Planar Chiral p,p'-Terphenyl-Based Cyclophanes with Remarkable Enantiomer Stability: Synthesis, Theoretical Investigations, and Complexation Studies.

Design of conformationally stable compounds with planar chirality is a topic of great interest mainly because of their potential applications as enantioselective ligands or other functional materials. Herein, we present the design and synthesis of novel planar chiral cyclophanes, obtained by ortho, ortho″ anchoring of the p,p'-terphenyl unit, with bridges of different lengths and rigidities, along with their nuclear magnetic resonance, mass spectrometry, and X-ray characterizations. We investigated the influence of the structural particularities of the bridges over the stability of the enantiomers, by means of nuclear magnetic resonance and chiral high-performance liquid chromatography as well as by density functional theory calculations. We also demonstrated the ability of one of the cyclophanes to preferentially bind arginine with Ka > 110 M-1 (ΔG > -11 kJ mol-1) in acetonitrile solutions containig 10 % water, in the presence of other amino acids.

Active-metal template clipping synthesis of novel [2]rotaxanes.

Mechanically interlocked molecules (MIMs) have been important synthetic targets in supramolecular chemistry due to their beautiful structures and intriguing properties. We present herein a new synthetic strategy to access [2]rotaxanes, namely active-metal template clipping. We discuss the design of the target [2]rotaxanes, synthesis and characterization of the axle, macrocycle precursors and macrocycles as well as preparation of the final [2]rotaxanes by active template copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) as key step of the synthesis. HRMS and NMR experiments have been performed to confirm the formation of the interlocked structures.

Removal and degradation of sodium diclofenac via radical-based mechanisms using S. sclerotiorum laccase.

The recently isolated Sclerotinia sclerotiorum laccase was used for the degradation of sodium diclofenac, a nonsteroidal anti-inflammatory drug widely found in the aquatic environment. The Michaelis-Menten parameters, half-life of diclofenac at different pH values in presence of this enzyme and potential inhibitors were evaluated. Diclofenac-based radicals formed in presence of laccase were spin-trapped and detected using EPR spectroscopy. Almost complete diclofenac degradation (> 96%) occurred after a 30-h treatment via radical-based generated oligomers and their rapid precipitation, thus ensuring an unprecedented green formula suitable not only for degradation but also for straightforward removal of the degradation products. High performance liquid chromatography coupled with atmospheric pressure chemical ionization-ion trap mass spectrometry (HPLC-APCI-MS) analyses of the degradation products of diclofenac in aqueous dosage revealed the presence of at least seven products while HR Orbitrap MS analysis showed that the enzymatic treatment produced high molecular weight metabolites through a radical oligomerization mechanism of diclofenac. The enzymatically formed products precipitated and its constituting components were also characterized using UV-vis spectroscopy, infrared spectroscopy (FTIR) and thermogravimetric analysis (TGA).

Synthetic Approaches of Epoxysuccinate Chemical Probes.

Synthetic chemical probes are powerful tools for investigating biological processes. They are particularly useful for proteomic studies such as activity-based protein profiling (ABPP). These chemical methods initially used mimics of natural substrates. As the techniques gained prominence, more and more elaborate chemical probes with increased specificity towards given enzyme/protein families and amenability to various reaction conditions were used. Among the chemical probes, peptidyl-epoxysuccinates represent one of the first types of compounds used to investigate the activity of the cysteine protease papain-like family of enzymes. Structurally derived from the natural substrate, a wide body of inhibitors and activity- or affinity-based probes bearing the electrophilic oxirane unit for covalent labeling of active enzymes now exists. Herein, we review the literature regarding the synthetic approaches to epoxysuccinate-based chemical probes together with their reported applications, from biological chemistry and inhibition studies to supramolecular chemistry and the formation of protein arrays.

Exploring the Optoelectronic Properties of D-A and A-D-A 2,2'-bi[3,2-b]thienothiophene Derivatives.

The synthesis of some novel donor-acceptor and acceptor-donor-acceptor systems containing a 2,2'-bi[3,2-b]thienothiophene donor block and various electron-accepting units is described alongside their photophysical properties studied using electrochemistry, optical spectroscopy and theoretical calculations. The obtained results show that the energy levels can be modulated by changing the strength of the acceptor unit. Among the three investigated end-groups, 1,1-dicyanomethylene-3-indanone exhibited the largest bathochromic shift and the lowest band gap suggesting the strongest electron-withdrawing character. Moreover, the emissive properties of the investigated systems vary greatly with the nature of the terminal group and are generally lower compared to their precursor aldehyde derivatives.

Exploring Arylazo-3,5-Bis(trifluoromethyl)pyrazole Switches.

Arylazopyrazoles stand out among the azoheteroarene photoswitches due to their excellent properties in terms of stability of the least stable isomer and conversion between isomers, leading to their use in several interesting applications. We report herein the synthesis of arylazo-trifluoromethyl-substituted pyrazoles and their switching behavior under light irradiation. UV-vis and NMR experiments showed that arylazo-1H-3,5-bis(trifluoromethyl)pyrazoles displayed very long half-lives in DMSO (days), along with reasonable values of other parameters that characterize a photoswitch. Inclusion of naphthyl moieties as aryl counterparts of the arylazopyrazoles is beneficial only in combination with trifluoromethyl groups, while extending the conjugation by grafting the pyrazole moiety with electron-donating or -withdrawing substituents positively affects the photoswitching behavior, in terms of isomerization yield and half-lives of the least stable isomer. The experimental values were correlated with theoretical calculations indicating the valuable influence of the trifluoromethyl groups onto the photoswitching behavior.

Sonogashira Synthesis of New Porous Aromatic Framework-Entrapped Palladium Nanoparticles as Heterogeneous Catalysts for Suzuki-Miyaura Cross-Coupling.

Palladium nanoparticles entrapped in porous aromatic frameworks (PAFs) or covalent organic frameworks may promote heterogeneous catalytic reactions. However, preparing such materials as active nanocatalysts usually requires additional steps for palladium entrapment and reduction. This paper reports as a new approach, a simple procedure leading to the self-entrapment of Pd nanoparticles within the PAF structure. Thus, the selected Sonogashira synthesis affords PAF-entrapped Pd nanoparticles that can catalyze the C-C Suzuki-Miyaura cross-coupling reactions. Following this new concept, PAFs were synthesized via Sonogashira cross-coupling of the tetraiodurated derivative of tetraphenyladamantane or spiro-9,9'-bifluorene with 1,6-diethynylpyrene, then characterized them using powder X-ray diffraction, diffuse reflectance infrared Fourier transform spectroscopy, X-ray photoelectron spectroscopy, high-resolution scanning transmission electron microscopy, and textural properties (i.e., adsorption-desorption isotherms). The PAF-entrapped Pd nanocatalysts showed high catalytic activity in Suzuki-Miyaura coupling reactions (demonstrated by preserving the turnover frequency values) and stability (demonstrated by palladium leaching and recycling experiments). This new approach presents a new class of PAFs with unique structural, topological, and compositional complexities as entrapped metal nanocatalysts or for other diverse applications.

An attempt to synthesize a terthienyl-based analog of indacenedithiophene (IDT): unexpected synthesis of a naphtho[2,3-b]thiophene derivative.

We report herein our attempt to synthesize an analog of indacenedithiophene (IDT) based on a tetraphenylhexyl substituted, covalently bridged syn-terthienyl unit. Instead of the expected compound the adopted synthetic route led to the formation of an unexpected, new naphtho[2,3-b]thiophene derivative. The structure of this compound was fully characterized by NMR and HRMS as well as single crystal X-ray diffraction and its electronic properties have been analyzed by UV-vis absorption spectroscopy and cyclic voltammetry. A possible mechanism for the formation of this compound is also proposed on the basis of detailed theoretical investigations.

Excess Ascorbate is a Chemical Stress Agent against Proteins and Cells.

Excess ascorbate (as expected in intravenous treatment proposed for COVID-19 management, for example) oxidizes and/or degrades hemoglobin and albumin, as evidenced by UV-vis spectroscopy, gel electrophoresis, and mass spectrometry. It also degrades hemoglobin in intact blood or in isolated erythrocytes. The survival rates and metabolic activities of several leukocyte subsets implicated in the antiviral cellular immune response are also affected. Excess ascorbate is thus an unselective biological stress agent.

"Yellow" laccase from Sclerotinia sclerotiorum is a blue laccase that enhances its substrate affinity by forming a reversible tyrosyl-product adduct.

Yellow laccases lack the typical blue type 1 Cu absorption band around 600 nm; however, multi-copper oxidases with laccase properties have been reported. We provide the first evidence that the yellow laccase isolated from Sclerotinia sclerotiorum is obtained from a blue form by covalent, but nevertheless reversible modification with a phenolic product. After separating the phenolics from the extracellular medium, a typical blue laccase is obtained. With ABTS as model substrate for this blue enzyme, a non-natural purple adduct is formed with a spectrum nearly identical to that of the 1:1 adduct of an ABTS radical and Tyr. This modification significantly increases the stability and substrate affinity of the enzyme, not by acting primarily as bound mediator, but by structural changes that also alters the type 1 Cu site. The HPLC-MS analyses of the ABTS adduct trypsin digests revealed a distinct tyrosine within a unique loop as site involved in the modification of the blue laccase form. Thus, S. sclerotiorum yellow laccase seems to be an intrinsically blue multi-copper oxidase that boosts its activity and stability with a radical-forming aromatic substrate. This particular case could, at least in part, explain the enigma of the yellow laccases.

A polycarboxylic chelating ligand for efficient resin purification of His-tagged proteins expressed in mammalian systems.

We describe the synthesis of a novel polyamino polycarboxylic ligand, its ability to coordinate metal-ions and attachment to a solid support designed for protein purification through Immobilised Metal-ion Affinity Chromatography (IMAC). The resin was found to be highly efficient for purification of His-tagged HCV E2 glycoproteins expressed in 293T mammalian cells.

A novel adaptive fluorescent probe for cell labelling.

In this study we describe the synthesis and characterisation of a new hydrazone-based fluorescent compound that is able to selectively label the endoplasmic reticulum (ER) in yeast and mammalian living cells. The fluorescence properties of the compound depended on the DMSO/water ratio and on the pH. NMR experiments allowed determination of the conformation adopted in various environments. Apart from the convenient synthetic procedure, our compound displays low cell toxicity and blue emission compatible with filters routinely used in fluorescence microscopy.

A novel profluorescent paramagnetic diaza-crown ether: synthesis, characterization and alkaline metal-ion complexation.

Starting from Kryptofix 22 two different branches were covalently attached through the nitrogen atoms, one containing a fluorescent moiety and the other the stable free radical TEMPO. The novel derivative exhibits fluorescence and paramagnetic properties, while the diaza-crown part ensures the affinity for alkaline metal-ions.

A three-armed cryptand with triazine and pyridine units: synthesis, structure and complexation with polycyclic aromatic compounds.

The aromatic nucleophilic substitution reaction based synthesis of a three-armed cryptand displaying 2,4,6-triphenyl-1,3,5-triazine units as caps and pyridine rings in the bridges, along with NMR, MS and molecular modelling-based structural analysis of this compound are reported. Appropriate NMR and molecular modelling investigations proved the formation of 1:1 host-guest assemblies between the investigated cryptand and some polynuclear aromatic hydrocarbons or their derivatives.

Modulating short tryptophan- and arginine-rich peptides activity by substitution with histidine.

BACKGROUND: High antimicrobial efficacy of short tryptophan-and arginine-rich peptides makes them good candidates in the fight against pathogens. Substitution of tryptophan and arginine by histidine could be used to modulate the peptides efficacy by optimizing their structures. METHODS: The peptide (RRWWRWWRR), reported to showed good antimicrobial efficacy, was used as template, seven new analogs being designed substituting tryptophan or arginine with histidine. The peptides' efficacy was tested against E. coli, B. subtilis and S. aureus. The cytotoxicity and hemolytic effect were evaluated and the therapeutic index was inferred for each peptide. Atomic force microscopy and molecular simulation were used to analyze the effects of peptides on bacterial membrane. RESULTS: The substitution of tryptophan by histidine proved to strongly modulate the antimicrobial activity, mainly by changing the peptide-to-membrane binding energy. The substitution of arginine has low effect on the antimicrobial efficacy. The presence of histidine residue reduced the cytotoxic and hemolytic activity of the peptides in some cases maintaining the same efficacy against bacteria. The peptides' antimicrobial activity was correlated to the 3D-hydrophobic moment and to a simple structure-based packing parameter. CONCLUSION: The results show that some of these peptides have the potential to become good candidates to fight against bacteria. The substitution by histidine proved to fine tune the therapeutic index allowing the optimization of the peptide structure mainly by changing its binding energy and 3D-hydrophobic moment. GENERAL SIGNIFICANCE: The short tryptophan reach peptides therapeutic index can be maximized using the histidine substitution to optimize their structure.

"Click" access to multilayer functionalized Au surface: A terpyridine patterning example.

This work is focused on self-assembled monolayers (SAMs) fabrication, using two types of Au surfaces, by subsequent attachment of different layers in order to develop a stable platform consisting of covalent multilayer functionalized gold surfaces. The key step in the construction of SAMs is the covalent linkage to the gold surface, via an amino-thiol derivative, of a cyclooctyne unit exhibiting strained triple bonds which react fast (catalysts are not needed) and quantitatively with organic azides and enable the introduction of various chemical functionalized entities on the gold surface. The versatility of the system is demonstrated by the reaction of the cyclooctyne decorated gold surface with an azide functionalized terpyridine followed by step by step complexation with Fe(II) and another terpyridine unit resulting into a multilayer covered gold surface. The Au surfaces were characterized by XPS to determine the chemical composition of the resulting SAMs. SPR was applied for real-time monitoring of the molecular interactions that occurred on the Au surface for each deposited layer. DPN was used to direct pattern the terpyridine-ink on a pre-functionalized AuIDE electrode. The AFM topology resulted from DPN and PEIS demonstrated metal-coordinating ligand of Fe(II)-Terpy.

Supramolecular anion recognition by ß-HCH.

The formation of highly ordered supramolecular architectures via cooperative C(aliphatic)-H·anion contacts between ß-HCH and various anions (Cl-, Br-, I- and HSO4-) was investigated by single crystal X-ray diffractometry, molecular modelling, ESI-MS and 1H-NMR titrations.

Exclusive Hydrophobic Self-Assembly of Adaptive Solid-State Networks of Octasubstituted 9,9'-Spirobifluorenes.

An easy and powerful access to 3,3',6,6'-tetrasubstituted 9,9'-spirobifluorene derivatives with tetrahedral orientation of the peripheral groups (i.e., -I, -CN, -NO2, -CH═O, -COOH, -C≡CH, -4-Py) was developed. The NMR and HRMS results are in agreement with the proposed formula and the solid-state molecular structures obtained by single-crystal X-ray diffraction. They form molecular solids self-assembled via exclusive hydrophobic interactions. Solid-state selection and adaptation can be obtained on the basis of variable compact packing of functional groups present on the 9,9'-spirobifluorene backbone.

Selective host molecules obtained by dynamic adaptive chemistry.

Up till 20 years ago, in order to endow molecules with function there were two mainstream lines of thought. One was to rationally design the positioning of chemical functionalities within candidate molecules, followed by an iterative synthesis-optimization process. The second was the use of a "brutal force" approach of combinatorial chemistry coupled with advanced screening for function. Although both methods provided important results, "rational design" often resulted in time-consuming efforts of modeling and synthesis only to find that the candidate molecule was not performing the designed job. "Combinatorial chemistry" suffered from a fundamental limitation related to the focusing of the libraries employed, often using lead compounds that limit its scope. Dynamic constitutional chemistry has developed as a combination of the two approaches above. Through the rational use of reversible chemical bonds together with a large plethora of precursor libraries, one is now able to build functional structures, ranging from quite simple molecules up to large polymeric structures. Thus, by introduction of the dynamic component within the molecular recognition processes, a new perspective of deciphering the world of the molecular events has aroused together with a new field of chemistry. Since its birth dynamic constitutional chemistry has continuously gained attention, in particular due to its ability to easily create from scratch outstanding molecular structures as well as the addition of adaptive features. The fundamental concepts defining the dynamic constitutional chemistry have been continuously extended to currently place it at the intersection between the supramolecular chemistry and newly defined adaptive chemistry, a pivotal feature towards evolutive chemistry.

Luminogenic "clickable" lanthanide complexes for protein labeling.

Development of lanthanide-based luminescent "switch-on" systems via azide-alkyne [3+2] cycloaddition is described. We used these for non-specific protein labeling and as tags for specific and selective activity-based protein labeling.