Lignin-Based Catalysts for C-C Bond-Forming Reactions.

Carbon-carbon (C-C) bond formation is the key reaction in organic synthesis to construct the carbon framework of organic molecules. The continuous shift of science and technology toward eco-friendly and sustainable resources and processes has stimulated the development of catalytic processes for C-C bond formation based on the use of renewable resources. In this context, and among other biopolymer-based materials, lignin has attracted scientific attention in the field of catalysis during the last decade, either through its acid form or as a support for metal ions and metal nanoparticles that drive the catalytic activity. Its heterogeneous nature, as well as its facile preparation and low cost, provide competitive advantages over other homogeneous catalysts. In this review, we have summarized a variety of C-C formation reactions, such as condensations, Michael additions of indoles, and Pd-mediated cross-coupling reactions that were successfully carried out in the presence of lignin-based catalysts. These examples also involve the successful recovery and reuse of the catalyst after the reaction.

A pH-Triggered Polymer Degradation or Drug Delivery System by Light-Mediated Cis/Trans Isomerization of o-Hydroxy Cinnamates.

A new methodology for the pH-triggered degradation of polymers or for the release of drugs under visible light irradiation based on the cyclization of ortho-hydroxy-cinnamates (oHC) to coumarins is described. The key oHC structural motif can be readily incorporated into the rational design of novel photocleavable polymers via click chemistry. This main-chain moiety undergoes a fast photocleavage when irradiated with 455 nm light provided that a suitable base is added. A series of polyethylene glycol-alt-ortho-hydroxy cinnamate (polyethylene glycol (PEG)n -alt-oHC)-based polymers are synthesized and the time-dependent visible-light initiated cleavage of the photoactive monomer and polymer is investigated in solution by a variety of spectroscopic and chromatographic techniques. The photo-degradation behavior of the water-soluble poly(PEG2000 -alt-oHC) is investigated within a broad pH range (pH = 2.1-11.8), demonstrating fast degradation at pH 11.8, while the stability of the polymer is greatly enhanced at pH 2.1. Moreover, the neat polymer shows long-term stability under daylight conditions, thus allowing its storage without special precautions. In addition, two water-soluble PEG-based drug-carrier molecules (mPEG2000 -oHC-benzhydrol/phenol) are synthesized and used for drug delivery studies, monitoring the process by UV-vis spectroscopy in an ON/OFF intermittent manner.

Isomeric cationic ionenes as n-dopant agents of poly(3,4-ethylenedioxythiophene) for in situ gelation.

Three isomeric ionene polymers containing 1,4-diazabicyclo[2.2.2]octane (DABCO) and N,N'-(x-phenylene)dibenzamide (x = ortho-/meta-/para-) linkages have been used as dopant agents to produce n-doped poly(3,4-ethylenedioxythiophene) (PEDOT) electrodes by reducing already dedoped conducting polymer (CP) films. This work focuses on the influence of the ionene topology on both the properties of n-doped PEDOT:ionene electrodes and the success of the in situ thermal gelation of the ionene inside the CP matrix. The highest doping level is reached for the para-isomeric ionene-containing electrode, even though the content of ortho- and meta-topomers in the corresponding n-doped PEDOT:ionene electrodes is greater. Thus, many of the incorporated ionene units are not directly interacting with CP chains and, therefore, they do not play an active role as n-dopant agents but they are crucial for the in situ formation of the ionene hydrogels. The effect of the ionene topology is practically non-existent on properties such as the specific capacitance and wettability of PEDOT:ionene films, and it is small but non-negligible on the electrochemical and thermal stability. In contrast, the surface morphology, topography, and distribution of dopant molecules significantly depend on the ionene topology. In situ thermal gelation was successful in PEDOT films n-doped with the ortho- and para-topomers, even though this assembly process was much faster for the former than for the latter. The gelation considerably improved the mechanical response of the electropolymerized PEDOT film, which was practically non-existent before it. Molecular dynamics simulations prove that the strength and abundance of PEDOTionene specific interactions (i.e. π-π stacking, N-HS hydrogen bonds and both N+O and N+S interactions) are higher for the meta-isomeric ionene, for which the in situ gelation was not achieved, than for the ortho- and para-ones.

Paradigm Shift for Preparing Versatile M2+-Free Gels from Unmodified Sodium Alginate.

This manuscript describes a new route to prepare rapidly Ca2+-free hydrogels from unmodified sodium alginate by simply mixing with small organic molecules such as poly(carboxylic acid) compounds as cross-linker agents instead of classical divalent metal salts such as CaCl2. Dimethyl sulfoxide (DMSO) was also found to induce the rapid gelation of aqueous alginate solutions. The gelation process takes place at room temperature, and depending on the composition, gels with good thermal (90-100 °C) and mechanical properties compared to classical metal-containing analogs are obtained. DMSO-based gels showed remarkable self-supporting and thixotropic properties, which can be tuned by the biopolymer concentration. Furthermore, oxalic acid-based gels show superior elasticity than HCl, CaCl2 and DMSO-based gels. The possibility to prepare monoliths, beads, and films of these gels provide them with significant versatility. In particular, films made of alginate and oxalic acid show good potential as synergistic anticancer drug delivery carrier. Computational studies using both quantum mechanical and classical force-field methodologies reveal that hydrogen bonding networks between water and DMSO molecules located close to the alginate chains are responsible for the stability of DMSO-based gels. In contrast, the cohesion of oxalic acid-based gels is a consequence of the coexistence of multiple ionic associations involving oxalate, alginate, and Na+ counterions, which stabilize the system and keep all the interacting species grouped.

Antimicrobial and Hemolytic Studies of a Series of Polycations Bearing Quaternary Ammonium Moieties: Structural and Topological Effects.

A series of polycations bearing quaternary ammonium moieties have shown antimicrobial activity against the Gram-negative bacterium Escherichia coli. Different polymer topologies governed by a disubstituted aromatic core as well as different diamine-based linkers were found to influence the antimicrobial properties. Moreover, the hemolytic activity against human red blood cells was measured and demonstrated good biocompatibility and selectivity of these polycations for bacteria over mammalian cells.

Supramolecular phase-selective gelation by peptides bearing side-chain azobenzenes: effect of ultrasound and potential for dye removal and oil spill remediation.

Phase selective gelation (PSG) of organic phases from their non-miscible mixtures with water was achieved using tetrapeptides bearing a side-chain azobenzene moiety. The presence of the chromophore allowed PSG at the same concentration as the minimum gelation concentration (MGC) necessary to obtain the gels in pure organic phases. Remarkably, the presence of the water phase during PSG did not impact the thermal, mechanical, and morphological properties of the corresponding organogels. In the case of miscible oil/water mixtures, the entire mixture was gelled, resulting in the formation of quasi-hydrogels. Importantly, PSG could be triggered at room temperature by ultrasound treatment of the mixture or by adding ultrasound-aided concentrated solution of the peptide in an oil-phase to a mixture of the same oil and water. Moreover, the PSG was not affected by the presence of salts or impurities existing in water from natural sources. The process could be scaled-up, and the oil phases (e.g., aromatic solvents, gasoline, diesel fuel) recovered almost quantitatively after a simple distillation process, which also allowed the recovery and reuse of the gelator. Finally, these peptidic gelators could be used to quantitatively remove toxic dyes from aqueous solutions.

DNA-catalyzed Henry reaction in pure water and the striking influence of organic buffer systems.

In this manuscript we report a critical evaluation of the ability of natural DNA to mediate the nitroaldol (Henry) reaction at physiological temperature in pure water. Under these conditions, no background reaction took place (i.e., control experiment without DNA). Both heteroaromatic aldehydes (e.g., 2-pyridinecarboxaldehyde) and aromatic aldehydes bearing strong or moderate electron-withdrawing groups reacted satisfactorily with nitromethane obeying first order kinetics and affording the corresponding ß-nitroalcohols in good yields within 24 h. In contrast, aliphatic aldehydes and aromatic aldehydes having electron-donating groups either did not react or were poorly converted. Moreover, we discovered that a number of metal-free organic buffers efficiently promote the Henry reaction when they were used as reaction media without adding external catalysts. This constitutes an important observation because the influence of organic buffers in chemical processes has been traditionally underestimated.

Hydrogel composites based on chitosan and CuAuTiO2 photocatalysts for hydrogen production under simulated sunlight irradiation.

This study explored the photocatalytic hydrogen evolution reaction (HER) using novel biohydrogel composites comprising chitosan, and a photocatalyst consisting in TiO2 P25 decorated with Au and/or Cu mono- and bimetallic nanoparticles (NPs) to boost its optical and catalytic properties. Low loads of Cu and Au (1 mol%) were incorporated onto TiO2 via a green photodeposition methodology. Characterization techniques confirmed the incorporation of decoration metals as well as improvements in the light absorption properties in the visible light interval (λ > 390 nm) and electron transfer capability of the semiconductors. Thereafter, Au and/or Cu NP-supported TiO2 were incorporated into chitosan-based physically crosslinked hydrogels revealing significant interactions between chitosan functional groups (hydroxyls, amines and amides) with the NPs to ensure its encapsulation. These materials were evaluated as photocatalysts for the HER using water and methanol mixtures under simulated sunlight and visible light irradiation. Sample CuAuTiO2/ChTPP exhibited a maximum hydrogen generation of 1790 µmol g-1 h-1 under simulated sunlight irradiation, almost 12-folds higher compared with TiO2/ChTPP. Also, the nanocomposites revealed a similar tendency under visible light with a maximum hydrogen production of 590 µmol g-1 h-1. These results agree with the efficiency of photoinduced charge separation revealed by transient photocurrent and EIS.

Development and Evaluation of PEG-Gelatin-Based Microparticles to Enhance the Oral Delivery of Insulin.

BACKGROUND: Diabetes mellitus is a global disease identified by hyperglycemia due to defects in insulin secretion, insulin action, or both. OBJECTIVE: The main objective of this research was to evaluate the ability of gelatinized Poly(ethylene glycol) (PEG) microparticles to be used as carriers for oral insulin delivery via double emulsion preparation. METHODS: Five different batches of the formulation consisting of gelatin:PEG were prepared as follows: 0:1 (W1), 1:0 (W2), 1:1 (W3), 1:3 (W4), and 3:1 (W5). The prepared microparticles (from insulin-loaded batches) had particle sizes ranging from 19.5 ± 0.32-23.9 ± 0.22 µm and encapsulation and loading capacities ranging from 78.8 ± 0.24-88.9 ± 0.95 and 22.2 ± 0.96-29.7 ± 0.86%, respectively. The minimum and maximum in vitro release rates were 8.0 and 66.0%, respectively, for batches W1 and W2 at 8 h. RESULTS: Insulin-loaded MPs induced a significant decrease in glucose levels, with a reduction from 100 to 33.35% in batch W5 at 9 h compared to that of subcutaneous insulin (100 to 22.63%). A liver function study showed that the formulation caused no obvious toxicity to the experimental rats. CONCLUSION: Gelatinized PEG-based microparticles as insulin delivery systems may open a new window into the development of oral insulin for diabetic treatment.

Dual electro-/pH-responsive nanoparticle/hydrogel system for controlled delivery of anticancer peptide.

An electro-chemo-responsive carrier has been engineered for the controlled release of a highly hydrophilic anticancer peptide, CR(NMe)EKA (Cys-Arg- N-methyl-Glu-Lys-Ala). Remotely controlled on demand release of CR(NMe)EKA, loaded in electro-responsive poly(3,4-ethylenedioxythiophene) (PEDOT) nanoparticles, has been achieved by applying electrical stimuli consisting of constant positive (+0.50 V) or negative voltages (-0.50 V) at pre-defined time intervals. In addition, after loading CR(NMe)EKA/PEDOT nanoparticles into an injectable pH responsive hydrogel formed by phenylboronic acid grafted to chitosan (PBA-CS), the efficiency of the controlled peptide release has increased approximately by a factor of 2.6. The hydration ratio of such hydrogel is significantly lower in acidic environments than in neutral and basic media, which has been attributed to the dissociation of the boronate bonds between polymer chains. Hence, the electro-controlled peptide release from PBA-CS/CR(NMe)EKA/PEDOT hydrogels, in the acidic environment of tumors, combines the effects of the oxidation and reduction of PEDOT chains on the interactions with the peptide and the carrier, with the peptide concentration gradient at the interface between the collapsed hydrogel and the release medium. Furthermore, the peptide released by electro-stimulation preserved its bioactivity assessed by promoting human prostate cancer cells death. Overall, this work is a promising attempt to develop a carrier platform for small hydrophilic anticancer peptides, which delivery rationale is synergistically regulated by the electrical and pH responsiveness of the carrier.

Hydrolytic conversion of a metal-organic polyhedron into a metal-organic framework.

Twist and release: The metal-organic polyhedron 1 synthesized from 5-(prop-2-ynyloxy)isophthalic acid and Cu(NO3 )2 ⋅ 3 H2 O has a hydrophobic outer surface and a hydrophilic inner core. In an aqueous medium, the resulting polarity gradient led to the transformation of 1 into the 2D metal-organic framework 2. This unique phenomenon enabled the gradual release of entrapped drug molecules.

Antinociceptive effect of cyclic and linear diterpenoids as new atypical agonists of κ-opioid receptors obtained from four species of the Baccharis genus, and vehiculated in nanometric niosomes.

New natural analgesic compounds that act in KORs are important alternatives for potential therapeutical use in medicine. In this work, we report and compare here the antinociceptive activity displayed by cyclic and linear diterpenes, obtained from the genus Baccharis. The antinociceptive activities determined were relatively strong, in comparison whit morphine. The antinociceptive mechanism of action was made through naloxone administration (a non-selective antagonist of opioid receptors). The more active compounds were vehiculized successfully in niosomes at nanometric scale. The observed antinociceptive activity for Bartemidiolide oxide (BARTO), obtain from Baccharis artemisioides, was greater than Flabeloic acid dimer (DACD), the first compound isolated from Baccharis flabellata that was reported possessing antinociceptive effects. We also conducted docking calculations and molecular dynamics simulations, which suggested that the newly identified diterpenes might share the molecular action mechanism reported for Salvinorin A (SalA). Molecular simulations have allowed us to appreciate some subtle differences between molecular interactions of these ligands stabilizing their respective complexes; such information might be useful for designing and searching for new inhibitors of KORs.

CuAu bimetallic plasmonic-enhanced catalysts supported on alginate biohydrogels.

We describe the synthesis, characterization and catalytic properties of a series of hybrid materials composed of inorganic plasmonic mono- and bimetallic nanoparticles supported on organic bio-based hydrogel beads. The bimetallic materials showed a localized surface plasmon resonance in the visible region, with a maximum light absorption correlated to the metal composition of the alloyed systems. Thermogravimetric analysis revealed a total water content near to 90 % w/w, which was in good agreement with the free-volume calculated from µCT scan reconstruction of lyophilized samples. Catalytic essays for the reduction of 4-nitrophenol demonstrated that alginate beads loaded with bimetallic nanoparticles exhibit a 5.4-fold higher apparent kinetic constant (kapp) than its monometallic counterparts. Additionally, taking advantage of the plasmonic properties given by the nanoparticles is that the materials were tested as photocatalysts. The activity of the catalysts was enhanced by near 2.2 times higher in comparison with its performance in dark conditions.

Porous chitosan-based nanocomposites containing gold nanoparticles. Increasing the catalytic performance through film porosity.

The preparation of porous and non-porous chitosan thin-films containing gold nanoparticles was carried out, aiming to evaluate the effect of porosity on their catalytic response using the p-nitrophenol reduction as model reaction. To achieve this, both types of samples were decorated with gold nanoparticles having similar characteristics in terms of amount, size and shape, which were synthesized following a two-step adsorption-reduction process. The results demonstrated that the presence of porosity generates a considerable enhancement of the catalytic property. This behavior is reflected in higher kinetic constant and conversion values, along with a better recyclability after consecutive cycles. The inclusion of porosity in nanocomposites afforded kobs values 7.5 times higher than the non-porous material, as well as conversion values as high as 80 % in <20 min. On the other hand, as an additional experiment, a porous sample prepared with half the amount of gold also exhibited a better performance than the non-porous catalyst, revealing that the porosity allowed to decrease the amount of catalytic metal used and still exhibiting kobs values 5.9 times higher than the non-porous specimen. These studies demonstrate that there is an important synergistic support-nanostructure relationship, which strongly influences the performance of the nanomaterial.

Graphene-based hybrid materials as promising scaffolds for peripheral nerve regeneration.

Peripheral nerve injury (PNI) is a serious clinical health problem caused by the damage of peripheral nerves which results in neurological deficits and permanent disability. There are several factors that may cause PNI such as localized damage (car accident, trauma, electrical injury) and outbreak of the systemic diseases (autoimmune or diabetes). While various diagnostic procedures including X-ray, magnetic resonance imaging (MRI), as well as other type of examinations such as electromyography or nerve conduction studies have been efficiently developed, a full recovery in patients with PNI is in many cases deficient or incomplete. This is the reason why additional therapeutic strategies should be explored to favor a complete rehabilitation in order to get appropriate nerve injury regeneration. The use of biomaterials acting as scaffolds opens an interesting approach in regenerative medicine and tissue engineering applications due to their ability to guide the growth of new tissues, adhesion and proliferation of cells including the expression of bioactive signals. This review discusses the preparation and therapeutic strategies describing in vitro and in vivo experiments using graphene-based materials in the context of PNI and their ability to promote nerve tissue regeneration.

Highly Efficient Production of Heteroarene Phosphonates by Dichromatic Photoredox Catalysis.

A new strategy to achieve efficient aerobic phosphorylation of five-membered heteraroenes with excellent yields using dichromatic photoredox catalysis in a gel-based nanoreactor is described here. The procedure involves visible aerobic irradiation (cold white LEDs) of a mixture containing the heteroarene halide, trisubstituted phospite, N,N-diisopropylethylamine (DIPEA) as sacrificial agent, and catalytic amounts of 9,10-dicyanoanthracene (DCA) in the presence of an adequate gelator, which permits a faster process than at the homogeneous phase. The methodology, which operates by a consecutive photoinduced electron transfer (ConPET) mechanism, has been successfully applied to the straightforward and clean synthesis of a number of different heteroarene (furan, thiophene, selenophene, pyrrole, oxazole, or thioxazole) phosphonates, extending to the late-stage phosphonylation of the anticoagulant rivaroxaban. Strategically, employment of cold white light is critical since it provides both selective wavelengths for exciting first DCA (blue region) and subsequently its corresponding radical anion DCA•- (green region). The resultant strongly reducing excited agent DCA•-* is capable of even activate five-membered heteroarene halides (Br, Cl) with high reduction potentials (∼-2.7 V) to effect the C(sp2)-P bond formation. Spectroscopic and thermodynamic studies have supported the proposed reaction mechanism. Interestingly, the rate of product formation has been clearly enhanced in gel media because reactants can be presumably localized not only in the solvent pools but also through to the fibers of the viscoelastic gel network. This has been confirmed by field-emission scanning electron microscopy images where a marked densification of the network has been observed, modifying its fibrillary morphology. Finally, rheological measurements have shown the resistance of the gel network to the incorporation of the reactants and the formation of the desired products.

Amphiphilic Polymer Co-Networks.

Amphiphilic Polymer Co-networks: Synthesis, Properties, Modelling and Applications is a new and very interesting book published by the Royal Society of Chemistry and edited by Prof. Costas S. Patrickios (University of Cyprus). Herein, a brief review of the most important features of the book and its contents is provided from a personal perspective.

Insulin-loaded mucoadhesive nanoparticles based on mucin-chitosan complexes for oral delivery and diabetes treatment.

In this study, insulin-loaded nanoparticles (NPs) were prepared via self-gelation method using chitosan and aqueous soluble snail mucin as natural polymers. Herein, mucins were ionically interacted with chitosan at different concentrations to obtained insulin-loaded NPs, labelled as A1 (1:1) (i.e., chitosan 2 % w/v + mucin 2 % w/v) and A2 (2:1) (chitosan 4 % w/v + mucin 2 % w/v), using poloxamer and poly vinyl alcohol as solid surfactant. Such formulation was selected to provide the necessary dynamics for the formation of the nanoparticles while maintaining the surface properties that will favor the encapsulation of insulin. Each system was characterized in terms of their particle size distribution, morphology, zeta potential, and polydispersity index. In vitro release of insulin was evaluated in acidic solution (pH 1.2) and phosphate buffer solution (pH 7.4), and the hypoglycaemic activity was evaluated in diabetes rats. The prepared insulin-loaded NPs displayed particles with relatively smooth surfaces and an average particle size of 479.6 and 504.1 nm for A1 and A2, respectively. Zeta potential and polydispersity index, ranged from 22.1 to 31.2 mV and 0.155-0.185, respectively. The encapsulating efficiency for the systems A1 and A2 were 88.6 and 92.5, respectively, and a self-sustained release of encapsulated insulin was observed for over a period of 8 h. In vivo studies revealed a pronounced hypoglycaemic effect in diabetic rats after peroral administration of the insulin-loaded NPs compared to the effect caused by free oral insulin solution. In addition, both the pharmacokinetic and toxicity results showed low plasma clearance of insulin and no signs of toxicity on the liver enzyme and cell viability, which suggested good biocompatibility of the NPs formulations. Overall, the formation of NPs of insulin with chitosan and snail mucin represents a potentially safe and promising approach to protect insulin and enhance its peroral delivery.

Use of a pH-sensitive polymer in a microextraction and preconcentration method directly combined with high-performance liquid chromatography.

A pH-sensitive polymer based on the poly(styrene-alt-maleic anhydride) co-polymer serves as basis to develop a microextraction method (pH-HGME) in direct combination with high-performance liquid chromatography (HPLC) and fluorescence detection (FD) for the determination of seven organic compounds, including three polycyclic aromatic hydrocarbons (PAHs), three monohydroxylated PAHs and one alkylphenol, in urine. The method bases on the structural modification of the pH-sensitive polymer in the aqueous sample at a high pH value, followed by the formation and insolubilization of a hydrogel containing the preconcentrated analytes by decreasing the pH, and the direct injection of the hydrogel-rich phase in the HPLC-FD system. The optimization of the main variables permitted the selection of low amounts of aqueous sample (10 mL), which was mixed with 10 mg of co-polymer also present in a low volume (150 µL) of concentrated NaOH. The method further requires the addition of 200 µL of concentrated HCl, 3 min of stirring, and 15 min of centrifugation. This pH-HGME-HPLC-FD method presented low limits of detection, ranging from 0.001 µg L-1 to 0.09 µg L-1 in ultrapure water, average relative recoveries of 96.9% for the concentration level of 0.60 µg L-1, and enrichment factors between 1.50 and 17.7. The proposed method also exhibited high precision, with intermediate relative standard deviations lower than 16% for a concentration level of 0.60 µg L-1. The developed pH-HGME-HPLC-FD method performed adequately when analyzing two human urine samples provided by a non-smoker male and a smoker female, respectively. One of the target analytes (2-hydroxynaphthalene) was quantified in both samples using the standard addition method, with a predicted concentration of 7.3 ± 0.4 µg L-1 in the non-smoker male urine and 19.3 ± 0.6 µg L-1 in the smoker female urine.

Sulfonamide as amide isostere for fine-tuning the gelation properties of physical gels.

(S)-2-Stearamidopentanedioic acid (C18-Glu) is a known LMW gelator that forms supramolecular gels in a variety of solvents. In this work, we have carried out the isosteric substitution of the amide group by a sulfonamide moiety yielding the new isosteric gelator (S)-2-(octadecylsulfonamido)pentanedioic acid (Sulfo-Glu). The gelation ability and the key properties of the corresponding gels were compared in terms of gelation concentration, gel-to-sol transition temperature, mechanical properties, morphology, and gelation kinetics in several organic solvents and water. This comparison was also extended to (S)-2-(4-hexadecyl-1H-1,2,3-triazol-4-yl)pentanedioic acid (Click-Glu), which also constitutes an isostere of C18-Glu. The stabilizing interactions were explored through computational calculations. In general, Sulfo-Glu enabled the formation of non-toxic gels at lower concentrations, faster, and with higher thermal-mechanical stabilities than those obtained with the other isosteres in most solvents. Furthermore, the amide-sulfonamide isosteric substitution also influenced the morphology of the gel networks as well as the release rate of an embedded antibiotic (vancomycin) leading to antibacterial activity in vitro against Staphylococcus aureus.