Search Results (712)

A collection of 40 derivatives of 1,2-diphenyl-2-[1,2,3]triazol-1-yl-ethanol was obtained through a sequence of reactions, starting with benzoin as the initial raw material and using the CuAAC reaction as the key step in this process. The structure of a pair of these compounds was ultimately corroborated by single-crystal X-ray diffraction studies, which also reveals important O-H···N interactions. The antimicrobial activity of synthesized 1,2,3-triazoles was assessed against strains that include Candida albicans and Staphylococcus aureus. The antiproliferative properties of some of these novel compounds were also tested using a variety of tumor cell lines, including U251 (human glioblastoma), PC-3 (human prostate cancer cell line), K562 (human leukemia), HCT-15 (human colorectal adenocarcinoma), MCF-7 (human breast adenocarcinoma), and SKLU (human lung adenocarcinoma). Full article

Macrocyclic drugs are promising for targeting undruggable proteins, including those in cancer. Our prior work identified BE-43547A₂ (BE) as a selective inhibitor of pancreatic cancer stem cells in PANC-1 cultures, but its high lipophilicity limits clinical application. To address this, we designed derivatives retaining BE’s backbone while modifying tail groups to improve its properties. A concise total synthesis enabled a versatile late-stage intermediate (compound 17), serving as a platform for efficient diversification of BE analogs via modular click chemistry. This approach introduced a central triazole ring connected by flexible alkyl spacers. Key properties, including lipophilicity, solubility, and Caco-2 permeability, were experimentally determined. These derivatives exhibited reduced lipophilicity and improved solubility but unexpectedly lost cellular activity. Direct target engagement studies using MicroScale Thermophoresis (MST) revealed compound-dependent deactivation mechanisms: certain derivatives retained binding to eEF1A1 with only modestly reduced affinity (e.g., compound 29), while others showed no detectable binding (e.g., compound 31). Microsecond-scale molecular dynamics simulations and free-energy calculations showed that, for derivatives retaining target affinity, tail modifications disrupted the delicate balance of drug–membrane and drug–solvent interactions, resulting in substantially higher transmembrane free-energy penalties (>5 kcal/mol) compared to active compounds (<2 kcal/mol). These insights emphasize the need to simultaneously preserve both target engagement and optimal permeability when modifying side chains in cell-permeable macrocyclic peptides, positioning compound 17 as a robust scaffold for future lead optimization. This work furnishes a blueprint for balancing drug-like properties with therapeutic potency in macrocyclic therapeutics. Full article

Click chemistry, and particularly the Cu-catalyzed Azide Alkyne Cycloaddition (CuAAC) reaction has gained increased attention in recent years as an invaluable tool for synthesizing pharmaceutical active organic compounds. In this study, quinolinones and triazoles, two bioactive heterocyclic moieties amenable to various substitutions, were employed to design and synthesize novel quinolinone–triazole hybrid molecules via the CuAAC click reaction under microwave irradiation. The synthesized hybrid molecules and their alkyne precursors were structurally characterized and evaluated for their antioxidant capacity, lipoxygenase (LOX) inhibitory activity, cell viability using HaCaT epithelial cells, and cytotoxicity against two cancer lines. The results indicated that, among the precursors, alkyne 4c exhibits the best combined antioxidant and anti-inflammatory activity (100% lipid peroxidation inhibition, IC₅₀ = 22.5 μM for LOX inhibition); among the hybrid molecules, compound 5a was the most potent (98.0% lipid peroxidation inhibition, IC₅₀ = 10.0 μM for LOX inhibition). Regarding the assessment of HaCaT cell viability, all studied compounds showed encouraging results, with cell viability rates between 61.5% and 100%. Moreover, based on the results of the cytotoxicity against cancer lines A549 and A375, it emerged that the tested compounds exhibited moderate–low or no cytotoxicity. These results highlight the potential of quinolinone–triazole hybrids as valuable candidates in drug discovery. Full article

Background: High expression of nucleolin (NCL) on the surface of tumor cells is closely associated with disease progression and poor prognosis. The aptamer–PROTAC conjugate (APC) technology provides a novel molecular design strategy for the targeted degradation of NCL. Methods: Based on the principles of PROTAC technology and chemical modification techniques, in this study, a series of AS1411-lenalidomide chimeras featuring different linker structures were designed and synthesized for the specific purpose of targeted degradation of NCL. Four AS1411-PROTACs (C1–C4) were successfully constructed via a click chemistry strategy, and their structures were validated. Results: In vitro experimental results showed that C4 exhibited the most optimal activity, significantly downregulating NCL expression and inhibiting the proliferation of breast cancer cells (MCF-7). Notably, the activity of C4 remained unaltered regardless of the annealing process. Mechanistic studies demonstrated that C4 induced NCL degradation through the ubiquitin–proteasome pathway while also promoting apoptosis and cell cycle arrest. In a nude mouse tumor model, C4 displayed potent antitumor efficacy, with no discernible signs of obvious systemic toxicity. Conclusions: This study provides compelling evidence demonstrating that C4 is a highly promising anticancer compound. It also provides important evidence for the development of novel nucleic acid aptamer–PROTAC conjugate drugs for more clinical applications. Full article

Nucleopeptides (NPs) are unnatural hybrid polymers designed by coupling nucleobases to the side chains of amino acid residues within peptides. In this study, we present the synthesis of an Fmoc-protected nucleobase amino acid (NBA) monomer (Fmoc-1,4-TzlNBA_A) with adenine attached to the side chain of L-homoazidoalanine (Aha) through a 1,4-linked-1,2,3-triazole. The coupling was accomplished by a Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) of Fmoc-Aha and N9-propargyladenine. Subsequently, a homotrinucleopeptide (HalTzl_AAA) containing three 1,4-TzlNBA_A residues was synthesized, using different solid-phase peptide synthesis (SPPS) approaches, and its ability to recognize U-rich motifs of RNAs involved in the HIV replication cycle was studied using circular dichroism (CD) and fluorescence spectroscopy. CD curves confirmed the binding of HalTzl_AAA to U-rich motifs of the transactivation responsive element (TAR UUU RNA HIV-1) bulge and the anticodon stem–loop domain of human tRNALys3 (ASLLys3) by a decrease in the positive ellipticity band intensity around 265 nm during the complexation. 5′-(FAM(6))-labeled TAR UUU and hASLLys3 were used for fluorescence anisotropy binding studies. Fluorescence data revealed that HalTzl_AAA bound TAR’s UUU bulge with a moderate affinity (K_d ≈ 38 µM), whereas the ASLLys3 UUUU-containing loop sequence was recognized with 2.5 times lower affinity (with K_d ≈ 75 µM). Both the standard SPPS method and its variants, which involved the attachment of adenine to the L-Aha side chain using the click reaction during the synthesis on the resin or after the nucleopeptide cleavage, were characterized by a similar efficiency and yield. The CD and fluorescence results demonstrated that HalTzl_AAA recognized the U-rich sequences of the RNAs with moderate and varied affinities. It is likely that both the hydrogen bonds associated with the complementarity of the interacting sequences and the conformational aspects associated with the high conformational dynamics of U-rich motifs are important in the recognition process. The nucleopeptide represents a new class of RNA binders and may be a promising scaffold for the development of new antiviral drugs. Full article

The growing demand for sustainable and high-performance lubricants has accelerated interest in biolubricants derived from renewable feedstocks. Vegetable oils are attractive candidates due to their biodegradability, low toxicity, and favorable viscosity index. However, their application is limited by poor oxidative and thermal stability. The epoxidation of unsaturated fatty acids offers a versatile route to address these drawbacks by enhancing stability and introducing reactive epoxy groups for further functionalization. This review highlights the advances in the use of epoxidized vegetable oils (EVOs), as platforms for lubricant design. Post-epoxidation modifications, such as ring-opening reactions, crosslinking, hybridization with additives, and click-type chemistries, are critically examined with emphasis on their impact on viscosity, polarity, tribofilm formation, and overall tribological behaviour. Structure–property relationships were discussed to establish design principles linking chemical modifications with lubrication regimes, wear resistance, and film-forming ability. In addition, sustainability aspects, including biodegradability, ecotoxicity, and life cycle assessment, are reviewed to evaluate the trade-offs between performance enhancement and environmental compatibility of these modifications. Current challenges and future perspectives are outlined, including the need for standardized testing protocols, the integration of multifunctional modifications, and predictive modelling tools. By bridging molecular engineering, tribological performance, and sustainability, this review provides a roadmap for the rational design of advanced epoxidized oil-based biolubricants. Full article

High-throughput screening (HTS) is an essential process in drug discovery, requiring platforms that ensure reagent economy, high efficiency, and resistance to cross-contamination. Click chemistry is well suited for HTS because of its biocompatibility, high selectivity, and quantitative fluorescent readout. We focus on droplet-array sandwiching technology (DAST), in which two droplet microarrays (DMAs) are vertically opposed to achieve solute transport and reagent mixing by controlled contact and separation. Herein, we integrate click chemistry with DAST and evaluate its feasibility as a HTS platform. In DAST, DMAs are formed on wettability-patterned (WP; hydrophilic/hydrophobic) substrates, preserving resistance to cross-contamination. First, we immobilized dibenzocyclooctyne (DBCO) on a WP substrate and verified the occurrence of DBCO–azide reaction using an azide-functional fluorescent dye. The fluorescence intensity increased with concentration and reached a plateau at higher concentrations, indicating saturation behavior in the DBCO–azide click reaction. Second, acoustic mixing with repeated droplet contact–separation was applied to generate concentration gradients on a single substrate while maintaining droplet independence. Third, we qualitatively reproduced the expected concentration dependence of manual handling by combining DAST-based gradient formation with click reaction fluorescence readout. These results reveal that DAST enables a reagent-efficient, cross-contamination-resistant, and low-instrument-dependent HTS foundation for click-chemistry-based assays. Full article

Background: Developing clinically relevant experimental models of the human airway can significantly advance our understanding of the mechanisms underlying airway diseases and aid in translating potential therapies to clinical settings. The aim of this study is to establish an ex vivo human airway tissue culture model. Methods: Human donor airway tissues were obtained from clinical cases of lung transplantation. Our established method is based on the concept of scavenging metabolic activity and controlling bacterial growth and includes increased media volume, frequent media exchange, and antifungal additives to efficiently maintain the homeostatic culture environment. After a 3-day culture period, the airway was investigated, and its viability and function were compared with a standard cell culture method. Results: Control tissue exhibited significant acidosis after 3 days, suggesting high metabolic activity of airway tissue and bacterial contamination. The airway epithelial viability—after culturing in our established method for 3 days—was better than that of the controls. We only performed an acute but early investigation of the cultures as airway complications have been known to start early at the proximal bronchus after transplantation. H&E and alcian blue staining showed intact morphology of the epithelium of airway tissue and mucus layers after 3 days in our model, while controls showed remarkable damage to the epithelial layer. Newly synthesized glycoproteins were detected in the epithelial layer using metabolic labeling and the click chemistry technique, suggesting cellular protein synthesis of the airway tissue in our established ex vivo model. Conclusions: We successfully established a reproducible model of human ex vivo airway tissue culture (n = 3 independent biological samples) that may be useful for investigating airway complications and developing their therapies. Full article

Although covalently crosslinked gelatin hydrogels have been investigated for use in 3D cell culture due to inherent bioactivity and proliferation within the denatured collagen precursor, the stability of the matrix, and relatively inexpensive synthesis, current systems lack precise control over mechanical properties, including homogeneity, stiffness, and efficient diffusion of nutrients to embedded cells. Difficulties in modifying gel matrix composition and functionalization have limited the use of covalently crosslinked gelatin hydrogels as a three-dimensional (3D) cell culture medium, lacking the ability to tailor the microenvironment for specific cell types. In addition, the currently utilized chain-growth photopolymerization mechanism for crosslinking hydrogels has a potential for side reactions between the matrix backbone and components of the cell surface, requires a high concentration of radicals for initiation, and only cures with long irradiation times, which could lead to cytotoxicity. To overcome these limitations, a superfast curing reaction mechanism, in which a thiol monomer reacts efficiently with non-homopolymerizable alkenes, is suggested. This mechanism reliably produces a well-defined matrix that does not require a high radical concentration for photoinitiation. Mechanical customization of the hydrogel is largely achievable through variation in degree of functionalization of the gelatin backbone, dependent on reaction conditions such as pH, allyl concentration, and time. This work provides a mechanistic framework for GelAGE hydrogel fabrication by elucidating the molecular mechanism of gelatin functionalization with AGE and the thiol-ene crosslinking reactions controlling network stiffness. These insights provide the foundation for engineering hydrogels that mimic the viscoelastic and structural characteristics of cartilage, enabling advanced in vitro models for osteoarthritis research. Full article

In recent years the global market of nanomedicine has experienced incredible growth owing to the advances in the field. This translation of the technique to the biomedical industry requires the development of production methods that deliver nanomedicines with a high degree of reproducibility between batches, combined with cost and time efficiency. The use of nanoparticles in medicine usually requires their surface functionalization to improve biocompatibility in addition to providing targeting capacities and/or stimuli-responsive behavior, among other interesting skills. Microfluidic technology has revolutionized the field both in nanomedicine synthesis and in preclinical evaluation. However, microfluidic-assisted synthetic procedures commonly require high-cost methods and equipment to fabricate the microreactors. The aim of this work is to present an ultra-low-cost microfluidic platform that permits the versatile modification of nanomaterials. To prove this approach, two different model nanoparticles with different natures: soft nanoparticles (liposomes) and rigid nanoparticles (mesoporous silica) have been decorated both with small molecules and with other nanoparticles, respectively, in order to evaluate the scope of this approach. The anchoring of the covalently attached elements has been performed using click chemistry, in compliance with the principles for further transfer to the drug industry. Full article

The recent SARS-CoV-2 pandemic has highlighted the need for quickly adaptable technologies in vaccine manufacturing. This can be achieved through virus-like particles (VLPs) as presentation platforms for target antigens. In this study, we investigated the purification of VLPs of the Hepatitis B Core antigen (HBc) and the SplitCore (SplCo) technology. The outer surface protein C (OspC) of Borrelia burgdorferi was genetically fused to HBc and its N-terminal SplCo protein. Product solubility in E. coli increased from 40% for HBc-OspC to 90% for SplCo-OspC. This could not be reproduced with similar SARS-CoV-2 receptor-binding domain fusions due to inclusion body formation. Hydrophobicity was found to be significantly lowered for the OspC fusions, in particular for the SplCo variant. Pre-purified samples were generated by precipitating soluble cell lysate. Subsequently, solubilized precipitates were subjected to anion exchange chromatography (AEX), and the elution fractions obtained contained VLPs, albeit with low purity. The VLPs were also disassembled prior to AEX for dissociative purification, but a subsequent reassembly could not be achieved for both fusion variants. A novel HBc variant was constructed for post-translational modification via click-chemistry. The solubility and hydrophobicity of this HBc variant remained high, but native AEX resulted in complete product loss. By contrast, a yield of 84% VLPs was obtained for the modified HBc after dissociative AEX. The surface-exposed azide group on the particles, introduced for click-chemistry, enabled coupling to fluorophores without compromising VLP stability. Conjugation efficiencies of up to 59% were obtained. These results suggest the potential of combining HBc and click-chemistry for future applications, e.g., the presentation of immunogenic epitopes or antigens. This underlines that for every antigen, both the optimal scaffold-decoration strategy and the subsequent manufacturing process should be carefully selected. Full article

In this work, the removal of Cu(II) ions from an aqueous effluent was studied using an Mg/Fe layered double hydroxide (LDH) as the adsorbent. The material was synthesized and characterized before and after the adsorption process to identify structural and morphological changes induced by copper uptake. Techniques such as X-ray diffraction (XRD), scanning electron microscopy with energy-dispersive spectroscopy (SEM-EDS), ultraviolet-visible spectroscopy (UV-Vis), Raman spectroscopy, and nitrogen physisorption (BET) were employed to confirm the interaction between the metal ions and the LDH surface. The LDH-Mg/Fe exhibited a high maximum adsorption capacity of 526 mg/g, and the adsorption kinetics followed a pseudo-second-order model, achieving over 90% removal of Cu(II) within 2.5 h. The Cu(II)-loaded material was subsequently evaluated as a sustainable catalyst in two applications: (i) an organic synthesis via “click” chemistry, reaching yields of up to 85%, and (ii) the decoloration of Congo Red via a Fenton-like process, achieving a decoloration efficiency of at least 84%. These dual uses demonstrate the potential of Cu(II)-loaded LDH as a cost-effective and environmentally friendly approach to simultaneous pollutant removal and catalytic valorization. Full article

The application of microsphere molecularly imprinted materials for the targeted extraction and purification of flavonoids derived from agricultural waste has emerged as a prominent area of investigation. An innovative boronate affinity imprinted microsphere (MC-CD@BA-MIP) was successfully synthesized using the Pickering emulsion interfacial assembly strategy for the selective separation of naringin (NRG). The double-bond functionalized covalent organic framework (COF)-based microspheres were synthesized through Schiff–base reaction and secondary interfacial emulsion polymerization. Then, the synthetic mono-(6-mercapto-6-deoxy)-β-cyclodextrin (SH-β-CD) was grafted onto the surface of the microspheres (MC) using click chemistry. The 1-allylpyridine-3-boronic acid (APBA) as a functional monomer was grafted onto the initiator (ABIB) through atom transfer radical polymerization (ATRP). Ultimately, the synthesized boronic acid-imprinted ABIB-BA-MIPs were immobilized onto the COFs microsphere surface through host–guest interactions. As expected, under neutral conditions, the MC-CD@BA-MIPs still exhibited a significant adsorption capacity (38.78 μmol g⁻¹ at 308 K) for NRG. The regenerated MC-CD@BA-MIPs maintained 92.56% of their initial adsorption capacity through six consecutive cycles. Full article

Background: Multitarget-directed ligands (MTDLs), particularly those combining cholinesterase inhibition with additional mechanisms, are promising candidates for Alzheimer’s disease (AD) therapy. Based on our previous identification of a dual-active coumarin derivative, we designed a new series of 7-alkoxyamino-3-(1,2,3-triazole)-coumarins. Methods: These compounds were synthesized by a new Sonogashira protocol and evaluated for AChE and BChE inhibition, enzymatic kinetics, molecular docking, neurotoxicity in SH-SY5Y cells, neuroprotection against H₂O₂-induced oxidative stress, and additional interactions with H₃R and MAOs. Results: All derivatives inhibited AChE with IC₅₀ values of 4–104 nM, displaying high selectivity over BChE (up to 686-fold). Kinetic and docking studies indicated mixed-type inhibition involving both CAS and PAS. The most potent compounds (1h, 1j, 1k, 1q) were non-neurotoxic up to 50 µM, while 1h and 1k also showed neuroprotective effects at 12.5 µM. Selected derivatives (1b, 1h, 1q) demonstrated multitarget potential, including H₃R affinity (K_i as low as 32 nM for 1b) and MAO inhibition (IC₅₀ of 1688 nM for 1q). Conclusions: This series of coumarin–triazole derivatives combines potent and selective AChE inhibition with neuroprotective and multitarget activities, highlighting their promise as candidates for AD therapy. Full article

Modification of synthetic oligonucleotides and DNA is widely used in many applications in the life sciences. However, in most cases, modified DNA cannot be restored to its native state. Here, we report the preparation of a thymidine-inosine dimer building block (TID) for oligonucleotide synthesis. The TID modification supports the functionalization of synthetic oligonucleotides, which can later be removed to restore the DNA strand to its native state. The TID unit allows for a wide spectrum of postsynthetic modifications of oligonucleotides through click chemistry, including conjugation with fluorescent tags and small molecules, preparation of branched oligonucleotide scaffolds, and anchoring to a solid support. Due to the modification of the thymine base, the TID unit reduces the stability of the DNA duplex. We found that the negative effect of internal TID modification on duplex stability does not exceed the same for a single base mismatch. As long as the TID modification is present in the DNA strand, it disrupts its natural functionality. The “caging” effect of TID in the template strand with respect to DNA polymerase was demonstrated in primer extension experiments. Traceless removal of the temporary functional group occurs through oxidative cleavage of the inosine subunit, resulting in the formation of a native DNA strand with the thymine base left at the cleavage site. An anthracene-modified dodecamer oligonucleotide and a branched oligonucleotide scaffold were used to study the cleavage of the reporter group or the oligonucleotide side strand, respectively. It was shown that aqueous tetramethylguanidine efficiently cleaves the oxidized inosine subunit of TID at 37 °C, forming the native DNA strand. Full article