope and the latter enables chemical recycling and hence sustainability. However, it is a long‐term challenge to balance the subtle trade‐off between mechanical robustness and dynamic properties in a single material. The rise of dynamic chemistry, including supramolecular and dynamic covalent chemistry, provides many opportunities and versatile molecular tools for designing constitutionally dynamic materials that can adapt, repair, and recycle. Facing the growing social need for developing advanced sustainable materials without compromising properties, recent progress showing how the toolbox of dynamic chemistry can be explored to enable high‐performance sustainable materials by molecular engineering strategies is discussed here. The state of the art and recent milestones are summarized and discussed, followed by an outlook toward future opportunities and challenges present in this field.

Controlling molecular motion at nanoscale is important for the design of nanomachines. Here the authors use ultrafast vibrational and electronic spectroscopy to characterize the mechanism of motion of a light driven molecular motor designed to support translational movement.

Combining photofunctionalities in a single molecule is challenging due to inherent detrimental interactions. Here, the authors construct a molecular motor that exhibits photoinduced rotary motion together with bright photoluminescence.

The application of photoswitches as light-responsive triggers for phase transitions of porous materials remains poorly explored. Here, the authors report a light-responsive flexible metal-organic framework which undergoes pore contraction upon combined application of light irradiation and adsorption stress via a buckling process of the framework-embedded azobenzene photoswitch.

Abstract Background Pretargeted immuno-PET tumor imaging has emerged as a valuable diagnostic strategy that combines the high specificity of antibody-antigen interaction with the high signal and image resolution offered by short-lived PET isotopes, while reducing the irradiation dose caused by traditional 89Zr-labelled antibodies. In this work, we demonstrate proof of concept of a novel ‘two-step’ immuno-PET pretargeting approach, based on bispecific antibodies (bsAbs) engineered to feature dual high-affinity binding activity for a fluorescein-based 18F-PET tracer and tumor markers. Results A copper(I)-catalysed click reaction-based radiolabeling protocol was developed for the synthesis of fluorescein-derived molecule [ 18 F]TPF. Binding of [ 18 F]TPF on FITC-bearing bsAbs was confirmed. An in vitro autoradiography assay demonstrated that [ 18 F]TPF could be used for selective imaging of EpCAM-expressing OVCAR3 cells, when pretargeted with EpCAMxFITC bsAb. The versatility of the pretargeting approach was showcased in vitro using a series of fluorescein-binding bsAbs directed at various established cancer-associated targets, including the pan-carcinoma cell surface marker EpCAM, EGFR, melanoma marker MCSP (aka CSPG4), and immune checkpoint PD-L1, offering a range of potential future applications for this pretargeting platform. Conclusion A versatile pretargeting platform for PET imaging, which combines bispecific antibodies and a fluorescein-based 18F-tracer, is presented. It is shown to selectively target EpCAM-expressing cells in vitro and its further evaluation with different bispecific antibodies demonstrates the versatility of the approach.

The molecular imaging of biomarkers plays an increasing role in medical diagnostics. In particular, the imaging of enzyme activity is a promising approach, as it enables the use of its inherent catalytic activity for the amplification of an imaging signal. The increased activity of a sulfatase enzyme has been observed in several types of cancers. We describe the development and in vitro evaluation of molecular imaging agents that allow for the detection of sulfatase activity using the whole-body, non-invasive MRI and CEST imaging methods. This approach relies on a responsive ligand that features a sulfate ester moiety, which upon sulfatase-catalyzed hydrolysis undergoes an elimination process that changes the functional group, coordinating with the metal ion. When Gd3+ is used as the metal, the complex can be used for MRI, showing a 25% decrease at 0.23T and a 42% decrease at 4.7T in magnetic relaxivity after enzymatic conversion, thus providing a “switch-off” contrast agent. Conversely, the use of Yb3+ as the metal leads to a “switch-on” effect in the CEST imaging of sulfatase activity. Altogether, the results presented here provide a molecular basis and a proof-of-principle for the magnetic imaging of the activity of a key cancer biomarker.

The circadian clock is an internal mechanism that controls various physiological processes, such as the sleep-wake cycle, but its precise regulation is challenging. Here, the authors develop a visible light-responsive inhibitor of casein kinase I which controls the period and phase of cellular and tissue circadian rhythms in a reversible manner.

Molecular motors and switches change conformation under the influence of an external stimulus and can be incorporated into functional systems, allowing the construction of adaptive materials and switchable catalysts. Here, the authors present two molecular motor-functionalized porphyrin macrocycles for future photo-switchable catalysis.

Abstract Molecular motors change conformation under the influence of light and when attached to host molecules, they may find applications as sensors and switchable catalysts. Here, we present a porphyrin macrocyclic host functionalized with two motor appendages for future catalytic applications. The compound is formed as a mixture of six stereoisomers (three sets of enantiomers), which have been separated by (chiral) chromatography. 1H NMR and chiral spectroscopy revealed that in one set of enantiomers, the two motors interact with the cavity of the host (bound‐bound), whereas in a second set, one interacts and the other one does not (bound‐loose). In the third set, both motors do not interact with the host compound (loose‐loose). The motorized hosts bind guest molecules in the order: (loose‐loose) > (bound‐loose) > (bound‐bound). They can be switched with light to pseudoidentical diastereomers, leading to orthogonal behavior in the light‐gated binding of guest molecules. Although the photoisomerization of the diastereomer set loose‐loose significantly lowers the binding affinity for viologen guests, the opposite is true for the diastereomer set bound‐bound, that is, the binding affinity increases. For the diastereomer set bound‐loose, no influence on guest binding is observed as the effect of photoisomerization on the motors is cancelled out. Key Points We present a porphyrin cage compound with two light‐switchable molecular motors for future catalytic applications The double‐motorized porphyrin cage compound is formed as a mixture of six stereoisomers (three sets of enantiomers), which could be separated, and by photoswitching converted to pseudoidentical stereoisomers The stereoisomers display different binding affinities for guest molecules, which reverse on photoswitching, leading to orthogonal guest binding behavior

Abstract It is established that electron transmission through chiral molecules depends on the electron's spin. This phenomenon, termed the chiral‐induced spin selectivity (CISS), effect has been observed in chiral molecules, supramolecular structures, polymers, and metal‐organic films. Which spin is preferred in the transmission depends on the handedness of the system and the tunneling direction of the electrons. Molecular motors based on overcrowded alkenes show multiple inversions of helical chirality under light irradiation and thermal relaxation. The authors found here multistate switching of spin selectivity in electron transfer through first generation molecular motors based on the four accessible distinct helical configurations, measured by magnetic‐conductive atomic force microscopy. It is shown that the helical state dictates the molecular organization on the surface. The efficient spin polarization observed in the photostationary state of the right‐handed motor coupled with the modulation of spin selectivity through the controlled sequence of helical states, opens opportunities to tune spin selectivity on‐demand with high spatio‐temporal precision. An energetic analysis correlates the spin injection barrier with the extent of spin polarization.

In recent years, increasing efforts have been devoted to designing new functional stimuli-responsive supramolecular assemblies. Here, we present three isomeric supramolecular coordination complexes consisting of a Pd2L4 stoichiometry. As shown by NMR, CD and X-ray studies, as well as DFT calculations, these complexes form cage-like structures by chiral self-sorting. Photochromic ligands derived from first generation molecular motors enable light-driven interconversion between the three isomers. Two of the isomers were able to form host–guest complexes opening up new prospects toward stimuli-controlled substrate binding and release.

Protein kinases are responsible for healthy cellular processes and signalling pathways, and their dysfunction is the basis of many pathologies. There are numerous small molecule inhibitors of protein kinases that systemically regulate dysfunctional signalling processes. However, attaining selectivity in kinase inhibition within the complex human kinome is still a challenge that inspires unconventional approaches. One of those approaches is photopharmacology, which uses light-controlled bioactive molecules to selectively activate drugs only at the intended space and time, thereby avoiding side effects outside of the irradiated area. Still, in the context of kinase inhibition, photopharmacology has thus far been rather unsuccessful in providing light-controlled drugs. Here, we present the discovery and optimisation of a photoswitchable inhibitor of casein kinase 1δ (CK1δ), important for the control of cell differentiation, circadian rhythm, DNA repair, apoptosis, and numerous other signalling processes. Varying the position at which the light-responsive azobenzene moiety has been introduced into a known CK1δ inhibitor, LH846, revealed the preferred regioisomer for efficient photo-modulation of inhibitory activity, but the photoswitchable inhibitor suffered from sub-optimal (photo)chemical properties. Replacement of the bis-phenyl azobenzene group with the arylazopyrazole moiety yielded a superior photoswitch with very high photostationary state distributions, increased solubility and a 10-fold difference in activity between irradiated and thermally adapted samples. The reasons behind those findings are explored with molecular docking and molecular dynamics simulations. Results described here show how the evaluation of privileged molecular architecture, followed by the optimisation of the photoswitchable unit, is a valuable strategy for the challenging design of the photoswitchable kinase inhibitors.

Unidirectional rotation in a synthetic molecular motor is typically driven by intrinsic asymmetry or sequences of chemical transformations. Here, the authors control the direction of a molecule’s rotation through supramolecular binding of a chiral guest and subsequent transfer of its chiral information.

Fluorescence sensing in biological environments is prone to background signal interference. Here the authors design a photochromic fluorescent glycoprobe for light-controlled photo-switchable cell imaging and photo-activated target recognition, resulting in an increased sensing precision.

During the last decades, a continuous rise of multi-drug resistant pathogens has threatened antibiotic efficacy. To tackle this key challenge, novel antimicrobial therapies are needed with increased specificity for the site of infection. Photopharmacology could enable such specificity by allowing for the control of antibiotic activity with light, as exemplified by trans/cis-tetra-ortho-chloroazobenzene-trimethoprim (TCAT) conjugates. Resistance development against the on (irradiated, TCATa) and off (thermally adapted, TCATd) states of TCAT were compared to that of trimethoprim (TMP) in Escherichia coli mutant strain CS1562. Genomics and transcriptomics were used to explore the acquired resistance. Although TCAT shows TMP-like dihydrofolate reductase (DHFR) inhibition in vitro, transcriptome analyses show different responses in acquired resistance. Resistance against TCATa (on) relies on the production of exopolysaccharides and overexpression of TolC. While resistance against TCATd (off) follows a slightly different gene expression profile, both indicate hampering the entrance of the molecule into the cell. Conversely, resistance against TMP is based on alterations in cell metabolism towards a more persister-like phenotype, as well as alteration of expression levels of enzymes involved in the folate biosynthesis. This study provides a deeper understanding of the development of new therapeutic strategies and the consequences on resistance development against photopharmacological drugs.

While molecular photoswitches have proven useful in many fields, selective and reversible control over multiple switches is an unsolved challenge. Here, the authors report on a system consisting of two classes of photoswitches that can be addressed orthogonally and demonstrate the applicability in phase-transfer control.

Cross-coupling reactions typically are carried out under dilute conditions of ethereal solvents. Here, the authors report a method for palladium catalysed cross-coupling of organolithium reagents that avoids the use of any added solvent with reaction times of only minutes.

Thanks to its innocuousness and high spatiotemporal resolution, light is used in several established and emerging applications in biomedicine. Among them is the modulation of magnetic resonance imaging (MRI) contrast agents’ relaxivity with the aim to increase the sensitivity, selectivity and amount of functional information obtained from this outstanding whole-body medical imaging technique. This approach requires the development of molecular contrast agents that show high relaxivity and strongly pronounced photo-responsiveness. To this end, we report here the design and synthesis of a light-activated MRI contrast agent, together with its evaluation using UV–vis spectroscopy, Fast Field Cycling (FFC) relaxometry and relaxometric measurements on clinical MRI scanners. The high relaxivity of the reported agent changes substantially upon irradiation with light, showing a 17% decrease in relaxivity at 0.23T upon irradiation with λ = 400 nm (violet) light for 60 min. On clinical MRI scanners (1.5T and 3.0T), irradiation leads to a decrease in relaxivity of 9% and 19% after 3 and 60 min, respectively. The molecular design presents an important blueprint for the development of light-activatable MRI contrast agents.

Femtosecond Stimulated Raman Spectroscopy (FSRS) reports on structure and dynamics of excited states. Here we record FSRS for a photomolecular motor in its stable and metastable states, and thus map the entire excited state PES.

A glycerophospholipid (1-O-tuberculostearoyl-2-O-palmitoyl-sn-glycero-3-phosphoethanolamine) from Mycobacterium tuberculosis was isolated from the reference strain H37Rv. The molecular structure of this tuberculostearoyl [(R)-10-methyloctadecyl] and palmitoyl containing phosphatidylethanolamine (PE) has been resolved. The substitution pattern on the glycerol backbone could be determined by comparison of the isolate to the two synthetically prepared regioisomers. MS/MS analysis was used to determine its molecular structure. Production of this synthetic version of mycobacterial PE in high yield, with a stereochemically correct and pathogen-specific fatty acyl group, can be used as a standard in LC-MS based lipidomic analyses to detect trace amounts of mycobacterial PE in human blood, sputum, or tissues as a marker of infection by mycobacteria.

The field of molecular and organic electronics has seen rapid progress in recent years, developing from concept and design to actual demonstration devices in which both single molecules and self-assembled monolayers are employed as light-responsive components. Research in this field has seen numerous unexpected challenges that have slowed progress and the initial promise of complex molecular-based computers has not yet been realised. Primarily this has been due to the realisation at an early stage that molecular-based nano-electronics brings with it the interface between the hard (semiconductor) and soft (molecular) worlds and the challenges which accompany working in such an environment. Issues such as addressability, cross-talk, molecular stability and perturbation of molecular properties (e.g. inhibition of photochemistry) have nevertheless driven development in molecular design and synthesis as well as our ability to interface molecular components with bulk metal contacts to a very high level of sophistication. Numerous groups have played key roles in progressing this field not least teams such as those led by Whitesides, Aviram, Ratner, Stoddart and Heath. In this short review we will however focus on the contributions from our own group and those of our collaborators, in employing diarylethene based molecular components.

The assembly, integration and functioning of various molecular components in complex systems is illustrated.

On Monday, November 7, 2005, the rector Prof. Dr. K. Osterwalder presented the Prelog Medal 2005 to Prof. Dr. Ben L. Feringa, University of Groningen, The Netherlands. The title of the lecture that followed was 'In Control of Chirality, from Asymmetric Catalysis to Nanomachines'.

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