Clinical aspects and management of chronic itch.

Chronic pruritus (CP) (ie, itch that persists for more than 6 weeks) poses significant challenges to patients' health and quality of life. It is a common reason for visits to dermatologists and general practitioners and can be caused by a range of conditions, including systemic diseases such as chronic kidney disease or liver diseases, malignancies, neuropathic conditions, and dermatoses such as atopic dermatitis. CP often does not develop in parallel with the course of the disease and can become an entity of its own, which must be treated with antipruritic drugs, even if the underlying cause is already under therapy. Depending on the etiology of CP, different pathways in the pathogenesis have been analyzed recently, following which new treatments have been developed and tested in randomized controlled trials. This article discusses the recent results of these studies and highlights how best to manage health care for patients with CP.

[Pruritus in atopic dermatitis-comparative evaluation of novel treatment approaches]. / Pruritus bei atopischer Dermatitis ­ vergleichende Bewertung neuer Therapieansätze.

Chronic pruritus (duration ≥ 6 weeks) affects about 91% of patients suffering from atopic dermatitis (AD). Pruritus is often accompanied by sensations such as pain, burning, stinging, and heat, resulting in a high burden of affected patients; sleep and quality of life may be severely impaired. An important pillar of AD treatment is also to achieve sufficient control of pruritus. In addition to intensively used emollients, corticosteroids and calcineurin inhibitors have proven effective. In case of eczema affecting a large part of the body surface area (BSA), phototherapy may contribute to the healing of eczema and the relief of atopic pruritus. As to systemic therapies, several approved biologics (dupilumab, tralokinumab) and small molecules (baricitinib, upadacitinib, abrocitinib) lead to a rapid improvement of pruritus by interfering with the signal transduction of proinflammatory cytokines. While Janus kinase inhibitors initially lead to a faster relief of pruritus than biologics, the antipruritic efficacy of biologics and Janus kinase inhibitors seems to be similar in long-term use.

Aggregation-induced emission leading to two distinct emissive species in the solid-state structure of high-dipole organic chromophores.

The concept of aggregation-induced emission represents a means to rationalise photoluminescence of usually nonfluorescent excimers in solid-state materials. In this publication, we study the photophysical properties of selected diaminodicyanoquinone (DADQ) derivatives in the solid state using a combined approach of experiment and theory. DADQs are a class of high-dipole organic chromophores promising for applications in non-linear optics and light-harvesting devices. Among the compounds investigated, we find both aggregation-induced emission and aggregation-caused quenching effects rationalised by calculated energy transfer rates. Analysis of fluorescence spectra and lifetime measurements provide the interesting result that (at least) two emissive species seem to contribute to the photophysical properties of DADQs. The main emission peak is notably broadened in the long-wavelength limit and exhibits a blue-shifted shoulder. We employ high-level quantum-chemical methods to validate a molecular approach to a solid-state problem and show that the complex emission features of DADQs can be attributed to a combination of H-type aggregates, monomers, and crystal structure defects.

Fluorescence Quenching in J-Aggregates through the Formation of Unusual Metastable Dimers.

Molecular aggregation alters the optical properties of a system as fluorescence may be activated or quenched. This is usually described within the well-established framework of H- and J-aggregates. While H-aggregates show nonfluorescent blueshifted absorption bands with respect to the isolated monomer, J-aggregates are fluorescent displaying a redshifted peak. In this publication, we employ a combined approach of experiment and theory to study the complex aggregation features and photophysical properties of diaminodicyanoquinone derivatives, which show unusual and puzzling nonfluorescent redshifted absorption bands upon aggregation. Our theoretical analysis demonstrates that stable aggregates do not account for the experimental observations. Instead, we propose an unprecedented mechanism involving metastable dimeric species formed from stable dimers to generate nonfluorescent J-aggregates. These results represent a novel kind of aggregation-induced optical effect and may have broad implications for the photophysics of dye aggregates.

Thermodynamic and electrochemical study of tailor-made crown ethers for redox-switchable (pseudo)rotaxanes.

Crown ethers are common building blocks in supramolecular chemistry and are frequently applied as cation sensors or as subunits in synthetic molecular machines. Developing switchable and specifically designed crown ethers enables the implementation of function into molecular assemblies. Seven tailor-made redox-active crown ethers incorporating tetrathiafulvalene (TTF) or naphthalene diimide (NDI) as redox-switchable building blocks are described with regard to their potential to form redox-switchable rotaxanes. A combination of isothermal titration calorimetry and voltammetric techniques reveals correlations between the binding energies and redox-switching properties of the corresponding pseudorotaxanes with secondary ammonium ions. For two different weakly coordinating anions, a surprising relation between the enthalpic and entropic binding contributions of the pseudorotaxanes was discovered. These findings were applied to the synthesis of an NDI-[2]rotaxane, which retains similar spectroelectrochemical properties compared to the corresponding free macrocycle. The detailed understanding of the thermodynamic and electrochemical properties of the tailor-made crown ethers lays the foundation for the construction of new types of molecular redox switches with emergent properties.

Diaminodicyanoquinones: Fluorescent Dyes with High Dipole Moments and Electron-Acceptor Properties.

Fluorescent dyes are applied in various fields of research, including solar cells and light-emitting devices, and as reporters for assays and bioimaging studies. Fluorescent dyes with an added high dipole moment pave the way to nonlinear optics and polarity sensitivity. Redox activity makes it possible to switch the molecule's photophysical properties. Diaminodicyanoquinone derivatives possess high dipole moments, yet only low fluorescence quantum yields, and have therefore been neglected as fluorescent dyes. Here we investigate the fluorescence properties of diaminodicyanoquinones using a combined theoretical and experimental approach and derive molecules with a fluorescence quantum yield exceeding 90 %. The diaminodicyanoquinone core moiety provides chemical versatility and can be integrated into novel molecular architectures with unique photophysical features.

Scalable Production of Nanographene and Doping via Nondestructive Covalent Functionalization.

A new method for top-down, one-pot, gram-scale production of high quality nanographene by incubating graphite in a dilute sodium hypochlorite solution at only 40 °C is reported here. The produced sheets have only 4 at% oxygen content, comparable with nanographene grown by chemical vapor deposition. The nanographene sheets are covalently functionalized using a nondestructive nitrene [2+1] cycloaddition reaction that preserves their π-conjugated system. Statistical analyses of Raman spectroscopy and X-ray photoelectron spectroscopy indicate a low number of sp3 carbon atoms on the order of 2% before and 4% after covalent functionalization. The nanographene sheets are significantly more conductive than conventionally prepared nanographene oxide, and conductivity further increases after covalent functionalization. The observed doping effects and theoretical studies suggest sp2 hybridization for the carbon atoms involved in the [2+1] cycloaddition reaction leading to preservation of the π-conjugated system and enhancing conductivity via n-type doping through the bridging N-atom. These methods are easily scalable, which opens the door to a mild and efficient process to produce high quality nanographenes and covalently functionalize them while retaining or improving their physicochemical properties.

Naphthocage: A Flexible yet Extremely Strong Binder for Singly Charged Organic Cations.

We report a quite flexible naphthol-based cage (so-called "naphthocage") which adopts a self-inclusion conformation in its free state and is able to bind singly charged organic cations extremely strongly ( Ka > 107 M-1). Ion-selective electrodes prepared with this naphthocage show a super-Nernstian response to acetylcholine. In addition, the highly stable complex (1010 M-1) between ferrocenium and the naphthocage can be switched electrochemically, which lays a basis for its application in stimuli-responsive materials.

Chiroptical inversion of a planar chiral redox-switchable rotaxane.

A tetrathiafulvalene (TTF)-containing crown ether macrocycle with C s symmetry was designed to implement planar chirality into a redox-active [2]rotaxane. The directionality of the macrocycle atom sequence together with the non-symmetric axle renders the corresponding [2]rotaxane mechanically planar chiral. Enantiomeric separation of the [2]rotaxane was achieved by chiral HPLC. The electrochemical properties - caused by the reversible oxidation of the TTF - are similar to a non-chiral control. Reversible inversion of the main band in the ECD spectra for the individual enantiomers was observed after oxidation. Experimental evidence, conformational analysis and DFT calculations of the neutral and doubly oxidised species indicate that mainly electronic effects of the oxidation are responsible for the chiroptical switching. This is the first electrochemically switchable rotaxane with a reversible inversion of the main ECD band.

Switchable synchronisation of pirouetting motions in a redox-active [3]rotaxane.

In this study, the crown/ammonium [3]rotaxane R2 is reported which allows a switchable synchronisation of wheel pirouetting motions. The rotaxane is composed of a dumbbell-shaped axle molecule with two mechanically interlocked macrocycles which are decorated with a redox-active tetrathiafulvalene (TTF) unit. Electrochemical, spectroscopic, and electron paramagnetic resonance experiments reveal that rotaxane R2 can be reversibly switched between four stable oxidation states (R2, R2˙+, R22(˙+), and R24+). The oxidations enable non-covalent, cofacial interactions between the TTF units in each state-including a stabilised mixed-valence (TTF2)˙+ and a radical-cation (TTF˙+)2 dimer interaction-which dictate a syn (R2, R2˙+, and R22(˙+)) or anti (R24+) ground state co-conformation of the wheels in the rotaxane. Furthermore, the strength of these wheel-wheel interactions varies with the oxidation state, and thus electrochemical switching allows a controllable synchronisation of the wheels' pirouetting motions. DFT calculations explore the potential energy surface of the counter-rotation of the two interacting wheels in all oxidation states. The controlled coupling of pirouetting motions in rotaxanes can lead to novel molecular gearing systems which transmit rotational motion by switchable non-covalent interactions.

To Anion-π or not to Anion-π: The Case of Anion-Binding to Divalent Fluorinated Pyridines in the Gas Phase.

A series of mono- and divalent fluorinated pyridine derivatives is investigated by electrospray ionization (tandem) mass spectrometry and quantum chemical calculations with respect to their capability to bind anions in the gas phase. The pyridine derivatives differ not only in valency, but also with regard to the degree of fluorination of the pyridine rings, the positions of the fluorine atoms, the rigidity of the spacers connecting the two pyridines in the divalent compounds, and the relative configuration. While the monovalent compounds did not form anion complexes, the divalent analogues exhibit anion binding even to weakly coordinating anions such as tetrafluoroborate. Three different tandem mass spectrometric experiments were applied to rank the gas-phase binding energies: (i) collision-induced dissociation (CID) experiments in a Fourier transform ion-cyclotron-resonance (FTICR) mass spectrometer on two different, simultaneously mass-selected complexes with different receptors, (ii) determination of the collision energy required to fragment 50 % of the mass-selected complexes in an ESI-QToF mass spectrometer, and (iii) CID of heterodimers formed from two different, competing pyridine receptors and indigo carmine, a dianion with two identical binding sites. All three experiments result in consistent binding energy ranking. This ranking reveals surprising features, which are not in agreement with binding through anion-π interactions. Density functional theory (DFT) calculations comparing different potential binding modes provide evidence that the ranking can instead nicely be explained, when C-H⋅⋅⋅anion interactions with the spacers are invoked. These results are supported by gas-phase IR spectroscopy and ion mobility-mass spectrometry (IM-MS) on a selected set of chloride pyridine complexes.

An aryl-fused redox-active tetrathiafulvalene with enhanced mixed-valence and radical-cation dimer stabilities.

Molecular recognition of stable organic radicals is a relatively novel, but important structural binding motif in supramolecular chemistry. Here, we report on a redox-switchable veratrole-fused tetrathiafulvalene derivative VTTF which is ideally suited for this purpose and for the incorporation into stimuli-responsive systems. As revealed by electrochemistry, UV/Vis measurements, X-ray analysis, and electrocrystallisation, VTTF can be reversibly oxidised to the corresponding radical-cation or dication which shows optoelectronic and structural propterties similar to tetrathiafulvalene and tetrakis(methylthio)tetrathiafulvalene. However, theoretical calculations, variable temperature EPR, and NIR spectroscopy indicate that the dispersion-driven binding in the mixed-valence dimer (VTTF2)˙+ (KMV = 69 M-1 in CH2Cl2) and the radical-cation dimer (VTTF˙+)2 (KRC = 38 M-1 in CH3CN) is significantly enhanced by the additional veratrole π-surface in comparison to pristine tetrathiafulvalene.