“Click-switch” – one-step conversion of organic azides into photochromic diarylethenes for the generation of light-controlled systems

Diarylethenes (DAEs) are an established class of photochromic molecules, but their effective incorporation into pre-existing targets is synthetically difficult. Here we describe a new class of DAEs in which one of the aryl rings is a 1,2,3-triazole that is formed by “click” chemistry between an azide on the target and a matching alkyne–cyclopentene–thiophene component. This late-stage zero-length linking allows for tight integration of the DAE with the target, thereby increasing the chances for photomodulation of target functions. Nineteen different DAEs were synthesized and their properties investigated. All showed photochromism. Electron-withdrawing groups, and in particular −M-substituents at the triazole and/or thiophene moiety resulted in DAEs with high photo- and thermostability. Further, the chemical nature of the cyclopentene bridge had a strong influence on the behaviour upon UV light irradiation. Incorporation of perfluorinated cyclopentene led to compounds with high photo- and thermostability, but the reversible photochromic reaction was restricted to halogenated solvents. Compounds containing the perhydrogenated cyclopentene bridge, on the other hand, allowed the reversible photochromic reaction in a wide range of solvents, but had on average lower photo- and thermostabilities. The combination of the perhydrocyclopentene bridge and electron-withdrawing groups resulted in a DAE with improved photostability and no solvent restriction. Quantum chemical calculations helped to identify the photoproducts formed in halogenated as well as non-halogenated solvents. For two optimized DAE photoswitches, photostationary state composition and reaction quantum yields were determined. These data revealed efficient photochemical ring closure and opening. We envision applications of these new photochromic diarylethenes in photonics, nanotechnology, photobiology, photopharmacology and materials science.

New photochromic diarylethenes are reported in which one aryl ring is a 1,2,3-triazole that is formed by “click” chemistry between an azide on the target and a matching alkyne–cyclopentene–thiophene component.     

4-Azidocinnoline—Cinnoline-4-amine Pair as a New Fluorogenic and Fluorochromic Environment-Sensitive Probe

A new type of fluorogenic and fluorochromic probe based on the reduction of weakly fluorescent 4-azido-6-(4-cyanophenyl)cinnoline to the corresponding fluorescent cinnoline-4-amine was developed. We found that the fluorescence of 6-(4-cyanophenyl)cinnoline-4-amine is strongly affected by the nature of the solvent. The fluorogenic effect for the amine was detected in polar solvents with the strongest fluorescence increase in water. The environment-sensitive fluorogenic properties of cinnoline-4-amine in water were explained as a combination of two types of fluorescence mechanisms: aggregation-induced emission (AIE) and excited state intermolecular proton transfer (ESPT). The suitability of an azide–amine pair as a fluorogenic probe was tested using a HepG2 hepatic cancer cell line with detection by fluorescent microscopy, flow cytometry, and HPLC analysis of cells lysates. The results obtained confirm the possibility of the transformation of the azide to amine in cells and the potential applicability of the discovered fluorogenic and fluorochromic probe for different analytical and biological applications in aqueous medium.     

Resources and Methods for Engineering “Designer” Glycan-Binding Proteins

This review provides information on available methods for engineering glycan-binding proteins (GBP). Glycans are involved in a variety of physiological functions and are found in all domains of life and viruses. Due to their wide range of functions, GBPs have been developed with diagnostic, therapeutic, and biotechnological applications. The development of GBPs has traditionally been hindered by a lack of available glycan targets and sensitive and selective protein scaffolds; however, recent advances in glycobiology have largely overcome these challenges. Here we provide information on how to approach the design of novel “designer” GBPs, starting from the protein scaffold to the mutagenesis methods, selection, and characterization of the GBPs.     

Highly Norbornylated Cellulose and Its “Click” Modification by an Inverse-Electron Demand Diels–Alder (iEDDA) Reaction

A facile, catalyst-free synthesis of a norbornylated cellulosic material (NC) with a high degree of substitution (2.9) is presented by direct reaction of trimethylsilyl cellulose with norbornene acid chloride. The resulting NC is highly soluble in organic solvents and its reactive double bonds were exploited for the copper-free inverse-electron demand Diels–Alder (iEDDA) “click” reaction with 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazine. Reaction kinetics are comparable to the well-known Huisgen type 1,3-dipolar cycloaddition of azide with alkynes, while avoiding toxic catalysts.     

Carbon Quantum Dots from Pomelo Peel as Fluorescence Probes for “Turn-Off–On” High-Sensitivity Detection of Fe3+ and L-Cysteine

This study designed a “turn-off–on” fluorescence analysis method based on carbon quantum dots (CQDs) to detect metal ions and amino acids in real sample systems. CQDs were derived from green pomelo peel via a one-step hydrothermal process. The co-doped CQDs with N and S atoms imparted excellent optical properties (quantum yield = 17.31%). The prepared CQDs could be used as fluorescent “turn-off” probes to detect Fe³⁺ with a limit of detection of 0.086 µM, a linear detection range of 0.1–160 µM, and recovery of 83.47–106.53% in water samples. The quenched CQD fluorescence could be turned on after adding L-cysteine (L-Cys), which allowed detection of L-Cys with a detection limit of 0.34 µM and linear range of 0.4–85 µM. Recovery of L-Cys in amino acid beverage was 87.08–122.74%. Visual paper-based testing strips and cellulose/CQDs composite hydrogels could be also used to detect Fe³⁺ and L-Cys.     

Oligomer Sensor Nanoarchitectonics for “Turn-On” Fluorescence Detection of Cholesterol at the Nanomolar Level

Sensitive and rapid monitoring of cholesterol levels in the human body are highly desirable as they are directly related to the diagnosis of cardiovascular diseases. By using the nanoarchitectonic approach, a novel fluorescent conjugated oligofluorene (OFP-CD) functionalized with β-cyclodextrin (β-CD) was assembled for “Turn-On” fluorescence sensing of cholesterol. The appended β-CD units in OFP-CD enabled the forming of host-guest complexes with dabsyl chloride moieties in water, resulting in fluorescence quenching of the oligofluorene through intermolecular energy transfer. In the presence of cholesterol molecules, a more favorable host-guest complex with stoichiometry 1 cholesterol: 2 β-CD units was formed, replacing dabsyl chloride in β-CD’s cavities. This process resulted in fluorescence recovery of OFP-CD, owing to disruption of energy transfer. The potential of this nanoarchitectonic system for “Turn-On” sensing of cholesterol was extensively studied by fluorescence spectroscopy. The high selectivity of the sensor for cholesterol was demonstrated using biologically relevant interfering compounds, such as carbohydrates, amino acids, metal ions, and anions. The detection limit (LOD value) was as low as 68 nM, affirming the high sensitivity of the current system.     

Towards photoswitchable quadruple hydrogen bonds via a reversible “photolocking” strategy for photocontrolled self-assembly

Developing new photoswitchable noncovalent interaction motifs with controllable bonding affinity is crucial for the construction of photoresponsive supramolecular systems and materials. Here we describe a unique “photolocking” strategy for realizing photoswitchable control of quadruple hydrogen-bonding interactions on the basis of modifying the ureidopyrimidinone (UPy) module with an ortho-ester substituted azobenzene unit as the “photo-lock”. Upon light irradiation, the obtained Azo-UPy motif is capable of unlocking/locking the partial H-bonding sites of the UPy unit, leading to photoswitching between homo- and heteroquadruple hydrogen-bonded dimers, which has been further applied for the fabrication of novel tunable hydrogen bonded supramolecular systems. This “photolocking” strategy appears to be broadly applicable in the rational design and construction of other H-bonding motifs with sufficiently photoswitchable noncovalent interactions.

A photolocking strategy is described to achieve the construction of effectively photoswitchable quadruple hydrogen bonds featuring with photoregulable H-bonding affinities, which is further applied in the photocontrollable H-bonded self-assemblies.     

Rational design of an “all-in-one” phototheranostic

We report here porphodilactol derivatives and their corresponding metal complexes. These systems show promise as “all-in-one” phototheranostics and are predicated on a design strategy that involves controlling the relationship between intersystem crossing (ISC) and photothermal conversion efficiency following photoexcitation. The requisite balance was achieved by tuning the aromaticity of these porphyrinoid derivatives and forming complexes with one of two lanthanide cations, namely Gd³⁺ and Lu³⁺. The net result led to a metalloporphodilactol system, Gd-trans-2, with seemingly optimal ISC efficiency, photothermal conversion efficiency and fluorescence properties, as well as good chemical stability. Encapsulation of Gd-trans-2 within mesoporous silica nanoparticles (MSN) allowed its evaluation for tumour diagnosis and therapy. It was found to be effective as an “all-in-one” phototheranostic that allowed for NIR fluorescence/photoacoustic dual-modal imaging while providing an excellent combined PTT/PDT therapeutic efficacy in vitro and in vivo in 4T1-tumour-bearing mice.

We report here porphodilactol derivatives and their corresponding metal complexes as “all-in-one” phototheranostics by controlling the relationship between intersystem crossing (ISC) and photothermal conversion efficiency following photoexcitation.     

Observation of “de Vries-like” properties in bent-core molecules

“de Vries” liquid crystals, defined by a maximum layer shrinkage of ≤1% from the smectic A to C phase transition, are an integral component of ferroelectric liquid crystal (FLC) displays. Bona fide de Vries materials described in the literature are primarily perfluorinated, polysiloxane and polysilane-terminated rod-like (or calamitic) LCs. Herein, for the first time, we report a series of newly designed achiral unsymmetrical bent-core molecules with terminal alkoxy chains exhibiting similar properties to “de Vries” LCs. The new molecular structure is based on the systematic distribution of four phenyl rings attached via ester and imine linkers having 3-amino-2-methylbenzoic acid as the central core with a bent angle of 147°. Detailed microscopic investigations in differently aligned (planar as well as homeotropic) cells along with SAXS/WAXS studies revealed that the materials exhibited a SmA–SmC phase sequence along with the appearance of the nematic phase at higher temperatures. SAXS measurements divulged the layer spacings (d-spacings) and hence, the layer shrinkage was calculated ranging from 0.19% to 0.68% just below the SmA–SmC transition. The variation of the calculated molecular tilt angle (α) derived from the temperature-dependent SAXS data, followed the power law with exponent values 0.29 ± 0.01 and 0.25 ± 0.01 for compounds 1/10 and 1/12, respectively. The experimental values obtained were very close to the theoretically predicted values for the materials with de Vries-like properties. The analysis of temperature-dependent birefringence studies based on the prediction of the Landau theory, showed a dip across the SmA–SmC phase transition typical of compounds exhibiting the de Vries characteristics. The collective results obtained suggest “de Vries” SmA as a probable model for this bent-core system which may find applications in displays.

A simple molecular design of unsymmetrical bent-core molecules exhibiting low layer shrinkage and a dip in the birefringence at the SmA–SmC phase transition, typical characteristics of “de Vries” liquid crystals.     

Metabolite Profiling of “Green” Extracts of Cynara cardunculus subsp. scolymus,Cultivar “Carciofo di Paestum” PGI by 1H NMR and HRMS-Based Metabolomics

Globe artichoke (Cynara cardunculus L. var. scolymus L.), is a perennial plant widely cultivated in the Mediterranean area, known for its edible part named capitula or heads. Its functional properties are related to its high levels of polyphenolic compounds and inulin. “Carciofo di Paestum”, an Italian traditional cultivar, is a labeled PGI (Protected Geographical Indication) product of the Campania region, representing an important economic resource. So far, a few chemical investigations were performed on this cultivar, mainly focused on the analysis of methanol extracts. Due to the increasing use of food supplements, in this study, a comprehensive analysis of green extracts of “Carciofo di Paestum” PGI heads was performed. EtOH, EtOH: H₂O (80:20, 70:30, 60:40) extracts, as well as infusions and decoctions prepared according to Pharmacopeia XII were analyzed by LC-ESI/QExactive/MS/MS. A total of 17 compounds corresponding to caffeoylquinic acid derivatives, phenolics, flavonoids, and terpenoids were identified. The extracts were further submitted to NMR analysis to highlight the occurrence of primary metabolites. Both LCMS and NMR data were analyzed by Principal Component Analysis (PCA), showing significant differences among the extraction methods. Moreover, 5-caffeoylquinic acid and 1,5-dicaffeoylquinic acid were quantified in the extracts by LC-ESI/QTrap/MS/MS using the Multiple Reaction Monitoring (MRM) method. Furthermore, the phenolic content, antioxidant activity, and α-glucosidase inhibitory activity of C. cardunculus var. scolymus “Carciofo di Paestum” extracts were evaluated.     

Understanding the electrochemistry of “water-in-salt” electrolytes: basal plane highly ordered pyrolytic graphite as a model system

A new approach to expand the accessible voltage window of electrochemical energy storage systems, based on so-called “water-in-salt” electrolytes, has been expounded recently. Although studies of transport in concentrated electrolytes date back over several decades, the recent demonstration that concentrated aqueous electrolyte systems can be used in the lithium ion battery context has rekindled interest in the electrochemical properties of highly concentrated aqueous electrolytes. The original aqueous lithium ion battery conception was based on the use of concentrated solutions of lithium bis(trifluoromethanesulfonyl)imide, although these electrolytes still possess some drawbacks including cost, toxicity, and safety. In this work we describe the electrochemical behavior of a simple 1 : 1 electrolyte based on highly concentrated aqueous solutions of potassium fluoride (KF). Highly ordered pyrolytic graphite (HOPG) is used as well-defined model carbon to study the electrochemical properties of the electrolyte, as well as its basal plane capacitance, from a microscopic perspective: the KF electrolyte exhibits an unusually wide potential window (up to 2.6 V). The faradaic response on HOPG is also reported using K₃Fe(CN)₆ as a model redox probe: the highly concentrated electrolyte provides good electrochemical reversibility and protects the HOPG surface from adsorption of contaminants. Moreover, this electrolyte was applied to symmetrical supercapacitors (using graphene and activated carbon as active materials) in order to quantify its performance in energy storage applications. It is found that the activated carbon and graphene supercapacitors demonstrate high gravimetric capacitance (221 F g⁻¹ for activated carbon, and 56 F g⁻¹ for graphene), a stable working voltage window of 2.0 V, which is significantly higher than the usual range of water-based capacitors, and excellent stability over 10 000 cycles. These results provide fundamental insight into the wider applicability of highly concentrated electrolytes, which should enable their application in future of energy storage technologies.

The stability of water-in-salt electrolyte systems is investigated using highly concentrated solutions of KF(aq) with graphite as a model system.     

An “OFF–ON–OFF” fluorescence protein-labeling probe for real-time visualization of the degradation of short-lived proteins in cellular systems

The ability to monitor proteolytic pathways that remove unwanted and damaged proteins from cells is essential for understanding the multiple processes used to maintain cellular homeostasis. In this study, we have developed a new protein-labeling probe that employs an ‘OFF–ON–OFF’ fluorescence switch to enable real-time imaging of the expression (fluorescence ON) and degradation (fluorescence OFF) of PYP-tagged protein constructs in living cells. Fluorescence switching is modulated by intramolecular contact quenching interactions in the unbound probe (fluorescence OFF) being disrupted upon binding to the PYP-tag protein, which turns fluorescence ON. Quenching is then restored when the PYP-tag–probe complex undergoes proteolytic degradation, which results in fluorescence being turned OFF. Optimization of probe structures and PYP-tag mutants has enabled this fast reacting ‘OFF–ON–OFF’ probe to be used to fluorescently image the expression and degradation of short-lived proteins.

An “OFF–ON–OFF” fluorescence probe for real-time imaging of the expression (fluorescence ‘OFF’) and degradation (fluorescence ‘ON’) of short lived PYP-tag proteins in cellular systems.     

A “Double-Locked” and Enzyme/pH-Activated Theranostic Agent for Accurate Tumor Imaging and Therapy

Theranostic agents for concurrent cancer therapy and diagnosis have begun attracting attention as a promising modality. However, accurate imaging and identification remains a great challenge for theranostic agents. Here, we designed and synthesized a novel theranostic agent H6M based on the “double-locked” strategy by introducing an electron-withdrawing nitro group into 1-position of a pH-responsive 3-amino-β-carboline and further covalently linking the hydroxamic acid group, a zinc-binding group (ZBG), to the 3-position of β-carboline to obtain histone deacetylase (HDAC) inhibitory effect for combined HDAC-targeted therapy. We found that H6M can be specifically reduced under overexpressed nitroreductase (NTR) to produce H6AQ, which emits bright fluorescence at low pH. Notably, H6M demonstrated a selective fluorescence imaging via successive reactions with NTR (first “key”) and pH (second “key”), and precisely identified tumor margins with a high S/N ratio to guide tumor resection. Finally, H6M exerted robust HDAC1/cancer cell inhibitory activities compared with a known HDAC inhibitor SAHA. Therefore, the NTR/pH-activated theranostic agent provided a novel tool for precise diagnosis and efficient tumor therapy.     

Physico-Chemical and Phytochemical Characterization of Moroccan Wild Jujube “Zizyphus lotus (L.)” Fruit Crude Extract and Fractions

Wild jujube “Ziziphus lotus (L.) Desf.” belongs to the Rhamnaceae family and is a traditionally herbaceous medicinal plant. It is very common in arid and semi-arid regions and is currently used for its antidiabetic, sedative, analgesic, anti-inflammatory and hypoglycemic activities. The aim of the present work was to characterize the physico-chemical properties and the phytochemical profile of wild jujube sample collected from the Guercif region, in order to determine the polyphenolic compounds and the antioxidant ability Analyses were carried out directly after the harvest for the determination of pH, refractive index, total soluble solid (°Brix), dry matter, sugar/acidity, total sugars, reducing sugars, as well as lipid and protein content. Results showed that the investigated fruit is acidic (pH 4.9 ± 0.23) and rich in sugars (80.2 g/100 g ± 3.81). The GC-MS analysis of the fruit revealed a number of volatile compounds, as many as 97, belonging to different chemical classes. The HPLC-DAD-ESI/MS analysis showed the presence of a total of 20 polyphenolic compounds in both EtOAc and MeOH-water extracts. Among them, p-Hydroxybenzoic acid was the most abundant in the EtOAc extract (185.68 µg/100 mg ± 0.5) whereas Quercetin 3-O-rhamnoside-7-O-glucoside was found in higher amounts in the MeOH-water extract (25.40 µg/100 mg ± 0.5). These components have medical interest, notably for human nutrition, as well as health benefits and therapeutic effects. Therefore, Moroccan jujube “Zizyphus lotus (L.)” fruit may have potential industrial applications for food formulations.     

Synthesis of MAPA Reagents and 2-Alkyl(aryl)aminopyridines from 2-Bromopyridine Using the Goldberg Reaction

A short and economical synthesis of various 2-methylaminopyidine amides (MAPA) from 2-bromopyridine has been developed using the catalytic Goldberg reaction. The effective catalyst was formed in situ by the reaction of CuI and 1,10-phenanthroline in a 1/1 ratio with a final loading of 0.5–3 mol%. The process affords high yields and can accommodate multigram-scale reactions. A modification of this method provides a new preparation of 2-N-substituted aminopyridines from various secondary N-alkyl(aryl)formamides and 2-bromopyridine. The intermediate aminopyridine formamide is cleaved in situ through methanolysis or hydrolysis to give 2-alkyl(aryl)aminopyridines in high yields.     

Dispersion of Carbon Nanotubes with “Green” Detergents

Solubilization of carbon nanotubes (CNTs) is a fundamental technique for the use of CNTs and their conjugates as nanodevices and nanobiodevices. In this work, we demonstrate the preparation of CNT suspensions with “green” detergents made from coconuts and bamboo as fundamental research in CNT nanotechnology. Single-walled CNTs (SWNTs) with a few carboxylic acid groups (3–5%) and pristine multi-walled CNTs (MWNTs) were mixed in each detergent solution and sonicated with a bath-type sonicator. The prepared suspensions were characterized using absorbance spectroscopy, scanning electron microscopy, and Raman spectroscopy. Among the eight combinations of CNTs and detergents (two types of CNTs and four detergents, including sodium dodecyl sulfate (SDS) as the standard), SWNTs/MWNTs were well dispersed in all combinations except the combination of the MWNTs and the bamboo detergent. The stability of the suspensions prepared with coconut detergents was better than that prepared with SDS. Because the efficiency of the bamboo detergents against the MWNTs differed significantly from that against the SWNTs, the natural detergent might be useful for separating CNTs. Our results revealed that the use of the “green” detergents had the advantage of dispersing CNTs as well as SDS.     

Rational design of a “dual lock-and-key” supramolecular photosensitizer based on aromatic nucleophilic substitution for specific and enhanced photodynamic therapy

Photosensitizing agents are essential for precise and efficient photodynamic therapy (PDT). However, most of the conventional photosensitizers still suffer from limitations such as aggregation-caused quenching (ACQ) in physiological environments and toxic side-effects on normal tissues during treatment, leading to reduced therapeutic efficacy. Thus, integrating excellent photophysical properties and accurate carcinoma selectivity in a photosensitizer system remains highly desired. Herein, a “dual lock-and-key” supramolecular photosensitizer BIBCl–PAE NPs for specific and enhanced cancer therapy is reported. BIBCl–PAE NPs are constructed by encapsulating a rationally designed glutathione (GSH)-activatable photosensitizer BIBCl in a pH-responsive diblock copolymer. In normal tissues, BIBCl is “locked” in the hydrophobic core of the polymeric micelles due to ACQ. Under the “dual key” activation of low pH and high levels of GSH in a tumor microenvironment, the disassembly of micelles facilitates the reaction of BIBCl with GSH to release water-soluble BIBSG with ideal biocompatibility, enabling the highly efficient PDT. Moreover, benefiting from the Förster resonance energy transfer effect of BIBSG, improved light harvesting ability and ¹O₂ production are achieved. In vitro and vivo experiments have demonstrated that BIBCl–PAE NPs are effective in targeting and inhibiting carcinoma. BIBCl–PAE NPs show superior anticancer efficiency relative to non-activatable controls.

The “dual lock-and-key” supramolecular photosensitizers enable specific and enhanced photodynamic therapy (PDT).     

Syntheses and NMR,MS and X‐ray investigations of homoadamantane‐fused pyridopyrimidinones

The reactions of ethyl 5‐oxotricyclo[4.3.1.1^3,8]undecane‐4‐carboxylate (2) with methyl‐substituted 2‐aminopyridines in polyphosphoric acid (PPA) gave two products, linearly‐condensed pyridopyrimidinones 4a‐c and 2‐pyridylcarboxamides 5a‐c , whereas the reactions with amino, hydroxy and nitro derivatives of 2‐aminopyridine furnished only linearly‐condensed pyridopyrimidinones (4g‐j). Use of a mixture of PPA and phosphorus oxychloride as solvent afforded both linearly‐ (4a‐c,e,f) and angularly‐condensed (6a–c,e,f) pyridopyrimidinones. In toluene, with p‐toluenesulfonic acid as catalyst, 2‐pyridylcarboxamides 5a‐f were obtained. In a mixture of PPA and phosphorus oxychloride at 80–120 °C, 5a‐f yielded angularly‐condensed pyridopyrimidinones 6a‐f. All the products exhibited characteristic features, as determined by NMR and electron ionization mass spectrometry and X‐ray crystallography.     

Identification of Bioactive Compounds of Asparagus officinalis L.: Permutation Test Allows Differentiation among “Triguero” and Hybrid Green Varieties

In this study, we determined the phytochemical profile of the Spanish “triguero” asparagus landrace “verde-morado” (Asparagus officinalis L.), a wild traditional landrace, and the improved “triguero” HT-801, together with two commercial green asparagus varieties. For comparison, we used reverse-phase high-performance liquid chromatography coupled with diode array electrospray time-of-flight mass spectrometry (RP-HPLC-DAD-ESI-TOF/MS) followed by a permutation test applied using a resampling methodology valid under a relaxed set of assumptions, such as i.i.d. errors (not necessarily normal) that are exchangeable under the null hypothesis. As a result, we postulate that “triguero” varieties (the improved HT-801 followed by its parent “verde-morado”) have a significantly different phytochemical profile from that of the other two commercial hybrid green varieties. In particular, we found compounds specific to the “triguero” varieties, such as feruloylhexosylhexose isomers, or isorhamnetin-3-O-glucoside, which was found only in the “triguero” variety HT-801. Although studies relating the phytochemical content of “triguero” asparagus varieties to its health-promoting effects are required, this characteristic phytochemical profile can be used for differentiating and revalorizating these asparagus cultivars.