Site Selectivity of Peptoids as Azobenzene Scaffold for Molecular Solar Thermal Energy Storage.

Storing solar energy is a key challenge in modern science. MOlecular Solar Thermal (MOST) systems, in particular those based on azobenzene switches, have received great interest in the last decades. The energy storage properties of azobenzene (t1/2 <4 days; ΔH~270 kJ/kg) must be improved for future applications. Herein, we introduce peptoids as programmable supramolecular scaffolds to improve the energy storage properties of azobenzene-based MOST systems. We demonstrate with 3-unit peptoids bearing a single azobenzene chromophore that dynamics of the MOST systems can be tuned depending on the anchoring position of the photochromic unit on the macromolecular backbone. We measured a remarkable increase of the half-life of the metastable form up to 14 days at 20 °C for a specific anchoring site, significantly higher than the isolated azobenzene moiety, thus opening new perspectives for MOST development. We also highlight that liquid chromatography coupled to mass spectrometry does not only enable to monitor the different stereoisomers during the photoisomerization process as traditionally done, but also allows to determine the thermal back-isomerization kinetics.

Influence of the dispersity and molar mass distribution of conjugated polymers on the aggregation type and subsequent chiral expression.

This study aims to determine the influence of the dispersity on the aggregation of conjugated polymers and their subsequent chiral expression. Dispersity has been thoroughly investigated for industrial polymerizations, but research on conjugated polymers is lacking. Nonetheless, knowledge thereof is crucial for controlling the aggregation type (type I versus type II) and its influence is therefore investigated. For that purpose, a series of polymers is synthesized via metered initiator addition, resulting in dispersities ranging from 1.18-1.56. The lower dispersity polymers yield type II aggregates and the resulting symmetrical electronic circular dichroism (ECD) spectra while the higher dispersity polymers are predominantly type I due to the longer chains effectively acting as a seed and therefore yield asymmetrical ECD spectra. Furthermore, a monomodal and bimodal molar mass distribution of similar dispersity are compared, demonstrating that bimodal distributions show both aggregation types and therefore more disorder, leading to a decrease in chiral expression.

Synthesis and Characterization of Tetraphenylethene AIEgen-Based Push-Pull Chromophores for Photothermal Applications: Could the Cycloaddition-Retroelectrocyclization Click Reaction Make Any Molecule Photothermally Active?

Three new tetraphenylethene (TPE) push-pull chromophores exhibiting strong intramolecular charge transfer (ICT) are described. They were obtained via [2 + 2] cycloaddition-retroelectrocyclization (CA-RE) click reactions on an electron-rich alkyne-tetrafunctionalized TPE (TPE-alkyne) using both 1,1,2,2-tetracyanoethene (TCNE), 7,7,8,8-tetracyanoquinodimethane (TCNQ) and 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F4-TCNQ) as electron-deficient alkenes. Only the starting TPE-alkyne displayed significant AIE behavior, whereas for TPE-TCNE, a faint effect was observed, and for TPE-TCNQ and TPE-F4-TCNQ, no fluorescence was observed in any conditions. The main ICT bands that dominate the UV-Visible absorption spectra underwent a pronounced red-shift beyond the near-infrared (NIR) region for TPE-F4-TCNQ. Based on TD-DFT calculations, it was shown that the ICT character shown by the compounds exclusively originated from the clicked moieties independently of the nature of the central molecular platform. Photothermal (PT) studies conducted on both TPE-TCNQ and TPE-F4-TCNQ in the solid state revealed excellent properties, especially for TPE-F4-TCNQ. These results indicated that CA-RE reaction of TCNQ or F4-TCNQ with donor-substituted are promising candidates for PT applications.

Electrophilic and nucleophilic gas phase reactivity of the Janus cluster-based anions [{Mo6Cl8}Cl5□]- (□ = lacuna).

The lacunary monocharged anion [{Mo6Cli8}Cla5□a]- presents concomitantly a strongly electrophilic site and a nucleophilic one. This Janus character in terms of reactivity is confirmed by its gas phase reaction with [Br6Cs4K]- to form [{Mo6Cli8}Cla5Bra]2- and by its unusual self-reactivity leading to [{Mo6Cli8}Cla6]2- dianions.

The expression of chirality in linked poly(thiophene)s.

Conjugated polymers have demonstrated to express chirality, for instance, by strong circular dichroism (CD). However, the shape and intensity of the spectra can be quite different and are very difficult to predict. Molecular irregularity, star-shapes, and linking polymers have demonstrated to affect the CD, often in a positive way. In this research, we design two different chiral arms, in which the molecular irregularity results in a significantly different CD. Next, the arms are coupled to a linear core in all possible combinations. In this way, we demonstrate that rather small irregularities and linking arms to a central core increases CD, whereas heterogenous combinations result in smaller CD.

Gas-phase structure of polymer ions: Tying together theoretical approaches and ion mobility spectrometry.

An increasing number of studies take advantage of ion mobility spectrometry (IMS) coupled to mass spectrometry (IMS-MS) to investigate the spatial structure of gaseous ions. Synthetic polymers occupy a unique place in the field of IMS-MS. Indeed, due to their intrinsic dispersity, they offer a broad range of homologous ions with different lengths. To help rationalize experimental data, various theoretical approaches have been described. First, the study of trend lines is proposed to derive physicochemical and structural parameters. However, the evaluation of data fitting reflects the overall behavior of the ions without reflecting specific information on their conformation. Atomistic simulations constitute another approach that provide accurate information about the ion shape. The overall scope of this review is dedicated to the synergy between IMS-MS and theoretical approaches, including computational chemistry, demonstrating the essential role they play to fully understand/interpret IMS-MS data.

Modulation of Cytosolic Phospholipase A2 as a Potential Therapeutic Strategy for Alzheimer's Disease.

Background: Alzheimer's disease (AD) is a neurodegenerative disorder lacking any curative treatment up to now. Indeed, actual medication given to the patients alleviates only symptoms. The cytosolic phospholipase A2 (cPLA2-IVA) appears as a pivotal player situated at the center of pathological pathways leading to AD and its inhibition could be a promising therapeutic approach. Objective: A cPLA2-IVA inhibiting peptide was identified in the present work, aiming to develop an original therapeutic strategy. Methods: We targeted the cPLA2-IVA using the phage display technology. The hit peptide PLP25 was first validated in vitro (arachidonic acid dosage [AA], cPLA2-IVA cellular translocation) before being tested in vivo. We evaluated spatial memory using the Barnes maze, amyloid deposits by MRI and immunohistochemistry (IHC), and other important biomarkers such as the cPLA2-IVA itself, the NMDA receptor, AßPP and tau by IHC after i.v. injection in APP/PS1 mice. Results: Showing a high affinity for the C2 domain of this enzyme, the peptide PLP25 exhibited an inhibitory effect on cPLA2-IVA activity by blocking its binding to its substrate, resulting in a decreased release of AA. Coupled to a vector peptide (LRPep2) in order to optimize brain access, we showed an improvement of cognitive abilities of APP/PS1 mice, which also exhibited a decreased number of amyloid plaques, a restored expression of cPLA2-IVA, and a favorable effect on NMDA receptor expression and tau protein phosphorylation. Conclusions: cPLA2-IVA inhibition through PLP25 peptide could be a promising therapeutic strategy for AD.

Cellulose nanocrystals modification by grafting from ring opening polymerization of a cyclic carbonate.

Surface modification of cellulose nanocrystals (CNC) by organocatalysed grafting from ring-opening polymerization (ROP) of trimethylene carbonate was investigated. Organocatalysts including an amidine (DBU), a guanidine (TBD), an amino-pyridine (DMAP) and a phosphazene (BEMP) were successfully assessed for this purpose, with performances in the order TBD > BEMP > DMAP, DBU. The grafting ratio can be tuned by varying the experimental parameters, with the highest grafting of 74 % by weight obtained under mild conditions, i.e at room temperature in tetrahydrofuran with a low amount of catalyst. This value is much higher than that of typical ring opening polymerizations of cyclic esters initiated from the surface of cellulose nanoparticles. Additionally, DSC analysis of the modified material revealed the presence of a glass transition temperature, indicative of a sufficient graft length to display polymeric behaviour. This is, to our knowledge, the first example of cellulose nanocrystals grafted with polycarbonate chains.

Impact of the Hydrolysis and Methanolysis of Bidesmosidic Chenopodium quinoa Saponins on Their Hemolytic Activity.

Saponins are specific metabolites abundantly present in plants and several marine animals. Their high cytotoxicity is associated with their membranolytic properties, i.e., their propensity to disrupt cell membranes upon incorporation. As such, saponins are highly attractive for numerous applications, provided the relation between their molecular structures and their biological activities is understood at the molecular level. In the present investigation, we focused on the bidesmosidic saponins extracted from the quinoa husk, whose saccharidic chains are appended on the aglycone via two different linkages, a glycosidic bond, and an ester function. The later position is sensitive to chemical modifications, such as hydrolysis and methanolysis. We prepared and characterized three sets of saponins using mass spectrometry: (i) bidesmosidic saponins directly extracted from the ground husk, (ii) monodesmosidic saponins with a carboxylic acid group, and (iii) monodesmosidic saponins with a methyl ester function. The impact of the structural modifications on the membranolytic activity of the saponins was assayed based on the determination of their hemolytic activity. The natural bidesmosidic saponins do not present any hemolytic activity even at the highest tested concentration (500 µg·mL-1). Hydrolyzed saponins already degrade erythrocytes at 20 µg·mL-1, whereas 100 µg·mL-1 of transesterified saponins is needed to induce detectable activity. The observation that monodesmosidic saponins, hydrolyzed or transesterified, are much more active against erythrocytes than the bidesmosidic ones confirms that bidesmosidic saponins are likely to be the dormant form of saponins in plants. Additionally, the observation that negatively charged saponins, i.e., the hydrolyzed ones, are more hemolytic than the neutral ones could be related to the red blood cell membrane structure.

On the Conformation of Anionic Peptoids in the Gas Phase.

Although N-(S)-phenylethyl peptoids are known to adopt helical structures in solutions, the corresponding positively charged ions lose their helical structure during the transfer from the solution to the gas phase due to the so-called charge solvation effect. We, here, considered negatively charged peptoids to investigate by ion mobility spectrometry-mass spectrometry whether the structural changes described in the positive ionization mode can be circumvented in the negative mode by a fine-tuning of the peptoid sequence, that is, by positioning the negative charge at the positive side of the helical peptoid macrodipole. N-(S)-(1-carboxy-2-phenylethyl) (Nscp) and N-(S)-phenylethyl (Nspe) were selected as the negative charge carrier and as the helix inductor, respectively. We, here, report the results of a joint theoretical and experimental study demonstrating that the structures adopted by the NspenNscp anions remain compactly folded in the gas phase for chains containing up to 10 residues, whereas no evidence of the presence of a helical structure was obtained, even if, for selected sequences and lengths, different gas phase conformations are detected.

Pillar[5]arene-Based Polycationic Glyco[2]rotaxanes Designed as Pseudomonas aeruginosa Antibiofilm Agents.

Pseudomonas aeruginosa (P.A.) is a human pathogen belonging to the top priorities for the discovery of new therapeutic solutions. Its propensity to generate biofilms strongly complicates the treatments required to cure P.A. infections. Herein, we describe the synthesis of a series of novel rotaxanes composed of a central galactosylated pillar[5]arene, a tetrafucosylated dendron, and a tetraguanidinium subunit. Besides the high affinity of the final glycorotaxanes for the two P.A. lectins LecA and LecB, potent inhibition levels of biofilm growth were evidenced, showing that their three subunits work synergistically. An antibiofilm assay using a double ΔlecAΔlecB mutant compared to the wild type demonstrated that the antibiofilm activity of the best glycorotaxane is lectin-mediated. Such antibiofilm potency had rarely been reached in the literature. Importantly, none of the final rotaxanes was bactericidal, showing that their antibiofilm activity does not depend on bacteria killing, which is a rare feature for antibiofilm agents.

Helical Peptoid Ions in the Gas Phase: Thwarting the Charge Solvation Effect by H-Bond Compensation.

Folding and unfolding processes are key aspects that should be mastered for the design of foldamer molecules for targeted applications. In contrast to the solution phase, in vacuo conditions represent a well-defined environment to analyze the intramolecular interactions that largely control the folding/unfolding dynamics. Ion mobility mass spectrometry coupled to theoretical modeling represents an efficient method to decipher the spatial structures of gaseous ions, including foldamers. However, charge solvation typically compacts the ion structure in the absence of strong stabilizing secondary interactions. This is the case in peptoids that are synthetic peptide regioisomers whose side chains are connected to the nitrogen atoms of the backbone instead of α-carbon as in peptides, thus implying the absence of H-bonds among the core units of the backbone. A recent work indeed reported that helical peptoids based on Nspe units formed in solution do not retain their secondary structure when transferred to the gas phase upon electrospray ionization (ESI). In this context, we demonstrate here that the helical structure of peptoids bearing (S)-N-(1-carboxy-2-phenylethyl) bulky side chains (Nscp) is largely preserved in the gas phase by the creation of a hydrogen bond network, induced by the presence of carboxylic moieties, that compensates for the charge solvation process.

Organocatalytic Synthesis of Alkyne-Functional Aliphatic Polycarbonates via Ring-Opening Polymerization of an Eight-Membered-N-Cyclic Carbonate.

The synthesis of well-defined propargyl-functional aliphatic polycarbonates is achieved via the organocatalytic ring-opening polymerization of prop-2-yn-1-yl 2-oxo-1,3,6-dioxazocane-6-carboxylate (P-8NC) using a wide variety of commercially available or readily made, shelf-stable organocatalysts. The resulting homopolymers show low dispersities and end-group fidelity, with the versatility of the system being demonstrated by the synthesis of telechelic copolymers and block copolymers with molar mass up to 40 kDa.

Assessing the Structural Heterogeneity of Isomeric Homo and Copolymers: an Approach Combining Ion Mobility Mass Spectrometry and Molecular Dynamics Simulations.

Synthetic polymers occupy a unique place in the field of ion mobility mass spectrometry (IMS-MS). Indeed, due to their intrinsic dispersity, they have the asset to offer a broad range of homologous ions with different lengths that can be detected in several charge states. In addition, the gas-phase structure of polymer ions mostly depends on their ability to screen the adducted charges. Several works dealing with linear, cyclic, and star-shaped polymers have already shown that the gas-phase structure of polymer ions heavily relies on the polymer architecture, i.e., the primary structure. In the present work, we move a step further by evaluating whether a relationship exists between the primary and secondary structures of synthetic homo and copolymers. The IMS-MS experiments will be further complemented by MD simulations. To highlight the effectiveness of IMS separation, we selected isomeric homo and copolymers made of lactide (LA) and propiolactone (PL) units. In this way, the mass analysis becomes useless since isomeric comonomer sequences can coexist for any given chain length. An UPLC method was implemented in the workflow to successfully separate all PL-LA comonomer sequences before infusion in the IMS-MS instrument. The analysis of doubly charged copolymers showed that the comonomer sequence has an impact on the IMS response. However, this only holds for copolymer ions with precise sizes and charge states, and this is therefore not a rule of thumb.

Design of naturally inspired jellyfish-shaped cyclopolylactides to manage osteosarcoma cancer stem cells fate.

We report the synthesis, characterization and biological profile of new bis-triazoled cyclopolylactides (c-PLA, c-PLA-FA, c-PLA-Rhod) obtained by an optimized combination of ROP and click chemistry reactions. Cyclo-PLA having a number average molecular weight of 6000 g mol-1 and a polydispersity index of 1.52 was synthetized by click ring-closure of well-defined α,ω-heterodifunctional linear precursors, followed by quaternarization of N3-triazole nodes, and subsequent CuAAC with azido-folate and azido-rhodamine yielding jellyfish-shaped c-PLA-FA and c-PLA-Rhod. Salinomycin (Sal) was loaded into jellyfish-shaped c-PLA-FA and c-PLA-Rhod nanoparticles (NPs) by nanoprecipitation, with a good encapsulation efficiency (79% and 84%, respectively) and loading content (7.1% and 7.6%, respectively). The biological studies focused on their antiproliferative effects on osteosarcoma bulk MG63 and cancer stem cells (CSCs). The cycloPLA-based NPs, with a size ranging between 125 and 385 nm, killed CSCs and MG63, with a higher efficacy on CSCs; they (unloaded or Sal-loaded) evoked on CSCs a cellular response similar to the payload, with a higher effect than the free Sal. Internalization studies indicated a fast cellular uptake (within 2 h) and sarcospheres remained fluorescent till 72 h. To the best of our knowledge, this is the first study reporting anti-CSCs properties of cycloPLA with jellyfish architecture and we believe could contribute to the development of effective strategies for osteosarcoma targeting.

Efficient Convergent Energy Transfer in a Stereoisomerically Pure Heptanuclear Luminescent Terpyridine-Based Ru(II)-Os(II) Dendrimer.

The stereoisomerically pure synthesis of a novel heptanuclear Ru(II)-Os(II) antenna bearing multitopic terpyridine ligands is reported. An unambiguous structural characterization was obtained by 1H NMR spectroscopy and ion mobility spectrometry (IMS-MS). The heptanuclear complex exhibits large molar absorption coefficients (77900 M-1 cm-1 at 497 nm) and undergoes unitary, downhill, convergent energy transfer from the peripheral Ru(II) subunits to the central Os(II) that displays photoluminescence with a lifetime (τ = 161 ns) competent for diffusional excited-state electron transfer reactivity in solution.

How Spherical Are Gaseous Low Charged Dendrimer Ions: A Molecular Dynamics/Ion Mobility Study?

The globular shape of gaseous ions, resulting from the ionization of large molecules such as polymers and proteins, is a recurring subject that has undergone a renewed interest with the advent of ion mobility spectrometry (IMS), especially in conjunction with theoretical chemistry techniques such as Molecular Dynamics (MD). Globular conformations result from a fine balance between entropy and enthalpy considerations. For multiply charged ions isolated in the gas phase of a mass spectrometer, the Coulombic repulsion between the different charges tends to prevent the ions from adopting a compact, and folded 3D structure. In the present paper, we closely associate data from IMS experiments and MD simulations to unambiguously access the conformations of dendrimer ions in the gas phase with special attention paid to the dendrimer structure, the generation, and the charge state. By doing so, we here combine a set of structural tools able to evaluate the (non)globular shape of ions based on both experimental and theoretical results.

Effects of electrospray mechanisms and structural relaxation on polylactide ion conformations in the gas phase: insights from ion mobility spectrometry and molecular dynamics simulations.

Recent advances in molecular dynamics (MD) simulations have made it possible to examine the behavior of large charged droplets that contain analytes such as proteins or polymers, thereby providing insights into electrospray ionization (ESI) mechanisms. In the present study, we use this approach to investigate the release of polylactide (PLA) ions from water/acetonitrile ESI droplets. We found that cationized gaseous PLA ions can be formed via various competing pathways. Some MD runs showed extrusion and subsequent separation of polymer chains from the droplet, as envisioned by the chain ejection model (CEM). On other occasions the PLA chains remained inside the droplets and were released after solvent evaporation to dryness, consistent with the charge residue model (CRM). Following their release from ESI droplets, the nascent gaseous PLA ions were subjected to structural relaxation for several µs in vacuo. The MD conformations generated in this way for various PLA charge states compared favorably to experimental results obtained by ion mobility spectrometry-mass spectrometry (IMS-MS). The structures of all PLA ions evolved during relaxation in the gas phase. However, some macroion species retained features that resembled their nascent structures. For this subset of ions, the IMS-MS response appears to be strongly correlated with the ESI release mechanism (CEM vs. CRM). The former favored extended structures, whereas the latter preferentially generated compact conformers.

Helicity of Peptoid Ions in the Gas Phase.

Peptoids are attractive substitutes for peptides in several research areas, especially when they adopt a helical structure. The chain-size evolution of the secondary structure of the widely studied (S)-N-1-phenylethyl peptoids is here analyzed by means of the ion mobility mass spectrometry technique increasingly used as a powerful analytical tool and is further supported by theoretical modeling. We conclude that the helical shape of the peptoids prevailing in solution is lost in the gas phase by the need to screen the positive charge borne by the peptoid even though the collisional cross sections are close to the values expected for helical systems. We further illustrate that trend line analyses predicting molecular shapes from fits of the size evolution of cross sections can be very misleading since they critically depend on the range of polymerization degrees under study.

Limitations of ion mobility spectrometry-mass spectrometry for the relative quantification of architectural isomeric polymers: A case study.

Since their discovery, cyclic polymers have attracted great interest because of their unique properties. Today, the preparation of these macrocyclic structures still remains a challenge for polymer chemists, and most of the preparation pathways lead to an inescapable contamination by linear by-products. As the properties of the polymers are closely related to their structure, it is of prime importance to be able to assess the architectural purity of a sample. METHODS: In this work, the suitability of ion mobility spectrometry-mass spectrometry (IMS-MS) for the quantification of two isomers was investigated. A cyclic poly(L-lactide) was prepared through photodimerization of its linear homologue. Since IMS-MS can be used to differentiate cyclic polymer ions from their linear analogues because of their more compact three-dimensional conformation, the present work envisaged the use of IMS-MS for the quantification of residual linear polymers within the cyclic polymer sample. RESULTS: Using the standard addition method to plot calibration curves, the fraction of linear contaminants in the sample was determined. By doing so, unrealistically high values of contamination were measured. CONCLUSIONS: These results were explained by an ionization efficiency issue. This work underlines some intrinsic limitations when using IMS-MS in the context of the relative quantification of isomers having different ionization efficiencies. Nevertheless, the linear-to-cyclic ratio can be roughly estimated by this method.