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Click chemistry refers to selective reactions developed for grafting of bio(macro)molecules in their biological media. Caged click compounds have been employed to spatiotemporally control click reactions. Here, we survey the uncaging of photo-dibenzocyclooctyne-OH (photoDIBO-OH) to its click-chemistry active form DIBO-OH, with particular attention to its conversion timescale and efficiency. Ultraviolet pump–infrared probe experiments reveal a stepwise decarbonylation: first, carbon monoxide (C≡O) is released within 1.8 ps, and then, it converts, within 10 ps, to DIBO-OH. Completion of uncaging is achieved with an efficiency of ∼50%. A successful demonstration of two-photon uncaging of photoDIBO-OH at long wavelength (700 nm) confers enhanced in vivo compatibility and proceeds on the same timescale. [ABSTRACT FROM AUTHOR]

Protein lipidation dynamically controls protein localization and function within cellular membranes. A unique form of protein O-fatty acylation in Corynebacterium, termed protein O-mycoloylation, involves the attachment of mycolic acids─unusually large and hydrophobic fatty acids─to serine residues of proteins in these organisms outer mycomembrane. However, as with other forms of protein lipidation, the scope and functional consequences of protein O-mycoloylation are challenging to investigate due to the inherent difficulties of enriching and analyzing lipidated peptides. To facilitate the analysis of protein lipidation and enable the comprehensive profiling and site mapping of protein O-mycoloylation, we developed a chemical proteomics strategy integrating metabolic labeling, click chemistry, cleavable linkers, and a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method employing LC separation and complementary fragmentation methods tailored to the analysis of lipophilic, MS-labile O-acylated peptides. Using these tools in the model organism Corynebacterium glutamicum, we identified approximately 30 candidate O-mycoloylated proteins, including porins, mycoloyltransferases, secreted hydrolases, and other proteins with cell envelope-related functions─consistent with a role for O-mycoloylation in targeting proteins to the mycomembrane. Site mapping revealed that many of the proteins contained multiple spatially proximal modification sites, which occurred predominantly at serine residues surrounded by conformationally flexible peptide motifs. Overall, this study (i) discloses the putative protein O-mycoloylome for the first time, (ii) yields new insights into the undercharacterized proteome of the mycomembrane, which is a hallmark of important pathogens (e.g., Corynebacterium diphtheriae, Mycobacterium tuberculosis), and (iii) provides generally applicable chemical strategies for the proteomic analysis of protein lipidation.

The development of synthetic oligomers as discrete single molecular entities with accurate control over the number and nature of functional groups along the backbone has enabled a variety of new research opportunities. From fundamental studies of self-assembly in materials science to understanding efficacy and safety profiles in biology and pharmaceuticals, future directions are significantly impacted by the availability of discrete, multifunctional oligomers. However, the preparation of diverse libraries of discrete and stereospecific oligomers remains a significant challenge. We report a novel strategy for accelerating the synthesis and isolation of discrete oligomers in a high-throughput manner based on click chemistry and simplified bead-based purification. The resulting synthetic platform allows libraries of discrete polyether oligomers to be prepared and the impact of variables such as chain length, number, and nature of side chain functionalities and molecular dispersity on antibacterial behavior examined. Significantly, discrete oligomers were shown to exhibit enhanced activity with lower toxicity compared with traditional disperse samples. This work provides a practical and scalable methodology for nonexperts to prepare libraries of multifunctional discrete oligomers and demonstrates the advantages of discrete materials in biological applications.

AbstractThe efficacy of therapeutics can be enhanced with their off-target effects being minimized through targeted delivery. In vaccination and cancer immunotherapy, targeting dendritic cells (DCs) and macrophages (Mφs) is crucial for the activation of the immune system. To this end, we have developed a set of carbohydrate-based ligands targeting C-type lectins (CTLs) present on the surface of DCs for receptor-mediated uptake. Branched structures functionalized with up to four mannose units were synthesized through CuI-catalysed click chemistry, and the products were further functionalized with the DBCO group to facilitate their conjugation with cargos of interest via Cu-free click chemistry. Thus, the ligands were conjugated with fluorescein azide, and the fluorescent conjugates were assessed for their internalization in CTL expressing immature DCs. The results showed that high-mannose branched structures were efficiently internalized through the endocytic pathway, with a positive qualitative correlation between branching degree of sugar-based ligands and internalization. As evidence for payload delivery, conjugating with a mannotriose ligand quantitatively increased the uptake of a fluorescently labeled oligonucleotide by immature DCs. Our work supports the use of click chemistry to synthesize and conjugate promising ligands for efficient delivery of nucleic acid-based drugs. [ABSTRACT FROM AUTHOR]

The development of environmentally sustainable processes for polymer recycling is of paramount importance in the polymer industry. In particular, the implementation of chemical recycling for thermoset polymers via covalent adaptable networks (CANs), particularly those based on the dynamic hindered urea bond (HUB), has garnered intensive attention from both the academic and industrial sectors. This interest stems from its straightforward chemical structure and reaction mechanism, which are well‐suited for commercial polyurethane and polyurea applications. However, a substantial drawback of these CANs is the requisite use of toxic isocyanate curing agents for their synthesis. Herein, we propose a new HUB synthesis pathway involving thiazolidin‐2‐one and a hindered amine. This ring‐opening reaction facilitates the isocyanate‐free formation of a HUB and enables sequential reactions with acrylate and epoxide monomers via thiol–Michael and thiol–epoxy click chemistry. The CANs synthesized using this methodology exhibit superior reprocessability, chemical recyclability, and reutilizability, facilitated by specific catalytic and solvent conditions, through the reversible HUB, thiol–Michael addition, and transesterification processes. [ABSTRACT FROM AUTHOR]

Comprehensive Summary We report the design and development of a β‐glucuronidase (β‐Glu)‐responsive ManNAz derivative, Glu‐AAM, for tumor‐selective metabolic glycoengineering. Glu‐AAM enables specific labeling of tumor cell surface sialoglycans in the presence of overexpressed β‐Glu in cancer cells, including breast, leukemia, and colorectal cancer cells. We demonstrate the high selectivity and efficiency of Glu‐AAM‐mediated metabolic glycoengineering across multiple cancer cell lines. Furthermore, we synthesized multivalent antibody‐recruiting molecules (DBCO‐Rha) that can be covalently attached to the azido‐modified tumor cell surface, leading to potent antibody‐dependent cellular phagocytosis and complement‐dependent cytotoxicity. The octameric DBCO‐Rha8 construct exhibited the most effective immune response. This integrated strategy of β‐Glu‐responsive metabolic glycoengineering and antibody‐recruiting immunotherapy provides a promising platform for targeted cancer therapies and expands the toolbox of metabolic glycoengineering for cancer immunotherapy. We report the design and development of a β‐glucuronidase (β‐Glu)‐responsive ManNAz derivative, Glu‐AAM, for tumor‐selective metabolic glycoengineering. Glu‐AAM enables specific labeling of tumor cell surface sialoglycans in the presence of overexpressed β‐Glu in cancer cells, including breast, leukemia, and colorectal cancer cells. We demonstrate the high selectivity and efficiency of Glu‐AAM‐mediated metabolic glycoengineering across multiple cancer cell lines. Furthermore, we synthesized multivalent antibody‐recruiting molecules (DBCO‐Rha) that can be covalently attached to the azido‐modified tumor cell surface, leading to potent antibody‐dependent cellular phagocytosis and complement‐dependent cytotoxicity. The octameric DBCO‐Rha8 construct exhibited the most effective immune response. This integrated strategy of β‐Glu‐responsive metabolic glycoengineering and antibody‐recruiting immunotherapy provides a promising platform for targeted cancer therapies and expands the toolbox of metabolic glycoengineering for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Lignin is a crucial component of plant cell walls, supporting plant growth by providing mechanical strength, aiding water transport, and enhancing resistance to pathogens. Despite extensive research on lignin biosynthesis as a renewable resource, understanding the transport and deposition of its monomers remains challenging. In this study, a novel precursor monomer was designed, SALK (alkyne-tagged sinapyl alcohol surrogate), for tracking and localizing lignin in flax cells, aiming to explore the in vivo lignification process. First, the dehydrogenation polymer (DHP) of SALK was synthesized and its biocompatibility was successfully verified. After click chemistry to label fluorescent dyes, incorporation of novel lignin monomers during the polymerization process was detected and imaged successfully. The results indicated that the chemical reporter could provide detailed localization information during polymerization. It was found that lignification in the bast fiber (R) cells and fiber tracheid (FT) cells of flax was different. FT cells closer to the pith showed higher maturity and lower lignification degree. While R cells, regardless of their proximity to the pith, show a relatively consistent lignification trend. At the single-cell level, lignin deposition initiates at cell corners and the middle lamella, followed by secondary cell wall, with the highest lignin content in the secondary wall of mature cells. The results of this work reveal the potential of chemical reporters in providing detailed insights into the in vivo lignification process, advancing the technology for studying the formation and function of plant cell walls. [ABSTRACT FROM AUTHOR]

Artificial metallo‐nucleases (AMNs) are small molecule DNA cleavage agents, also known as DNA molecular scissors, and represent an important class of chemotherapeutic with high clinical potential. This review provides a primary level of exploration on the concepts key to this area including an introduction to DNA structure, function, recognition, along with damage and repair mechanisms. Building on this foundation, we describe hybrid molecules where AMNs are covalently attached to directing groups that provide molecular scissors with enhanced or sequence specific DNA damaging capabilities. As this research field continues to evolve, understanding the applications of AMNs along with synthetic conjugation strategies can provide the basis for future innovations, particularly for designing new artificial gene editing systems. [ABSTRACT FROM AUTHOR]

A novel library of 4H‐chromene‐7‐azaindole‐1,2,3‐triazole hybrids (6 a‐n) utilizing 1‐(prop‐2‐yn‐1‐yl)‐1H‐pyrrolo[2,3‐b]pyridine‐3‐carbaldehyde, 5,5‐dimethylcyclohexane‐1,3‐dione and malononitrile as precursors involving multicomponent synthesis and click chemistry reactions. The title compounds were screened for their invitro anticancer activity against human breast adenocarcinoma (MCF‐7), human cervical cancer (HeLa) and prostate cancer (DU‐145) cells by using Doxorubicin as standard reference. The activities of all compounds could be more effecting against HeLa cells. Compound 6 g with 3‐nitro substitution on phenyl ring displayed outstanding activity against all three cell lines with IC50 value of 6.67±0.39 μM (MCF‐7), 4.49±0.32 μM (HeLa) and 10.38±0.42 μM (DU‐145) than reference drug. The compound 6 h with methyl group in ortho position of phenyl ring showed best activity with IC50 value of 7.32±0.62 μM, 6.87±0.33 μM and 15.40±0.60 μM against MCF‐7, HeLa and DU‐145 cells respectively. Performed molecular docking study against crystal structure of EGFR obtained favorable binding interactions showing consistency with experimental results. [ABSTRACT FROM AUTHOR]

ABSTRACT A new 1,2,3‐triazole functionalized ferrocene (1,2,3‐TAFc) produced by Cu(I)‐catalyzed click reaction was investigated as positive electrolyte for aqueous organic flow batteries (AOFBs). The molecule is highly soluble in 1 M hydrochloric acid and displays high electrochemical reversibility. 1,2,3‐TAFc demonstrated good stability during cycling with a low capacity decay (0.011%/cyc, 3.0%/day) and high Coulombic efficiency (99.4%) over 280 cycles when tested in a flow battery at low concentration. This low capacity decay was attributed to the instability of ferrocene. These findings indicate that a stable and water‐soluble catholyte for AOFBs can be obtained with structural modifications of 1,2,3‐TAFc. [ABSTRACT FROM AUTHOR]

Switchable adhesives are materials of utmost importance due to their capability of having their adhesion/cohesion properties reversibly triggered upon stimuli, allowing on‐demand surface attaching/detaching. Still, several challenges mainly associated with complex uncontrolled chemical processes hinders their production. In this study, it is found that unexpectedly vinyl ethers are able to react with thiols in the presence of a catalytic concentration of base, which allows the preparation of well‐defined phase‐separated switchable adhesives. Indeed, these findings show that base‐catalyzed thiol‐acrylate and thiol‐vinyl ether are highly orthogonal, making the acrylate reaction faster. This is explored to react in the first stage thiols with acrylates in the presence of vinyl ethers to end‐cap all the oligomers with stable vinyl ethers and suppress undesirable disulfide formation. In a second stage the UV‐triggered thiol‐ene “click reaction” is carried out, forming the network. It is shown that the network prepared by this approach presents superior adhesion due to greater backbone length, a controlled crosslinking motif, and better‐defined microphase separation. Additionally, the adhesives made by this strategy are thermo‐switchable due to the temperature‐triggered base‐catalyzed thioether dynamic covalent character at 200 °C. Despite providing superior adhesive properties, the proposed technology endows scalable, thermo‐switchable, and O2‐resistant adhesives with huge industrialization potential. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is characterized by cholinergic dysfunction, making the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) critical for improving cholinergic neurotransmission. However, the development of effective dual inhibitors remains challenging. Objective: This study aims to synthesize and evaluate novel pyridazine-containing compounds as potential dual inhibitors of AChE and BuChE for AD treatment. Methods: Ten novel pyridazine-containing compounds were synthesized and characterized using IR, 1H NMR, and 13C NMR. The inhibitory activities against AChE and BuChE were assessed in vitro, and pharmacokinetic properties were explored through in silico ADME studies. Molecular dynamics simulations were performed for the most active compound. Results: Compound 5 was the most potent inhibitor, with IC50 values of 0.26 µM for AChE and 0.19 µM for BuChE, outperforming rivastigmine and tacrine, and showing competitive results with donepezil. Docking studies revealed a binding affinity of −10.21 kcal/mol to AChE and −13.84 kcal/mol to BuChE, with stable interactions confirmed by molecular dynamics simulations. In silico ADME studies identified favorable pharmacokinetic properties for compounds 5, 8, and 9, with Compound 5 showing the best activity. Conclusions: Compound 5 demonstrates strong potential as a dual cholinesterase inhibitor for Alzheimer's disease, supported by both in vitro and in silico analyses. These findings provide a basis for further optimization and development of these novel inhibitors. [ABSTRACT FROM AUTHOR]

Background/Objectives: In this study, the efficacy of benzo[h]chromene derivatives as antiprotozoal and antimycobacterial agents was explored. Methods: A total of twenty compounds, including benzo[h]chromene alkyl diesters and benzo[h]chromene-triazole derivatives, were synthesized and tested against Trypanosoma cruzi, Leishmania braziliensis, L. infantum, and strains of Mycobacterium abscessus and Mycobacterium intracellulare LIID-01. Notably, compounds 1a, 1b, 2a, and 3f exhibited superior activity against Trypanosoma cruzi, with IC50 values of 19.2, 37.3, 68.7, and 24.7 µM, respectively, outperforming the reference drug benznidazole (IC50: 54.7 µM). Results: Compounds 1b and 3f showed excellent selectivity indices against Leishmania braziliensis, with SI values of 19 and 18, respectively, suggesting they could be potential alternatives to the commonly used, but more selective, miltefosine (IC50: 64.0 µM, SI: 43.0). Additionally, compounds 1a, 1b, and 3f were most effective against Leishmania infantum, with IC50 values of 24.9, 30.5, and 46.6 µM, respectively. Compounds 3f and 3h were particularly potent against various Mycobacterium abscessus strains, highlighting their significance given the inherent resistance of these bacteria to standard antimicrobials. Conclusions: The sensitivity of Mycobacterium intracellulare LIID-01 to these compounds also underscored their potential in managing infections by the Mycobacterium avium–intracellulare complex. [ABSTRACT FROM AUTHOR]

Background: The incorporation of radionuclides into peptides and larger biomolecules requires efficient and sometimes biorthogonal reaction conditions, to which click chemistry provides a convenient approach. Methods: Traditionally, click-based radiolabeling techniques have focused on classical click chemistry, such as copper(I)-catalyzed alkyne-azide [3+2] cycloaddition (CuAAC), strain-promoted azide-alkyne [3+2] cycloaddition (SPAAC), traceless Staudinger ligation, and inverse electron demand Diels–Alder (IEDDA). Results: However, newly emerging click-based radiolabeling techniques, including tyrosine-click, sulfo-click, sulfur(VI) fluoride exchange (SuFEx), thiol-ene click, azo coupling, hydrazone formations, oxime formations, and RIKEN click offer valuable alternatives to classical click chemistry. Conclusions: This review will discuss the applications of these techniques in peptide radiochemistry. [ABSTRACT FROM AUTHOR]

Coating of magnetic nanoparticles with functional polymers increases the applicability of these nanomaterials. A modular approach to functionalizing these polymer coatings can be achieved using click chemistry. This work reports the synthesis of magnetic nanoparticles coated with a dopamine anchoring group containing polymer with furan groups as side chain residues. Using the 'graft-to' approach, polymers are coated onto magnetic nanoparticles using a simple place exchange reaction. Various analytical techniques were used to characterize the polymer-coated nanoparticles for their size and surface composition. Utilization of poly(ethylene glycol) (PEG)-based polymer renders the magnetic nanoparticles water dispersible. The presence of the furan ring on the polymer brushes enables their facile functionalization using a maleimide group-bearing molecule under catalyst-free conditions. A hydrophobic fluorescent dye, used as a model drug, is conjugated onto the nanoparticles using the Diels-Alder reaction. One can anticipate that the facile fabrication and functionalization of these clickable polymer-coated magnetic nanoparticles will be attractive for various biomedical applications. [ABSTRACT FROM AUTHOR]

Levoglucosenone (LGO), a renewable compound obtained from cellulose biomass, has been utilized to prepare novel monomers bearing alkene functional groups. These monomer derivatives of LGO were subsequently cured via ultraviolet (UV)‐initiated radical thiol‐ene "click" chemistry with commercially available multifunctional thiols to obtain colourless, optically transparent cross‐linked thermosets. The monomers prepared in this work are unique due to utilising the internal double bond of the LGO ring during polymerization as part of the cross‐linked network. The thermal and mechanical properties along with the degradation of thermosets containing both ether and ester linkages within the LGO monomers were studied. These thermosets had tensile strengths of 1.3–3.3 MPa, glass transition temperatures between 23.2 and 27.2 °C, and good thermal stability of up to 300 °C. [ABSTRACT FROM AUTHOR]

The copper‐catalyzed azide alkyne [3+2]‐cycloaddition (CuAAC) reaction of organoboranes represents an attractive area of research within the field of click chemistry, with diverse applications in organic synthesis, medicinal chemistry, or materials science. Despite the potential issues caused by the copper insertion into the carbon‐boron bond, significant progress has been made to harness the reactivity of organoboron compounds in CuAAC. This review provides an overview of the catalytic methods reported for CuAAC with various organoboranes, discussing the stability of the boron group and highlighting recent advancements in this area. [ABSTRACT FROM AUTHOR]

During the last two decades, organosulfur compounds have been used in the field of transition metal catalysis. Some of such compounds are known for their ability to withstand their exposure to air and moisture. These compounds are very important ligands. They may be obtained using simple and smooth modular synthetic protocols which include nucleophilic substitution reactions. The development of click chemistry represents a new era of innovation. It is a lighthouse of reliable and efficient reactions. In recent past, click chemistry has also been applied for the synthesis of such organosulfur ligands specifically suited for the dynamic field of transition metal catalysis. In order to synthesize novel compounds containing sulfur and triazole ring, click chemistry is an advantageous methodology over other approaches. This article covers the general features and uses of this methodology for the development of catalytically active organosulfur compounds. The significant advances in the design of transition metal catalytic systems utilizing such ligands, their use in the catalysis of many chemical transformations are also covered in this article. Effort has also been made to present a comparative overview of the performances of such catalysts vis‐à‐vis the catalysts designed commonly used ligands. Catalytic performances have been discussed thoroughly in order to identify the impact of ligand architecture on efficacy of the catalyst. Effect of reaction conditions (such as time, temperature etc.) and mechanistic aspects have also been rationalized. [ABSTRACT FROM AUTHOR]

Bio-orthogonal labeling of vesicles conjugated with fluorescent molecular groups, enables in vivo bioimaging to monitor their behavior, thus aiding in diagnostics or revealing the internalization mechanisms of extracellular vesicles (EVs). Orthogonally based magnetic beads, microfluidics, and microarray chips specifically and in a high-throughput manner isolate EVs derived from various cancers for diagnosis of diseases and cancer development. By loading drugs onto the surface of EVs or forming covalent bonds between EVs and cells through bio-orthogonal methods, the therapeutic efficiency of EVs can be enhanced. Bio-orthogonal glycometabolism enables EVs to directly target tumor cells and their derived EVs in vivo , thereby inhibiting tumor metastasis and growth. Extracellular vesicle (EV)-based therapeutics have gained substantial interest in the areas of drug delivery, immunotherapy, and regenerative medicine. However, the clinical translation of EVs has been slowed due to limited yields and functional heterogeneity, as well as inadequate targeting. Engineering EVs to modify their inherent function and endow them with additional functions has the potential to advance the clinical translation of EV applications. Bio-orthogonal click chemistry is an engineering approach that modifies EVs in a controlled, specific, and targeted way without compromising their intrinsic structure. Here, we provide an overview of bio-orthogonal labeling approaches involved in EV engineering. We also present the isolation methods of bio-orthogonally labeled vesicles using magnetic beads, microfluidics, and microarray chip technologies. We highlight the in vivo applications of bio-orthogonal labeling EVs for diagnosis and therapy, especially the exciting potential of bio-orthogonal glycometabolic engineered EVs for targeted therapies. [ABSTRACT FROM AUTHOR]

A series of novel side-chain liquid crystalline (SCLC) copolymers were synthesized by attaching two distinct mesogenic units, namely a chiral cholesteryl-based monomer (M1) and an achiral biphenyl-based monomer (M2), to a poly(3-mercaptopropylmethylsiloxane) (PMMS) backbone via thiol-ene click chemistry. The influence of side chain composition on the self-assembly behavior and phase structures of these SCLC copolymers was systematically investigated using different instrument. Results indicate that three distinct liquid crystalline phases and four unique molecular configurations were identified within the polymer series, with the emergence of the liquid crystalline phase being a synergistic outcome of the two distinct side chains. This study underscores the critical influence of side chain dimensions, rigidity, and spatial volume on the self-assembly structures and phase characteristics of liquid crystalline polymers, providing valuable insights for the rational design and development of advanced functional materials with tailored properties. [ABSTRACT FROM AUTHOR]

A series of the new 1,2,3-triazole-acetophenone hybrid system are synthesized from the click reaction between 1-(2-(prop-2-yn-1-yloxy)phenyl)ethan-1-one 1 and different azido benzene derivatives 2-7. All compounds are characterized by 1H NMR, 13C NMR, mass spectra, and elemental analyses. Field Emission Scanning Electron Microscope (FESEM) detected highly ordered aggregations, and the morphology of the compounds was determined, directed by van der Waals (vdW) forces and π-π stacking interactions. The Gaussian 09 and Gaussian view 6.0 softwares are used for all Density Functional Theory (DFT) calculations at the B3LYP. Band gap, molecular softness, electronegativity, and electrophilicity measurements show that molecule 9 is a soft molecule with higher polarizability, lower kinetic stability, and more chemical reactivity than the other molecules, which tend to be the most stable and least reactive. The molecules can be divided into two categories based on their chemical potential values: Although compound 9 looks to have more activity, compounds 8, 10, 11, 12, and 13 often have the best stability and least reactivity. According to the MEPs, the nitrogen and oxygen atoms are the electronegative potential sites in all compounds, while the hydrogen atoms in the alkyl and aromatic cyclic groups are the electropositive potential sites. [ABSTRACT FROM AUTHOR]

Click ligation is a technology of joining DNA fragments based on azide–alkyne cycloaddition. In the most common variant, click ligation introduces a 4-methyl-1,2,3-triazole (trz) group instead of the phosphodiester bond between two adjacent nucleosides. While this linkage is believed to be biocompatible, little is known about the possibility of its recognition by DNA repair systems or its potential for DNA polymerase stalling and miscoding. Here we report that trz linkage is resistant to several human and bacterial endonucleases involved in DNA repair. At the same time, it strongly blocks some DNA polymerases (Pfu, DNA polymerase β) while allowing bypass by others (phage RB69 polymerase, Klenow fragment). All polymerases, except for DNA polymerase β, showed high frequency of misinsertion at the trz site, incorporating dAMP instead of the next complementary nucleotide. Thus, click ligation can be expected to produce a large amount of errors if used in custom gene synthesis. [ABSTRACT FROM AUTHOR]

High‐throughput synthesis and screening of chemical libraries play pivotal roles in drug discovery. Click chemistry has emerged as a powerful strategy for constructing highly modular chemical libraries. However, the development of new click reactions and unlocking new clickable building blocks remain exceedingly challenging. Herein, we describe a double‐click strategy that enables the sequential ligations of widely available carboxylic acids and amines with fluorosulfuryl isocyanate (FSO2NCO) via a modular amidation/SuFEx (sulfur‐fluoride exchange) process. This method provides facile access to chemical libraries of N‐fluorosulfonyl amides (RCONHSO2F) and N‐acylsulfamides (RCONHSO2NR′R′′) in near‐quantitative yields under simple and practical conditions. The robustness and efficiency of this double click strategy is showcased by the facile construction of chemical libraries in 96‐well microtiter plates from a large number of carboxylic acids and amines. Preliminary biological activity screening reveals that some compounds exhibit high antimicrobial activities against Gram‐positive bacterium S. aureus and drug‐resistant MRSA (MIC up to 6.25 μg ⋅ mL−1). These results provide compelling evidence for the potential application of modular click chemistry library as an enabling technology in high‐throughput medicinal chemistry. [ABSTRACT FROM AUTHOR]

Recombinant adeno-associated viruses (rAAVs) have been extensively studied for decades as carriers for delivering therapeutic genes. However, designing rAAV vectors with selective tropism for specific cell types and tissues has remained challenging. Here, we introduce a strategy for redirecting rAAV by attaching nanobodies with desired tropism at specific sites, effectively replacing the original tropism. To demonstrate this concept, we initially modified the genetic code of rAAV2 to introduce an azido-containing unnatural amino acid at a precise site within the capsid protein. Following a screening process, we identified a critical site (N587+1) where the introduction of unnatural amino acid eliminated the natural tropism of rAAV2. Subsequently, we successfully redirected rAAV2 by conjugating various nanobodies at the N587+1 site, using click and SpyTag-Spycatcher chemistries to form nanobody-AAV conjugates (NACs). By investigating the relationship between NACs quantity and effect and optimizing the linker between rAAV2 and the nanobody using a cathepsin B-susceptible valine-citrulline (VC) dipeptide, we significantly improved gene delivery efficiency both in vitro and in vivo. This enhancement can be attributed to the facilitated endosomal escape of rAAV2. Our method offers an exciting avenue for the rational modification of rAAV2 as a retargeting vehicle, providing a convenient platform for precisely engineering various rAAV2 vectors for both basic research and therapeutic applications. AAVs hold great promise in the treatment of genetic diseases, but their clinical use has been limited by off-target transduction and efficiency. Here, we report a strategy to construct NACs by conjugating a nanobody or scFv to an rAAV capsid site, specifically via biorthogonal click chemistry and a spy-spycatcher reaction. We explored the structure-effect and quantity-effect relationships of NACs and then optimized the transduction efficiency by introducing a valine-citrulline peptide linker. This approach provides a biocompatible method for rational modification of rAAV as a retargeting platform without structural disruption of the virus or alteration of the binding capacity of the nanobody, with potential utility across a broad spectrum of applications in targeted imaging and gene delivery. [Display omitted] [ABSTRACT FROM AUTHOR]

Novel Quinoline‐triazole hybrid derivatives (9 a–9 l) were designed and synthesized via click reaction methodology to develop lead compounds with good antibacterial and antifungal potency. Synthetic compounds have been characterized using 1H NMR, 13C NMR, and mass spectrum analysis. In‐vitro antibacterial activity against two gram‐positive and two gram‐negative strains and in‐vitro antifungal activity against three different strains were performed for the synthesized compounds. Compounds 9 a, 9 d, and 9 i exhibited potent inhibition activity against S. aureus ranging from MIC=12.5–50 μg/mL, and compounds 9 a, 9 c, 9 d, 9 e, 9 f, 9 j, and 9 l exhibited potent inhibition activity against C. albicans fungal strains ranging from MFC=250–500 μg/mL. Molecular docking study of C. albicans Sterol 14α‐demethylase (CYP51) protein (PDB ID:5TZ1) and S. aureus tyrosyl‐tRNA synthetase (PDB ID: 1JIJ) was performed to understand the mechanism of action through which these derivatives work. In silico studies of Hybrid 9 d demonstrated strong hydrogen bonding and π–π interactions with Tyr64, Phe233, and Phe228 in line with the co‐crystals SB‐239629 and VT1161 exhibiting favorable interactions that inhibits both bacterial and fungal strains. [ABSTRACT FROM AUTHOR]

The development of innovative strategies for cell membranes engineering is of prime interest to explore and manipulate cell–cell interactions. Herein, an enzyme‐sensitive recognition marker that can be introduced on cell surface via bioorthogonal chemistry is designed. Once functionalized in this fashion, the cells gain the ability to assemble with cell partners coated with the complementary marker through non‐covalent click chemistry. The artificial cell adhesion induces natural biological processes associated with cell proximity such as inhibiting cancer cell proliferation and migration. On the other hand, the enzymatic activation of the stimuli‐responsive marker triggers the disassembly of cells, thereby restoring the tumor cell proliferation and migration rates. Thus, the study shows that the ready‐to‐use complementary markers are valuable tools for controlling the formation and the breaking of bonds between cells, offering an easy way to investigate biological processes associated to cell proximity. [ABSTRACT FROM AUTHOR]

"Tandem" uncaging systems, in which a photolabile protecting group (PPG) is sensitized by an energy‐harvesting antenna, may increase the photosensitivity of PPGs by several orders of magnitude for two‐photon (2P) photorelease. Yet, they remain poorly accessible because of arduous multi‐step synthesis. In this work, we design efficient tandem uncaging systems by (i) using a convenient assembly of the building blocks relying on click chemistry, (ii) introducing H‐bonding induced proximity thus facilitating (iii) photoinduced electron transfer (PeT) as a cooperative mechanism. A strong two‐photon absorber electron‐donating quadrupolar antenna and various electron‐accepting PPGs (mDEAC, MNI or MDNI) were clicked stepwise onto a "tweezer‐shaped" pyrido‐2,6‐dicarboxylate platform whose H‐bonding and π‐stacking abilities were exploited to keep the antenna and the PPGs in close proximity. The different electron‐accepting ability of the PPGs led to dyads with wildly different behaviors. Whilst the MDNI and MNI dyads showed poor dark stability or no photo‐uncaging ability due to their too high electron‐accepting character, the mDEAC dyad benefited from optimum redox potentials to promote PeT and slow down charge recombination, resulting in enhanced uncaging quantum yield (Φu=0.38) compared to mDEAC (Φu=0.014). This unique combination resulted in large 2P photo‐sensitivity in the near‐infrared window (240 GM at 710 nm). [ABSTRACT FROM AUTHOR]

Bacterial conjugation, a commonly used method to horizontally transfer functional genes from donor to recipient strains, plays an important role in the genetic manipulation of bacteria for basic research and industrial production. Successful conjugation depends on the donor‐recipient cell recognition and a tight mating junction formation. However, the efficiency of conjugative transfer is usually very low. In this work, we developed a new technique that employed DNA molecule "glue" to increase the match frequency and the interaction stability between the donor and recipient cells. We used two E. coli strains, ETZ and BL21, as a model system, and modified them with the complementary ssDNA oligonucleotides by click chemistry. The conjugation efficiency of the modified bacteria was improved more than 4 times from 10 %–46 %. This technique is simple and generalizable as it only relies on the active amino groups on the bacterial surface. It is expected to have broad applications in constructing engineered bacteria. [ABSTRACT FROM AUTHOR]

AbstractDual-curing Epoxy thermosets has found widespread use in polymer materials in recent years. Dual-curing system is one of the ways used to control the curing rate of epoxy resin to design the final product through two different curing systems with different reaction conditions. This review begins with an introduction to dual-curing systems based on epoxy and relevant reaction mechanisms. It then provides an overview of the types of dual-curing epoxy resin such as epoxy-acrylate, epoxy-amine, epoxy-thiol, epoxy-siloxane and epoxy-allyl phenol that can be encountered in these systems. Due to the variety of dual-curing models of epoxy resin, different dual-curing models and systems can be used to control the properties of the materials. The review concludes with a review of recent and successful research on dual-cured materials for shape memory polymers, adhesive materials, 3D printed materials, structured surface topologies, and holographic materials. [ABSTRACT FROM AUTHOR]

Developing effective inhibitors of the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) has been challenging because of the enzyme shallow catalytic pocket and non-specific substrate binding interactions. Recently, we discovered a quinolone-binding hot spot in TDP1's active site proximal to the evolutionary conserved Y204 and F259 residues that position DNA. Sulfur (VI) fluoride exchange (SuFEx) is a biocompatible click chemistry reaction that enables acylation of protein residues, including tyrosine. Selective protein modifications can provide insights into the biological roles of proteins and inform ligand design. As we report herein, we used SuFEx chemistries to prepare covalent TDP1-bound binders showing site-specific covalent bonds with Y204. Our work presents the first application of SuFEx chemistries to TDP1 ligands. It validates the ability to covalently modify specific TDP1 residues by designed targeting and adds to the chemical biology resource toolbox for studying TDP1. Developing effective inhibitors of the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) is challenging because of the enzyme's shallow catalytic pocket and non-specific substrate binding interactions. Here, the authors use Sulfur (VI) fluoride exchange chemistries to prepare covalent TDP1-bound binders showing site-specific covalent bonds with the Y204 residue that position DNA. [ABSTRACT FROM AUTHOR]

Introduction: Phages are viruses that infect prokaryotes and can shape microbial communities by lysis, thus offering applications in various fields. However, challenges exist in sampling, isolation and accurate prediction of the host specificity of phages as well as in the identification of newly replicated virions in response to environmental challenges. Methods: A new workflow using biorthogonal non-canonical amino acid tagging (BONCAT) and click chemistry (CC) allowed the combined analysis of phages and their hosts, the identification of newly replicated virions, and the specific tagging of phages with biotin for affinity chromatography. Results: Replication of phage λ in Escherichia coli was selected as a model for workflow development. Specific labeling of phage λ proteins with the non-canonical amino acid 4-azido-L-homoalanine (AHA) during phage development in E. coli was confirmed by LC-MS/MS. Subsequent tagging of AHA with fluorescent dyes via CC allowed the visualization of phages adsorbed to the cell surface by fluorescence microscopy. Flow cytometry enabled the automated detection of these fluorescent phage-host complexes. Alternatively, AHA-labeled phages were tagged with biotin for purification by affinity chromatography. Despite biotinylation the tagged phages could be purified and were infectious after purification. Discussion: Applying this approach to environmental samples would enable host screening without cultivation. A flexible and powerful workflow for the detection and enrichment of phages and their hosts in pure cultures has been established. The developed method lays the groundwork for future workflows that could enable the isolation of phage-host complexes from diverse complex microbial communities using fluorescence-activated cell sorting or biotin purification. The ability to expand and customize the workflow through the growing range of compounds for CC offers the potential to develop a versatile toolbox in phage research. This work provides a starting point for these further studies by providing a comprehensive standard operating procedure. [ABSTRACT FROM AUTHOR]

In this work, using the combination of atom transfer radical polymerization and click chemistry, the graft copolymer polysulfone‐graft‐poly (methyl methacrylate) (PSf‐g‐PMMA) was synthesized as a modifying agent. The copolymer was embedded in the PSf substrate using a nonsolvent phase inversion method. Then, the modified substrate was used to make thin film composite forward osmosis (TFC‐FO) membranes using the interfacial polymerization method. Also, the effect of PSf‐g‐PMMA copolymer content on the surface properties of the membrane, as well as the filtration performance, was investigated. The increase in hydrophilicity, porosity, and average pore diameter indicated the favorable effect of PSf‐g‐PMMA copolymer on the characteristics of modified substrates. In addition, the improvement in the membrane morphology (an increase in the length and number of finger‐like pores) provided a substrate with low tortuosity and structure parameters. Therefore, the pure water permeability increased from 79.9 LMH/bar for the control membrane to 372.1 LMH/bar for the membrane containing 20 wt.% of PSf‐g‐PMMA copolymer. Investigating the FO separation properties of TFC‐FO membranes showed an increase in water flux and selectivity due to an improvement in the morphology of the modified substrate with low structural parameters. The new TFC‐FO membranes have been optimized, and water flux has significantly improved. Compared with the control membrane, which did not have copolymer blending, the new membranes have a triply enhanced water flux of 17.1 LMH. In addition, the selectivity of these optimized membranes has improved when 1 M NaCl is used as the draw, and DI water is used as the feed in the FO mode. [ABSTRACT FROM AUTHOR]

Bacterial evolution, particularly in hospital settings, is leading to an increase in multidrug resistance. Understanding the basis for this resistance is critical as it can drive discovery of new antibiotics while allowing the clinical use of known antibiotics to be optimized. Here, we report a photoactive chemical probe for superresolution microscopy that allows for the in situ probing of antibiotic-induced structural disruption of bacteria. Conjugation between a spiropyran (SP) and galactose via click chemistry produces an amphiphilic photochromic glycoprobe, which self-assembles into glycomicelles in water. The hydrophobic inner core of the glycomicelles allows encapsulation of antibiotics. Photoirradiation then serves to convert the SP to the corresponding merocyanine (MR) form. This results in micellar disassembly allowing for release of the antibiotic in an on-demand fashion. The glycomicelles of this study adhere selectively to the surface of a Gram-negative bacterium through multivalent sugar-lectin interaction. Antibiotic release from the glycomicelles then induces membrane collapse. This dynamic process can be imaged in situ by superresolution spectroscopy owing to the "fluorescence blinking" of the SP/MR photochromic pair. This research provides a high-precision imaging tool that may be used to visualize how antibiotics disrupt the structural integrity of bacteria in real time. [ABSTRACT FROM AUTHOR]

With the versatile utility of bio-conjugated peptides and proteins in the fields of agriculture, food, cosmetics and pharmaceutical industry, the design of smart protocols to conjugate and modulate biomolecules becomes highly desirable. During this process, the most important consideration for biochemists is the retention of configurational integrity of the biomolecules. Moreover, this type of bioconjugation of peptide and protein becomes frivolous if the reaction is not performed with precise amino acid residues. Hence, chemo-selective, as well as site-selective reactions, that are biocompatible and possess an appropriate level of reactivity are necessary. Based on click chemistry, there are so many tyrosine (Y) conjugation strategies, such as sulfur-fluoride exchange (SuFEx), sulfur-triazole exchange (SuTEx), coupling with π-allyl palladium complexes, diazonium salts, diazodicarboxyamide-based reagents etc. Among these techniques, diazodicarboxyamide-based Y-conjugation, which is commonly known as the "tyrosine-click (Y-click) reaction", has met the expectations of synthetic and biochemists for the tyrosine-specific functionalization of biomolecules. Over the past one and a half decades, significant progress has been made in the classical organic synthesis approach, as well as its biochemical, photochemical, and electrochemical variants. Despite such progress and increasing importance, the Y-click reaction has not been reviewed to document variations in its methodology, applications, and broad utility. The present article aims to provide a summary of the approaches for the modulation of biomolecules at the hotspot of tyrosine residue by employing the Y-click reaction. The article also highlights its application for the mapping of proteins, imaging of living cells, and in the fields of analytical and medicinal chemistry. [ABSTRACT FROM AUTHOR]

Introduction: As an essential part of plant cell walls, lignin provides mechanical support for plant growth, enhances water transport, and helps to defend against pathogens. As the most abundant natural aromatic-based renewable resource on earth, its biosynthesis has always been a research focus, and it is still currently under study. Methods: In this study, the p-coumaryl alcohol analog (HALK) and the coniferyl alcohol analog (GALK) containing an alkyne group at the ortho position were synthesized and applied to lignification in vivo and in vitro. The incorporation of these novel lignin monomers was observed via fluorescence imaging. Results and Discussion: It was found that the two monolignol analogs could be incorporated in dehydrogenated polymers (DHPs) in vitro and in flax cell walls in vivo. The results showed that as the cultivation time and precursor concentration varied, the deposition of H and G-type lignin exhibited differences in deposition mode. At the subcellular scale, the deposited lignin first appears in the cell corner and the middle lamella, and then gradually appears on the cell walls. Furthermore, lignin was also found in bast fiber. It was demonstrated that these new molecules could provide high-resolution localization of lignin during polymerization. [ABSTRACT FROM AUTHOR]

Cyclic polymers, which are found in the field of biopolymers, exhibit unique physical properties such as suppressed molecular mobility. Considering thermodynamics, the suppressed molecular mobility of cyclic polymers is expected to prevent unfavorable entropy loss in molecular interactions. In this study, we synthesized cyclic glycopolymers carrying galactose units and investigated the effects of their molecular mobility on the interactions with a lectin (peanut agglutinin). The synthesized cyclic glycopolymers exhibited delayed elution time on size exclusion chromatography and a short spin‐spin relaxation time, indicating typical characteristics of cyclic polymers, including smaller hydrodynamic size and suppressed molecular mobility. The hemagglutination inhibition assay revealed that the cyclic glycopolymers exhibited weakened interactions with peanut agglutinin compared to the linear counterparts, attributable to the suppressed molecular mobility. Although the results are contrary to our expectations, the impact of polymer topology on molecular recognition remains intriguing, particularly in the context of protein repellent activity in the biomedical field. [ABSTRACT FROM AUTHOR]

The neuronal glycine transporter GlyT2 removes glycine from the synaptic cleft through active Na+, Cl−, and glycine cotransport contributing to the termination of the glycinergic signal as well as supplying substrate to the presynaptic terminal for the maintenance of the neurotransmitter content in synaptic vesicles. Patients with mutations in the human GlyT2 gene (SLC6A5), develop hyperekplexia or startle disease (OMIM 149400), characterized by hypertonia and exaggerated startle responses to trivial stimuli that may have lethal consequences in the neonates as a result of apnea episodes. Post‐translational modifications in cysteine residues of GlyT2 are an aspect of structural interest we analyzed. Our study is compatible with a reversible and short‐lived S‐acylation in spinal cord membranes, detectable by biochemical and proteomics methods (acyl‐Rac binding and IP‐ABE) confirmed with positive and negative controls (palmitoylated and non‐palmitoylated proteins). According to a short‐lived modification, direct labeling using click chemistry was faint but mostly consistent. We have analyzed the physiological properties of a GlyT2 mutant lacking the cysteines with high prediction of palmitoylation and the mutant is less prone to be included in lipid rafts, an effect also observed upon treatment with the palmitoylation inhibitor 2‐bromopalmitate. This work demonstrates there are determinants of lipid raft inclusion associated with the GlyT2 mutated cysteines, which are presumably modified by palmitoylation. [ABSTRACT FROM AUTHOR]

The goal of this study was to explore a route for introducing functionalities into agarose-based hydrogels to tune the physical, chemical, and biological properties. Several agarose derivatives were prepared by homogeneous synthesis, including anionic agarose sulfates (ASs), reactive azido agaroses (AZAs), and cationic agarose carbamates (ACs), as well as agarose tosylates (ATOSs) and agarose phenyl carbonates (APhCs). The products were characterized in terms of their molecular structure and solubility behavior. The results suggest that the native gel-forming ability of agarose is retained if the introduced functionalities are hydrophilic, and the overall degree of substitution is low (DS < 0.5). Thus, functional hydrogels from several agarose derivatives could be obtained. The mechanical stability of the functional hydrogels was decreased compared to native agarose gels but was still in a range that enables safe handling. An increase in mechanical strength could be achieved by blending functional agarose derivatives and agarose into composite hydrogels. Finally, it was demonstrated that the novel functional agarose hydrogels are biocompatible and can potentially stimulate interactions with cells and tissue. [ABSTRACT FROM AUTHOR]

Click chemistry has emerged as a versatile and robust polymerization technique for the construction of functional polymers. In this work, organocatalyst-mediated consecutive thiol-yne and thiol-ene click reactions were performed for the synthesis and modification of the electron-deficient poly(vinylene sulfide) (PVS) structure. PVS was prepared within an hour in the presence of 1,4-diazabicyclo[2.2.2] octane (DABCO) and in an anti-Markovnikov fashion, with a high molecular weight (Mn = 12.9 kDa) and high stereoregularity (88% E-isomer). Following various optimization studies using 1-propanethiol as the model thiol, the obtained PVS was modified with various thiols in chloroform for 10 min using 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as the catalyst, resulting in thioacetal main chain polymers. The scope of thiols used in the modification studies spans from alkyl and cycloalkyl to aromatic and allylic, and the polymers were obtained with varying efficiencies. Primary alkyl and aromatic thiols exhibited high efficiencies ranging from 87% to 100%. Similar high efficiencies were found for secondary mercaptans (70% and 92%); however, a very low efficiency (5%) was found for a tertiary mercaptan due to steric hindrance. It is believed the proposed indirect polythioacetal synthesis method holds the potential to be utilized in bio-related applications and material science. [ABSTRACT FROM AUTHOR]

We developed a synthesis strategy involving a diazo transfer reaction and subsequent click reaction to conjugate a murine cathelicidin-related antimicrobial peptide (CRAMP18–35) to chitosan and hydroxypropyl chitosan (HPC), confirmed the structure, and investigated the antimicrobial activity. Chitosan azide and HPC-azide were prepared with a low degree of azidation by reacting the parent chitosan and HPC with imidazole sulfonyl azide hydrochloride. CRAMP18–35 carrying an N-terminal pentynoyl group was successfully grafted onto chitosan and HPC via copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction. The chitosan–peptide conjugates were characterized by IR spectroscopy and proton NMR to confirm the conversion of the azide to 1,2,3-triazole and to determine the degree of substitution (DS). The DS of the chitosan and HPC CRAMP18–35 conjugates was 0.20 and 0.13, respectively. The antibacterial activity of chitosan–peptide conjugates was evaluated for activity against two species of Gram-positive bacteria, Staphylococcus aureus (S. aureus) and Enterococcus faecalis (E. faecalis), and two species of Gram-negative bacteria, Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa). The antimicrobial peptide conjugates were selectively active against the Gram-negative bacteria and lacking activity against Gram-positive bacteria. [ABSTRACT FROM AUTHOR]

Convincing evidence suggests that aberrant gut microbiota changes play a critical role in the progression and pathogenesis of inflammatory bowel disease (IBD). Probiotic therapeutic interventions targeting the microbiota may provide alternative avenues to treat IBD, but currently available probiotics often suffer from low intestinal colonization and limited targeting capability. Here, we developed azido (N 3)-modified Prussian blue nanozyme (PB@N 3) spatio-temporal guidance enhances the targeted colonization of probiotics to alleviate intestinal inflammation. First, clickable PB@N 3 targets intestinal inflammation, simultaneously, it scavenges reactive oxygen species (ROS). Subsequently, utilizing "click" chemistry to spatio-temporally guide targeted colonization of dibenzocyclooctyne (DBCO)-modified Lactobacillus reuteri DSM 17938 (LR@DBCO). The "click" reaction between PB@N 3 and LR@DBCO has excellent specificity and efficacy both in vivo and in vitro. Despite the complex physiological environment of IBD, "click" reaction can prolong the retention time of probiotics in the intestine. Dextran sulfate sodium (DSS)-induced colitis mice model, demonstrates that the combination of PB@N 3 and LR@DBCO effectively mitigates levels of ROS, enhances the colonization of probiotics, modulates intestinal flora composition and function, regulates immune profiles, restores intestinal barrier function, and alleviates intestinal inflammation. Hence, PB@N 3 spatio-temporal guidance enhances targeted colonization of LR@DBCO provides a promising medical treatment strategy for IBD. [Display omitted] [ABSTRACT FROM AUTHOR]

Glucose has been extensively studied as a targeting ligand on nanoparticles for biomedical nanoparticles. A promising nanocarrier platform are single-chain polymer nanoparticles (SCNPs). SCNPs are well-defined 5–20 nm semi-flexible nano-objects, formed by intramolecularly crosslinked linear polymers. Functionality can be incorporated by introducing labile pentafluorophenyl (PFP) esters in the polymer backbone, which can be readily substituted by functional amine-ligands. However, not all ligands are compatible with PFP-chemistry, requiring different ligation strategies for increasing versatility of surface functionalization. Here, we combine active PFP-ester chemistry with copper(I)-catalyzed azide alkyne cycloaddition (CuAAC) click chemistry to yield dual-reactive SCNPs. First, the SCNPs are functionalized with increasing amounts of 1-amino-3-butyne groups through PFP-chemistry, leading to a range of butyne-SCNPs with increasing terminal alkyne-density. Subsequently, 3-azido-propylglucose is conjugated through the glucose C1- or C6-position by CuAAC click chemistry, yielding two sets of glyco-SCNPs. Cellular uptake is evaluated in HeLa cancer cells, revealing increased uptake upon higher glucose-surface density, with no apparent positional dependance. The general conjugation strategy proposed here can be readily extended to incorporate a wide variety of functional molecules to create vast libraries of multifunctional SCNPs. [Display omitted] [ABSTRACT FROM AUTHOR]

The condensation of 1,3‐diketones with hydrazine to access 4H‐pyrazoles is a well‐established synthetic route that travels through a 4H‐pyrazol‐1‐ium intermediate. In the route to a 3,5‐diphenyl‐4H‐pyrazole containing a cyclobutane spirocycle, density functional theory calculations predict, and experiments show that the protonated intermediate undergoes a rapid 1,5‐sigmatropic shift to form a tetrahydrocyclopenta[c]pyrazole. Replacing the 3,5‐diphenyl groups with 2‐furanyl groups decreases the calculated rate of the 1,5‐sigmatropic shift by 6.2 × 105‐fold and enables the isolation of new spirocyclic 4H‐pyrazoles for click chemistry. [ABSTRACT FROM AUTHOR]

Bacteria produce polycationic homopoly(amino acid)s, which are characterized by isopeptide backbones. We previously demonstrated that two representative bacterial polycationic isopeptides, ε-poly- l -α-lysine consisting of 25–35 l -α-lysine residues (ε-PαL 25-35) and ε-poly- l -β-lysine consisting of l -β-lysine residues (ε-PβL 4-13), were internalized into mammalian cells by both energy-independent direct penetration and energy-dependent endocytosis/macropinocytosis, and then diffused throughout the cytosol. In this study, we investigated the cell-penetrating activity of an ε-PαL short-chain derivative consisting of 5–14 l -α-lysine residues (ε-PαL 5-14) to gain insight into the relationship between the isopeptide-chain length and the manner of cellular internalization. We prepared a conjugate of ε-PαL 5-14 and a fluorescent dye (FAM) by click chemistry, and incubated the resulting polymer, ε-PαL 5-14 -FAM, with HeLa cells. Unlike ε-PαL 25-35 -FAM, ε-PαL 5-14 -FAM was internalized into cells only by energy-dependent endocytosis/macropinocytosis. Furthermore, a high concentration (>50 μM) was required for the internalization events. ε-PαL 5-14 has a chain length almost equal to that of the membrane permeable ε-PβL 4-13 , which can enter cells at low concentrations. Considering that the basicity of the β-amino group is higher than that of α-amino acid at physiological pH, ε-PβL is expected to have a greater cell-penetrating capacity than ε-PαL, provided their isopeptide-chain lengths are similar, suggesting that a more extended chain derivative of ε-PβL would be more advantageous for cellular internalization of cargo proteins than ε-PαL 25-35. [Display omitted] [ABSTRACT FROM AUTHOR]

Titanium dioxide/multi-walled carbon nanotubes (TiO2/MWCNTs) are nanocomposites (NCs) prepared via click reaction of TiO2 nanoparticles (TiO2 NPs) with azide groups (TiO2–N3) on the surface and MWCNTs with alkynyl groups (MWCNTs–ALK) on the surface. The phase structure, graphitization degree, structure, elemental composition, the microstructure of TiO2/MWCNTs NCs were characterized by XRD, Raman, IR, XPS and SEM, and their electromagnetic (EM) parameters were determined by the vector network analyser. For TiO2/MWCNTs NCs with click reaction, the minimum reflection loss (RLmin) is up to −47.87 dB at 12.02 GHz, the matching thickness is 2.0 mm, and the bandwidth is lower than −10 dB in the range of 7.7–12.48 GHz. Compared with the physically mixed TiO2/MWCNTs composites, TiO2/MWCNTs NCs prepared by click reaction show more excellent EM absorption properties, which is mainly due to the binding of covalent bonds between the two kinds of materials that lead to the enhancement of interfacial effects, the improvement of impedance matching and the increase of electron migration. [ABSTRACT FROM AUTHOR]

Bioorthogonal click chemistry has played a transformative role in many research fields, including chemistry, biology, and medicine. Click reactions are crucial to produce increasingly complex bioconjugates, to visualize and manipulate biomolecules in living systems and for various applications in bioengineering and drug delivery. As biological (model) systems grow more complex, researchers have an increasing need for using multiple orthogonal click reactions simultaneously. In this review, we will introduce the most common bioorthogonal reactions and discuss their orthogonal use on the basis of their mechanism and electronic or steric tuning. We provide an overview of strategies to create reaction orthogonality and show recent examples of mutual orthogonal chemistry used for simultaneous biomolecule labeling. We end by discussing some considerations for the type of chemistry needed for labeling biomolecules in a system of choice. [ABSTRACT FROM AUTHOR]

2‐Amino pyrimidines are vital molecules that exhibit diverse biological activities and serve as structural motifs in various pharmaceutical drugs. Four new series of triazole‐linked glycohybrids of 2‐amino‐pyrimidinones were designed and efficiently synthesized, using a microwave‐assisted method under click chemistry reaction conditions. The N‐propargyl‐2‐aminopyrimidinone and O‐propargyl‐2‐aminopyrimidine derivatives successfully underwent the click reactions with 1‐azido‐tetra‐O‐acetyl‐β‐D‐glucose, D‐galactose and D‐mannose. In this work, we reported the series of novel thirty‐three new triazole‐linked glycohybrid molecules with stereochemical diversity and diverse substitution patterns. [ABSTRACT FROM AUTHOR]

Light‐based 3D printing techniques represent powerful tools, enabling the precise fabrication of intricate objects with high resolution and control. An innovative addition to this set of printing techniques is Optical Fiber‐Assisted Printing (OFAP) introduced in this article. OFAP is a platform utilizing an LED‐coupled optical fiber (LOF) that selectively crosslinks photopolymer resins. It allows change of parameters like light intensity and LOF velocity during fabrication, facilitating the creation of structures with progressive features and multi‐material constructs layer‐by‐layer. An optimized formulation based on allyl‐modified gelatin (gelAGE) with food dyes as photoabsorbers is introduced. Additionally, a novel gelatin‐based biomaterial, alkyne‐modified gelatin (gelGPE), featuring alkyne moieties, demonstrates near‐visible light absorption thus fitting OFAP needs, paving the way for multifunctional hydrogels through thiol‐yne click chemistry. Besides 2D patterning, OFAP is transferred to embedded 3D printing within a resin bath demonstrating the proof‐of‐concept as a novel printing technology with potential applications in tissue engineering and biomimetic scaffold fabrication, offering rapid and precise freeform printing capabilities. [ABSTRACT FROM AUTHOR]

Polymer electrolytes play a crucial role in advancing rechargeable magnesium batteries (RMBs) owing to their exceptional characteristics, including high flexibility, superior interface compatibility, broad electrochemical stability window, and enhanced safety features. Despite these advantages, research in this domain remains nascent, plagued by single preparation approaches and challenges associated with the compatibility between polymer electrolytes and Mg metal anode. In this study, we present a novel synthesis strategy to fabricate a glycerol α,α′‐diallyl ether‐3,6‐dioxa‐1,8‐octanedithiol‐based composite gel polymer electrolyte supported by glass fiber substrate (GDT@GF CGPE) through anion modification and thiol‐ene click chemistry polymerization. The developed route exhibits novelty and high efficiency, leading to the production of GDT@GF CGPEs featuring exceptional mechanical properties, heightened ionic conductivity, elevated Mg2+ transference number, and commendable compatibility with Mg anode. The assembled modified Mo6S8||GDT@GF||Mg cells exhibit outstanding performance across a wide temperature range and address critical safety concerns, showcasing the potential for applications under extreme conditions. Our innovative preparation strategy offers a promising avenue for the advancement of polymer electrolytes in high‐performance rechargeable magnesium batteries, while also opens up possibilities for future large‐scale applications and the development of flexible electronic devices. [ABSTRACT FROM AUTHOR]

A phthalimide or 3‐formylindole functionality was incorporated into a tris(hydroxymethyl)ethane (THME) scaffold, and the resulting compounds were subsequently transformed into phosphoramidites and solid supports. These building blocks were then used to synthesise oligonucleotides containing amine or aldehyde groups at various positions within their sequences. The resulting modified oligonucleotides were further conjugated through either amide bond formation or oxime ligation. These novel building blocks expand the repertoire of phosphoramidites and solid supports available for modifying oligonucleotides. [ABSTRACT FROM AUTHOR]