Search Results (103)

In the realm of click-type reactions and their application to bioorthogonal chemistry in living organisms, metal-free [3+2] cycloadditions involving mesoionic rings and strained cycloalkynes have gained increasing attention and potentiality in recent years. While there has been a significant accretion of experimental data, biological assays, and assessments of reaction mechanisms, some pieces of the tale are still missing. For instance, which structural and/or stereoelectronic effects are actually interlocked and which remain unplugged. With the advent of data-driven methods, including machine learning simulations, quantitative estimations of relevant observables and their correlations will explore better the chemical space of these transformations. Here we unveil a series of linear relationships, such as Hammett-type correlations, as well as deviations of linearity, using the case study of phenylsydnone (and its 4-aryl-substituted derivatives) with a highly reactive bicyclo[6.1.0]nonyne carbinol. Through accurate estimation of activation barriers and prediction of rate constants, our findings further increase the significance of integrating strain release and electronic effects in organic reactivity. Moreover, such results could pave the way to use mesoionics cycloadditions as probes for measuring the extent of delocalization-assisted strain release, which can be applied to related reactions involving dipoles and strained rings. Full article

A novel and general approach to the practical ROMP polymerization of cinchona alkaloid derivatives providing novel hybrid materials having quinine attached on a poly(norbornene-5,6-dicarboxyimide) matrix is presented. The concept involves an easy modification of quinine (in general, any cinchona alkaloid) toward clickable 9-azide that reacts with N-propargyl-cis-5-norbornene-exo-2,3-dicarboxylic imide in Cu(I)-catalyzed Huisgen cycloaddition (click chemistry). The resulting monomers undergo a controllable ROMP reaction that leads to novel polymers of a desired length and solubility. This sequence allows for the facile preparation of a regularly decorated polymeric material having one quinine moiety per single mer of the polymer chain inaccessible using typical immobilization methods. A poly(norbornene-5,6-dicarboxyimide) type of polymeric matrix was selected due to the high reactivity of the exo-norbornene motif in Ru(II)-catalyzed ROMP and its chemical and thermal stability as well as convenient, scalable access from inexpensive cis-5-norbornene-exo-2,3-dicarboxylic anhydride (‘one-pot’ Diels–Alder reaction of dicyclopentadiene and maleic anhydride). An appropriate combination of a Grubbs catalyst, Ru(II) (G1, G2), and ROMP conditions allowed for the efficient synthesis of well-defined soluble polymers with mass parameters in the range Mn = 2.24 × 10⁴ – 2.26 × 10⁴ g/mol and Mw = 2.90 × 10⁴–3.05 × 10⁴ g/mol with good polydispersity, Đ_M = 1.32–1.35, and excellent thermal stability (up to 309°C T_d10). Spectroscopic studies (NMR and electronic circular dichroism (ECD)) of these products revealed a linear structure with the slight advantage of a trans-configuration of an olefinic double bond. The resulting short-chain polymer discriminates mandelic acid enantiomers with a preference for the (R)-stereoisomer in spectrofluorimetric assays. This concept seems to be rather general with respect to other molecules dedicated to incorporation into the poly(norbornene-5,6-dicarboxyimide) chain. Full article

Micromachines, small-scale engineered devices prepared to carry out exact tasks at the micro level, have garnered great interest across different fields such as drug delivery, chemical synthesis, and biomedical applications. In emerging applications, micromachines have indicated great potential in advancing click chemistry, a highly selective and efficient chemical technique widely applied in materials science, bioconjugation, and pharmaceutical development. Click chemistry, distinguished by its rapid reaction rates, high efficiency, and bioorthogonality, serves as a robust method for molecular assembly and functionalization. Incorporating micromachines into click chemistry processes paves the way for precise, automated, and scalable chemical synthesis. These tiny devices can effectively transport reactants, boost reaction efficiency through localized mixing, and enable highly exact site-specific modifications. Moreover, micromachines driven by external forces such as magnetic fields, ultrasound, or chemical fuels provide exceptional control over reaction conditions, significantly enhancing the selectivity and efficiency of click reactions. In this review, we explore the interaction between micromachines and click chemistry, showcasing recent advancements, potential uses, and future prospects in this cross-disciplinary domain. By leveraging micromachine-supported click chemistry, scientists can surpass conventional reaction constraints, opening doors to groundbreaking innovations in materials science, drug discovery, and beyond. Full article

Chitosan is a natural, biocompatible, biodegradable, and non-toxic polymer that has consistently garnered the attention of researchers in the development of new materials across various applications. Typically, to impart the desired properties to chitosan, chemical modification is necessary. Therefore, the development of simple and convenient methods for the chemical modification of chitosan is crucial in polymer chemistry. In this work, the approaches of Click chemistry and the necessary electrochemistry, which have recently illuminated the chemistry of chitosan, were combined to achieve a straightforward and efficient synthesis of new tetrazole chitosan derivatives. This was accomplished through electrochemical coupling. The proposed synthesis method is simple, convenient, and fast, hence allowing for the easy production of low- (10%), moderate- (30%), and highly substituted (65%) tetrazole chitosan derivatives. The highly substituted chitosan derivatives exhibit high activity as catalysts for the aldol reaction, achieving almost 100% conversion in just 15 min. Notably, these derivatives enable the aldol reaction to be catalyzed in water, aligning with one of the key principles of green chemistry. Furthermore, the new tetrazole chitosan derivatives demonstrate significant in vivo antibacterial effects in the treatment of peritonitis in rats. The primary mechanism of their antibacterial action is the disruption of the bacterial cell membrane integrity. Full article

Chitosan (CS), a versatile biopolymer obtained through the deacetylation of chitin, has gained significant interest in biomedical and pharmaceutical applications due to its biocompatibility, biodegradability, and unique gel-forming capabilities. This review comprehensively analyzes CS-based gel development, covering its extraction from various natural sources, gelation mechanisms, and biomedical applications. Different extraction methods, including chemical, biological, and green techniques, are discussed regarding efficiency and sustainability. The review explores the physicochemical properties of CS that influence its gelation behavior, highlighting various gelation mechanisms such as physical, ionic, and chemical cross-linking. Recent advances in gel formation, including Schiff base reactions, Diels–Alder click chemistry, and thermosensitive gelation, have expanded the applicability of CS hydrogels. Furthermore, CS-based gels have demonstrated potential in wound healing, tissue engineering, drug delivery, and antimicrobial applications, offering controlled drug release, enhanced biocompatibility, and tunable mechanical properties. The incorporation of nanomaterials, bioactive molecules, and functional cross-linkers has further improved hydrogel performance. The current review underscores the growing significance of CS-based gels as innovative biomaterials in regenerative medicine and pharmaceutical sciences. Full article

Fluorescent labeling utilizing Cu(I)-catalyzed azide–alkyne cycloaddition reactions (CuAAC) is among the leading applications of the “click” chemistry strategy. Fluorescent probes for this approach can be constructed by linking an azide or alkyne group to a fluorophore, such as the recently developed Safirinium derivatives. These compounds are water-soluble, highly fluorescent heterocycles based on 1,2,4-triazolium, with significant potential for various labeling applications, although they have not yet been converted to azide or alkyne probes. Herein, we report the synthesis of Safirinium-based azide and alkyne functionalized molecular probes for “click” chemistry labeling. We also describe their CuAAC reactions with model compounds, including a lipid mimetic long-chain azide, an azido sugar derivative, and azidothymidine, as well as two model alkynes. We demonstrate that the Safirinium-based probes and their derivatives are chemically stable, suitable for fluorescent microscopy observations, and safe to use. Most of these probes show no toxic effects on CHO-K1 and NIH-3T3 cells. Full article

Though polyurethanes (PUs) are widely used in people’s daily lives, traditional PUs are generally fabricated from toxic (poly)isocyanates. Furthermore, (poly)isocyanates are commonly industrially prepared from a seriously toxic and injurious chemical compound named phosgene, which is a dangerous gas that can cause lung irritation and eventually death. As is known to all, the consumption of carbon dioxide (CO₂)-based raw materials in chemical reactions and productions will be conducive to reducing the greenhouse effect. In this paper, non-isocyanate polyurethane (NIPU) diol was fabricated through a polyaddition reaction from ethylenediamine and CO₂-based ethylene carbonate, and then NIPU-based silicone-containing thiol hyperbranched polymers (NIPU-SiHPs) were synthesized from the NIPU diol. Finally, UV-curable optical-silicone-modified CO₂-based coatings (UV-NIPUs) were fabricated from NIPU-SiHPs and pentaerythritol triacrylate by a UV-initiated thiol-ene click reaction without a UV initiator. The UV-NIPUs demonstrated high transparency over 90% (400–800 nm), good mechanical performance with tensile strength reaching 3.49 MPa, superior thermal stability with an initial decomposition temperature (T_d5) in the range of 239.7–265.6 °C, moderate hydrophilicity with a water contact angle in the range of 42.6–62.1°, a high pencil hardness in the range of 5–9H, and good adhesive performance of grade 0. The results indicate that it is a promising green chemical strategy to fabricate CO₂-based high-performance materials. Full article

The separation and purification of molecular compounds and their functionalized derivatives is a common challenge in organic synthesis. In particular, calix[4]resorcinarenes present a high potential for chemical derivatization at their upper edge by aminomethylation reactions, and these compounds and their derivatives require appropriate analytical methodologies for their analysis, separation, and purification. In this study, C-tetra(propyl)calix[4]resorcinarene was synthesized and functionalized with maleimide groups by optimized aminomethylation reactions, obtaining a mixture of mono-, di-, tri-, and tetrasubstituted compounds. Initial separation by RP-HPLC with a core-shell column showed poorly resolved peaks, indicating a loss of separation efficiency. Therefore, a monolithic C18 column was used, which significantly improved the separation, thanks to its larger pore volume and continuous structure facilitating the diffusion of these bulky molecules, notably improving efficiency. Finally, the six compounds functionalized with maleimide groups were efficiently separated and enriched by RP-SPE by analytical method transfer, and the two peptides of six and the thirteen residues derived from LfcinB (20–25): RRWQWR were synthesized by SPPS-Fmoc/tBu and purified. These were modularly linked by the Michael thiol-maleimide addition reaction obtaining six (peptide)_n-resorcinarene conjugates. The analytical method by RP-HPLC with a monolithic C18 column, the separation and purification by RP-SPE were used transversally in all the steps to obtain compounds with adequate purities and quantities. Finally, the antibacterial activities of the six conjugates were evaluated against E. coli and E. faecalis strains, and it was determined that three aminomethylated compounds and one monosubstituted conjugate showed activity against E. faecalis. Our work established a new modular conjugation strategy between calix[4]resorcinarenes and peptides by thiol-maleimide click chemistry, and a methodology of separation, purification, and enrichment for these products by RP-HPLC and RP-SPE, which permitted us to obtain quantities with purities appropriate for their characterization by NMR, LC-MS and antibacterial activity assays. Full article

Cysteine plays a crucial role in the development of an efficient copper-catalyst system, where its thiol group serves as a strong anchoring site for metal coordination. By immobilizing copper onto cysteine-modified, polydopamine-coated magnetite particles, this advanced catalytic platform exhibits exceptional stability and catalytic activity. Chemical modification of the polydopamine (PDA) surface with cysteine enhances copper salt immobilization, leading to the formation of the Fe₃O₄@PDA-Cys@Cu platform. This system was evaluated in palladium-free, copper-catalyzed Sonogashira coupling reactions, effectively catalyzing the coupling of terminal acetylenes with aryl halides. Additionally, the Fe₃O₄@PDA-Cys@Cu platform was employed in click reactions, confirming the enhanced catalytic efficiency due to increased copper content. The reusability of the platform was further investigated, demonstrating improved performance, especially in recyclability tests in click reaction, making it a promising candidate for sustainable heterogeneous catalysis. Full article

Mechanical signals from the extracellular matrix are crucial in guiding cellular behavior. Two-dimensional hydrogel substrates for cell cultures serve as exceptional tools for mechanobiology studies because they mimic the biomechanical and adhesive characteristics of natural environments. However, the interdisciplinary knowledge required to synthetize and manipulate these biomaterials typically restricts their widespread use in biological laboratories, which may not have the material science expertise or specialized instrumentation. To address this, we propose a scalable method that requires minimal setup to produce 2D hydrogel substrates with independent modulation of the rigidity and adhesiveness within the range typical of natural tissues. In this method, norbornene-terminated 8-arm polyethylene glycol is stoichiometrically functionalized with RGD peptides and crosslinked with a di-cysteine terminated peptide via a thiol–ene click reaction. Since the synthesis process significantly influences the final properties of the hydrogels, we provide a detailed description of the chemical procedure to ensure reproducibility and high throughput results. We demonstrate examples of cell mechanosignaling by monitoring the activation state of the mechanoeffector proteins YAP/TAZ. This method effectively dissects the influence of biophysical and adhesive cues on cell behavior. We believe that our procedure will be easily adopted by other cell biology laboratories, improving its accessibility and practical application. Full article

The surface of calcined kaolinite particles underwent chemical modification using Vinyltriethoxysilane (VTMS) and 3-mercaptopropionic acid (3-MPA). The grafting ratio of VTMS on the calcined kaolinite surface was adjusted by varying its quantity. FT-IR analysis revealed the initial grafting of VTMS onto the kaolinite surface, resulting in the formation of a C=C reactive site on the surface. Subsequently, an olefin click reaction with 3-MPA occurred, leading to the effective grafting of 3-MPA onto the kaolinite surface and the formation of an efficient coating. Thermal analysis indicated that the optimal grafting level was achieved at a modifier content V:K ratio of 0.5. The estimated grafting ratio of the modifier on the kaolinite surface was approximately 40% when V:K was 0.5. Water contact angle and dispersion experiments demonstrated that the surface properties of kaolinite were effectively controlled by this modification approach. At V:K = 0.3, the modified kaolinite particles exhibited good dispersion in both polar and non-polar solvents. In polar solvents, the average particle size of modified kaolinite was below 1100 nm, while in non-polar solvents, it did not exceed 5000 nm. Considering all aspects, a V:K ratio of 0.3 is recommended. Further investigation into the impact of adding 3-MPA on the surface properties of modified kaolinite particles based on V:K = 0.3 revealed that the hydrophilicity of the modified particles could be enhanced. However, it is advised to keep the maximum M:V ratio (3-MPA to kaolinite) at 1.0. Full article

The synergistic effect of drug and gene delivery is expected to significantly improve cancer therapy. However, it is still challenging to design suitable nanocarriers that are able to load simultaneously anticancer drugs and nucleic acids due to their different physico-chemical properties. In the present work, an amphiphilic block copolymer comprising a biocompatible poly(ethylene glycol) (PEG) block and a multi-alkyne-functional biodegradable polycarbonate (PC) block was modified with a number of poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) side chains applying the highly efficient azide–alkyne “click” chemistry reaction. The resulting cationic amphiphilic copolymer with block and graft architecture (MPEG-b-(PC-g-PDMAEMA)) self-associated in aqueous media into nanosized micelles which were loaded with the antioxidant, anti-inflammatory, and anticancer drug quercetin. The drug-loaded nanoparticles were further used to form micelleplexes in aqueous media through electrostatic interactions with DNA. The obtained nanoaggregates—empty and drug-loaded micelles as well as the micelleplexes intended for simultaneous DNA and drug codelivery—were physico-chemically characterized. Additionally, initial in vitro evaluations were performed, indicating the potential application of the novel polymer nanocarriers as drug delivery systems. Full article

Silicon is the most commonly used material in the microelectronics industry, due to its inherent advantages of high natural abundance, low cost, and high purity, coupled with the chemical and electrical stability at the interface with its oxide. For molecular electronics applications, oxide-free Si surfaces are widely used because of the relative ease of removing the oxide (SiO_x) by chemical means, yielding a surface which forms strong covalent bonds with a wide range of chemical functional groups; another advantage is that these surfaces remain oxide-free in the absence of oxidising agents. Standard procedures require the use of either HF, NH₄F, or a mixture of both as the etching solution; however, these two chemicals are highly corrosive and toxic, posing a significant risk to the experimentalist. Here, we report that for silicon wafers etched by using potassium fluoride, a less toxic chemical, the resulting surface is free of oxides and can be functionalized by self-assembled monolayers of 1,8-nonadiyne. To demonstrate this, Si/SiO_x wafers were etched by using either KF or NH₄F, followed by hydrosilylation with 1,8-nonadiyne and a click reaction of the terminal alkyne with azidomethylferrocene. The surface coverages and electron transfer kinetics of the ferrocene-terminated KF-etched surfaces are comparable to those formed by acidic fluoride etching procedures. This is the first study comparing the differences between surfaces functionalized by self-assembled monolayers of 1,8-nonadiyne which were etched by KF and NH₄F. KF could be used as a replacement chemical for etching silicon wafers when a less corrosive and toxic chemical is required. Full article

To selectively target and treat murine melanoma B16BL6 tumors expressing α_vβ₃ integrin receptors, we engineered tumor-specific functional extracellular vesicles (EVs) tailored for the targeted delivery of antitumor drugs. This objective was achieved through the incorporation of a pH-responsive adjuvant, cyclic arginine-glycine-aspartic acid peptide (cRGD, serving as a tumor-targeting ligand), and 5-fluorouracil (5-FU, employed as a model antitumor drug). The pH-responsive adjuvant, essential for modulating drug release, was synthesized by chemically conjugating 3-(diethylamino)propylamine (DEAP) to deoxycholic acid (DOCA, a lipophilic substance capable of integrating into EVs’ membranes), denoted as DEAP-DOCA. The DOCA, preactivated using N-(2-aminoethyl)maleimide (AEM), was chemically coupled with the thiol group of the cRGD-DOCA through the thiol–maleimide click reaction, resulting in the formation of cRGD-DOCA. Subsequently, DEAP-DOCA, cRGD-DOCA, and 5-FU were efficiently incorporated into EVs using a sonication method. The resulting tumor-targeting EVs, expressing cRGD ligands, demonstrated enhanced in vitro/in vivo cellular uptake specifically for B16BL6 tumors expressing α_vβ₃ integrin receptors. The ionization characteristics of the DEAP in DEAP-DOCA induced destabilization of the EVs membrane at pH 6.5 through protonation of the DEAP substance, thereby expediting 5-FU release. Consequently, an improvement in the in vivo antitumor efficacy was observed for B16BL6 tumors. Based on these comprehensive in vitro/in vivo findings, we anticipate that this EV system holds substantial promise as an exceptionally effective platform for antitumor therapeutic delivery. Full article

Hydrogels, being hydrophilic polymer networks capable of absorbing and retaining aqueous fluids, hold significant promise in biomedical applications owing to their high water content, permeability, and structural similarity to the extracellular matrix. Recent chemical advancements have bolstered their versatility, facilitating the integration of the molecules guiding cellular activities and enabling their controlled activation under time constraints. However, conventional synthetic hydrogels suffer from inherent weaknesses such as heterogeneity and network imperfections, which adversely affect their mechanical properties, diffusion rates, and biological activity. In response to these challenges, hybrid hydrogels have emerged, aiming to enhance their strength, drug release efficiency, and therapeutic effectiveness. These hybrid hydrogels, featuring improved formulations, are tailored for controlled drug release and tissue regeneration across both soft and hard tissues. The scientific community has increasingly recognized the versatile characteristics of hybrid hydrogels, particularly in the biomedical sector. This comprehensive review delves into recent advancements in hybrid hydrogel systems, covering the diverse types, modification strategies, and the integration of nano/microstructures. The discussion includes innovative fabrication techniques such as click reactions, 3D printing, and photopatterning alongside the elucidation of the release mechanisms of bioactive molecules. By addressing challenges, the review underscores diverse biomedical applications and envisages a promising future for hybrid hydrogels across various domains in the biomedical field. Full article