Showing papers on "Click chemistry published in 2017"
TL;DR: In situ click chemistry is used to develop COX-2 specific inhibitors with high in vivo anti-inflammatory activity, significantly higher than that of widely used selective cyclooxygenase-2 inhibitors.
Abstract: Cyclooxygenase-2 isozyme is a promising anti-inflammatory drug target, and overexpression of this enzyme is also associated with several cancers and neurodegenerative diseases. The amino-acid sequence and structural similarity between inducible cyclooxygenase-2 and housekeeping cyclooxygenase-1 isoforms present a significant challenge to design selective cyclooxygenase-2 inhibitors. Herein, we describe the use of the cyclooxygenase-2 active site as a reaction vessel for the in situ generation of its own highly specific inhibitors. Multi-component competitive-binding studies confirmed that the cyclooxygenase-2 isozyme can judiciously select most appropriate chemical building blocks from a pool of chemicals to build its own highly potent inhibitor. Herein, with the use of kinetic target-guided synthesis, also termed as in situ click chemistry, we describe the discovery of two highly potent and selective cyclooxygenase-2 isozyme inhibitors. The in vivo anti-inflammatory activity of these two novel small molecules is significantly higher than that of widely used selective cyclooxygenase-2 inhibitors. Traditional inflammation and pain relief drugs target both cyclooxygenase 1 and 2 (COX-1 and COX-2), causing severe side effects. Here, the authors use in situ click chemistry to develop COX-2 specific inhibitors with high in vivo anti-inflammatory activity.
6,061 citations
TL;DR: Enhanced chain diffusion in (hyper)branched polymers, autocatalysis, or internal chelation concepts enable efficient click cross-linking already at 5 °C with a simultaneously reduced amount of Cu(I) catalyst and increased reaction rates, culminating in the first reported self-healing system based on click cycloaddition reactions.
Abstract: ConspectusClick chemistry has emerged as a significant tool for materials science, organic chemistry, and bioscience. Based on the initial concept of Barry Sharpless in 2001, the copper(I)-catalyzed azide/alkyne cycloaddition (CuAAC) reaction has triggered a plethora of chemical concepts for linking molecules and building blocks under ambient conditions, forming the basis for applications in autonomous cross-linking materials. Self-healing systems on the other hand are often based on mild cross-linking chemistries that are able to react either autonomously or upon an external trigger. In the ideal case, self-healing takes place efficiently at low temperatures, independent of the substrate(s) used, by forming strong and stable networks, binding to the newly generated (cracked) interfaces to restore the original material properties. The use of the CuAAC in self-healing systems, most of all the careful design of copper-based catalysts linked to additives as well as the chemical diversity of substrates, has l...
119 citations
TL;DR: This work provides a versatile platform for facile synthesis of Janus-type double-brushes with structural and functional control, in a minimum number of reactions, by one-pot concurrent atom transfer radical polymerization and Cu-catalyzed Click reaction.
Abstract: Asymmetric molecular brushes emerge as a unique class of nanostructured polymers, while their versatile synthesis keeps a challenge for chemists. Here we show the synthesis of well-defined asymmetric molecular double-brushes comprising two different side chains linked to the same repeat unit along the backbone by one-pot concurrent atom transfer radical polymerization (ATRP) and Cu-catalyzed azide/alkyne cycloaddition (CuAAC) reaction. The double-brushes are based on a poly(Br-acrylate-alkyne) homopolymer possessing an alkynyl for CuAAC reaction and a 2-bromopropionate initiating group for ATRP in each repeat unit. The versatility of this one-shot approach is demonstrated by CuAAC reaction of alkynyl/poly(ethylene oxide)-N3 and ATRP of various monomers. We also show the quantitative conversion of pentafluorophenyl ester groups to amide groups in side chains, allowing for the further fabrication of diverse building blocks. This work provides a versatile platform for facile synthesis of Janus-type double-brushes with structural and functional control, in a minimum number of reactions. Producing well-defined polymer compositions and structures facilitates their use in many different applications. Here the authors show the synthesis of well-defined asymmetric double-brushes by a one-pot concurrent atom transfer radical polymerization and Cu-catalyzed Click reaction.
118 citations
TL;DR: In this paper, the authors describe the use of polyhedral oligomeric silsesquioxane (POSS) to construct multifunctional nanohybrids and nanocomposites with tunable hierarchical structures and unparalleled properties.
111 citations
TL;DR: This minireview highlights the fruitful combination of these two topics for the preparation of sequence-controlled oligomeric and macromolecular structures and showcases the vast number of publications in this field within a relatively short span of time.
Abstract: During the previous decade, many popular chemical reactions used in the area of "click" chemistry and similarly efficient "click-inspired" reactions have been applied for the design of sequence-defined and, more generally, sequence-controlled structures. This combination of topics has already made quite a significant impact on scientific research to date and has enabled the synthesis of highly functionalized and complex oligomeric and polymeric structures, which offer the prospect of many exciting further developments and applications in the near future. This minireview highlights the fruitful combination of these two topics for the preparation of sequence-controlled oligomeric and macromolecular structures and showcases the vast number of publications in this field within a relatively short span of time. It is divided into three sections according to the click-(inspired) reaction that has been applied: copper-catalyzed azide-alkyne cycloaddition, thiol-X, and related thiolactone-based reactions, and finally Diels-Alder-chemistry-based routes are outlined, respectively.
86 citations
TL;DR: For the first time, a convenient copper-catalyzed azide-alkyne cycloaddition (CuAAC, click chemistry) was successfully introduced into injectable citrate-based mussel-inspired bioadhesives to improve both cohesive and wet adhesive strengths and elongate the degradation time, providing numerous advantages in surgical applications.
86 citations
TL;DR: A size-shrinkable drug delivery system based on a polysaccharide-modified dendrimer with tumor microenvironment responsiveness for the first time to the authors' knowledge is proposed and it is confirmed that the enzyme-responsive size shrink is an implementable strategy to enhance drug penetration and to improve therapeutic efficacy.
Abstract: Currently, the limited penetration of nanoparticles remains a major challenge for antitumor nanomedicine to penetrate into the tumor tissues. Herein, we propose a size-shrinkable drug delivery system based on a polysaccharide-modified dendrimer with tumor microenvironment responsiveness for the first time to our knowledge, which was formed by conjugating the terminal glucose of hyaluronic acid (HA) to the superficial amidogen of poly(amidoamine) (PAMAM), using a matrix metalloproteinase-2 (MMP-2)-cleavable peptide (PLGLAG) via click reaction. These nanoparticles had an initial size of ∼200 nm, but once deposited in the presence of MMP-2, they experienced a dramatic and fast size change and dissociated into their dendrimer building blocks (∼10 nm in diameter) because of cleavage of PLGLAG. This rapid size-shrinking characteristic not only promoted nanoparticle extravasation and accumulation in tumors benefited from the enhanced permeability and retention effect but also achieved faster nanoparticle diffusi...
85 citations
TL;DR: It is demonstrated that azides undergo efficient and regioselective room‐temperature annulations with thioalkynes in aqueous milieu when treated with catalytic amounts of a suitable ruthenium complex.
Abstract: The development of efficient metal-promoted bioorthogonal ligations remains as a major scientific challenge. Demonstrated herein is that azides undergo efficient and regioselective room-temperature annulations with thioalkynes in aqueous milieu when treated with catalytic amounts of a suitable ruthenium complex. The reaction is compatible with different biomolecules, and can be carried out in complex aqueous mixtures such as phosphate buffered saline, cell lysates, fetal bovine serum, and even living bacteria (E. coli). Importantly, the reaction is mutually compatible with the classical CuAAC.
84 citations
TL;DR: A copper-catalyzed click reaction inside living mammalian cells is demonstrated with the use of a cell-penetrating peptide-tethered CuI ligand.
Abstract: We demonstrated that the copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction could be performed inside live mammalian cells without using a chelating azide. Under optimized conditions, the reaction was performed in human ovary cancer cell line OVCAR5 in which newly synthesized proteins were metabolically modified with homopropargylglycine (HPG). This model system allowed us to estimate the efficiency of the reaction on the cell membranes and in the cytosol using mass spectrometry. We found that the reaction was greatly promoted by a tris(triazolylmethyl)amine CuI ligand tethering a cell-penetrating peptide. Uptake of the ligand, copper, and a biotin-tagged azide in the cells was determined to be 69 ± 2, 163 ± 3 and 1.3 ± 0.1 μM, respectively. After 10 minutes of reaction, the product yields on the membrane and cytosolic proteins were higher than 18% and 0.8%, respectively, while 75% of cells remained viable. By reducing the biothiols in the system by scraping or treatment with N-ethylmalemide, the reaction yield on the cytosolic proteins was greatly improved to ∼9% and ∼14%, respectively, while the yield on the membrane proteins remained unchanged. The results indicate that out of many possibilities, deactivation of the current copper catalysts by biothiols is the major reason for the low yield of the CuAAC reaction in the cytosol. Overall, we have improved the efficiency for the CuAAC reaction in live cells by 3-fold. Despite the low yield inside live cells, products that strongly bind to the intracellular targets can be detected by mass spectrometry. Hence, the in situ CuAAC reaction can be potentially used for screening of cell-specific enzyme inhibitors or biomarkers containing 1,4-substituted 1,2,3-triazoles.
81 citations
TL;DR: The synthetic approach developed for the fabrication of block copolymer brushes in the nanocomposite opened new opportunities for the design of more functional hybrid materials that will be useful in bioseparation and biomedical applications.
Abstract: In this report, we present a novel modular approach to the immobilization of a high density of boronic acid ligands on thermoresponsive block copolymer brushes for effective enrichment of glycoproteins via their synergistic multiple covalent binding with the immobilized boronic acids. Specifically, a two-step, consecutive surface-initiated atom transfer radical polymerization (SI-ATRP) was employed to graft a flexible block copolymer brush, pNIPAm-b-pGMA, from an initiator-functionalized nanosilica surface, followed by postpolymerization modification of the pGMA moiety with sodium azide. Subsequently, an alkyne-tagged boronic acid (PCAPBA) was conjugated to the polymer brush via a Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) click reaction, leading to a silica-supported polymeric hybrid material, Si@pNIPAm-b-pBA, with a potent glycol binding affinity. The obtained core-brush nanocomposite was systematically characterized with regard to particle size, morphology, organic content, brush density, and n...
81 citations
TL;DR: Bioconjugation based on crosslinking primary amines to carboxylic acid groups has found broad applications in protein modification, drug development, and nanomaterial functionalization.
Abstract: Bioconjugation based on crosslinking primary amines to carboxylic acid groups has found broad applications in protein modification, drug development, and nanomaterial functionalization. However, proteins, which are made up of amino acids, typically give nonselective bioconjugation when using primary amine-based crosslinking. In order to control protein orientation and activity after conjugation, selective bioconjugation is desirable. We herein report an efficient and cysteine-selective thiol-ene click reaction-based bioconjugation strategy using colloidal nanoparticles. The resulting thiol-ene based aptamer and enzyme nanoconjugates demonstrated excellent target binding ability and enzymatic activity, respectively. Thus, thiol-ene click chemistry can provide a stable and robust crosslinker in a biocompatible manner for bioconjugation of any thiol-containing biomolecule with nanomaterials. This will open more opportunities for applications of thiol-ene reactions and functional colloidal nanoparticles in chemical biology.
TL;DR: The dynamic covalent characteristics of oxime and boronate ester bonds have been explored and the tannic acid cross-linking network is selectively degraded returning the hydrogel storage modulus to its initial value and providing a means for the synthesis of materials with tunable mechanical properties.
Abstract: The dynamic covalent characteristics of oxime and boronate ester bonds have been explored. A small excess of a competing aldehyde under acidic conditions resulted in oxime polymer degradation from high molecular weights (30 kDa) to low molecular weight oligomers (2.2 kDa). The dynamic nature of oxime bonds imparts oxime cross-linked hydrogels with self-healing properties and the incorporation of phenyl boronic acid groups into the hydrogel network provides a platform for hydrogel functionalization. The addition of a polyphenol (tannic acid) proves a facile means to incorporate a second, dynamic covalent cross-linking network through boronate ester formation which, owing to the increase in the degree of cross-linking, is found to be nearly double the hydrogel strength (storage modulus increased from 4.6 to 8.5 kPa). Finally, the tannic acid cross-linking network is selectively degraded returning the hydrogel storage modulus to its initial value and providing a means for the synthesis of materials with tunable mechanical properties.
TL;DR: The chemically cross-linked chitosan-based hydrogel showed pH-sensitivity, biocompatibility and inhibitory bacterial activity, promising features for biomedical applications, particularly for targeted-drug delivery.
TL;DR: A new bioorthogonal click-and-release reaction involving iminosydnones and strained alkynes is discovered, which offers the possibility of exchanging tags on proteins for functionalized cyclooctynes under mild and bioorthogsonal conditions.
Abstract: We report the discovery of a new bioorthogonal click-and-release reaction involving iminosydnones and strained alkynes. This transformation leads to two products resulting from the ligation and fragmentation of iminosydnones under physiological conditions. Optimized iminosydnones were successfully used to design innovative cleavable linkers for protein modification, thus opening up new areas in the fields of drug release and target-fishing applications. This click-and-release technology offers the possibility of exchanging tags on proteins for functionalized cyclooctynes under mild and bioorthogonal conditions.
TL;DR: The inverse-electron demand Diels-Alder (IEDDA) click reaction between a thiocarbamate-functionalized trans-cyclooctene and a tetrazine is used to deliver carbonyl sulfide (COS), which is quickly converted to H2S by the uniquitous enzyme carbonic anhydrase (CA), thus providing a new strategy for bio-orthogonal COS/H2S donation.
TL;DR: A nucleic acid functionalized nanocapsule in which nucleic Acid ligands are assembled and disassembled in the presence of enzymes is described, which is highly stable, monodisperse in size, and maximizes the therapeutic potential of both the particles interior and exterior.
Abstract: Herein we describe a nucleic acid functionalized nanocapsule in which nucleic acid ligands are assembled and disassembled in the presence of enzymes. The particles are fully degradable in response to esterases due to an embedded ester cross-linker in the particle’s core. During synthesis the nanocapsules can be loaded with hydrophobic small molecules and post self-assembly undergo covalent cross-linking using copper catalyzed click chemistry. They can then be functionalized with thiolated DNA through stepwise thiolyne chemistry using UV light irradiation. Additionally, the capsule is compatible with enzyme mediated functionalization of a therapeutic mRNA-cleaving DNAzyme at the particle’s surface. The resulting particle is highly stable, monodisperse in size, and maximizes the therapeutic potential of both the particles interior and exterior.
TL;DR: This review introduces recent progress in molecular imaging based on the combination of metabolic glycoengineering and click chemistry, which showed promising results in specific tumor cell imaging for cancer diagnosis and therapy.
TL;DR: This compound proved to be a non-mitochondrial toxicant, which makes it a promising candidate for further lead optimization and development of a new and more efficient agent for the treatment of hepatocellular carcinoma.
TL;DR: In this article, a homodifunctional bimolecular ring-closure method using a self-accelerating double strain-promoted azide-alkyne click reaction as the intermolecular and subsequent intramolecular coupling reactions was developed.
Abstract: As the most straightforward synthetic strategy for cyclic polymers in theory, the traditional homodifunctional bimolecular ring-closure methods showed limited success for preparing pure cyclic polymers in practice even after several decades of development. A breakthrough was achieved in this paper to develop a successful homodifunctional bimolecular ring-closure method using a self-accelerating double strain-promoted azide–alkyne click reaction as the intermolecular and subsequent intramolecular coupling reactions. Because of the self-accelerating property of coupling reaction, this novel approach eliminated the usage of equimolar quantities between telechelic polymers and small molecule linkers, which was the prerequisite of traditional homodifunctional bimolecular ring-closure methods for pure cyclic polymers. More importantly, this approach could use an excess amount of small linkers to increase the intermolecular coupling reaction rate, further resulting in a significantly enhanced preparation efficie...
TL;DR: In this article, photoluminescent (PL) carbon quantum dots (CQDs) were used for catalyzing the Huisgen 1,3-dipolar cycloaddition between azides and alkynes, the prototypical reaction of click chemistry.
TL;DR: This work combines two developments: a polyprotein with versatile, genetically encoded short peptide tags functionalized via a mechanically robust Hydrazino-Pictet-Spengler ligation and the efficient site-specific conjugation of biomolecules to PEG-coated surfaces to demonstrate how efficient bioconjugation to otherwise nonstick surfaces can benefit diverse single-molecule studies.
Abstract: Atomic force microscopy (AFM)-based single-molecule force spectroscopy (SMFS) is a powerful yet accessible means to characterize mechanical properties of biomolecules. Historically, accessibility relies upon the nonspecific adhesion of biomolecules to a surface and a cantilever and, for proteins, the integration of the target protein into a polyprotein. However, this assay results in a low yield of high-quality data, defined as the complete unfolding of the polyprotein. Additionally, nonspecific surface adhesion hinders studies of α-helical proteins, which unfold at low forces and low extensions. Here, we overcame these limitations by merging two developments: (i) a polyprotein with versatile, genetically encoded short peptide tags functionalized via a mechanically robust Hydrazino-Pictet-Spengler ligation and (ii) the efficient site-specific conjugation of biomolecules to PEG-coated surfaces. Heterobifunctional anchoring of this polyprotein construct and DNA via copper-free click chemistry to PEG-coated ...
TL;DR: It is demonstrated that the nucleophilic thiol-yne click reaction presents a highly efficient chemistry for forming robust high water content (ca. 90%) hydrogel materials with tunable stiffness and mechanical properties.
Abstract: Synthetic hydrogel materials offer the ability to tune the mechanical properties of the resultant networks by controlling the molecular structure of the polymer precursors. Herein, we demonstrate that the nucleophilic thiol-yne click reaction presents a highly efficient chemistry for forming robust high water content (ca. 90%) hydrogel materials with tunable stiffness and mechanical properties. Remarkably, optimization of the molecular weight and geometry of the poly(ethylene glycol) (PEG) precursors allows access to materials with compressive strength up to 2.4 MPa, which can be repeatedly compressed to >90% stress. Beyond this, we demonstrate the ability to access hydrogels with storage moduli ranging from 0.2 to 7 kPa. Moreover, we also demonstrate that by a simple precursor blending process, we can access intermediate stiffness across this range with minimal changes to the hydrogel structure. These characteristics present the nucleophilic thiol-yne addition as an excellent method for the preparation o...
TL;DR: Recent advances in the field of supramolecular chemistry based on the use of pillar[n]arenes as substrates for copper(i)-catalysed alkyne-azide cycloaddition (CuAAC) "click" chemistry are discussed.
TL;DR: In order to improve the selectivity and binding affinity of quindoline derivatives as c-myc G-quadruplex binding ligands, novel triazole containing benzofuroquinoline derivatives (T-BFQs) were designed and synthesized by using the 1,3-dipolar cycloaddition of a series of alkyne and azide building blocks.
Abstract: The specificity of nucleic acids’ binders is crucial for developing this kind of drug, especially for novel G-quadruplexes’ binders Quindoline derivatives have been developed as G-quadruplex stabilizers with good interactive activities In order to improve the selectivity and binding affinity of quindoline derivatives as c-myc G-quadruplex binding ligands, novel triazole containing benzofuroquinoline derivatives (T-BFQs) were designed and synthesized by using the 1,3-dipolar cycloaddition of a series of alkyne and azide building blocks The selectivity toward c-myc G-quadruplex DNA of these novel T-BFQs was significantly improved, together with an obvious increase on binding affinity Further cellular and in vivo experiments indicated that the T-BFQs showed inhibitory activity on tumor cells’ proliferation, presumably through the down-regulation of transcription of c-myc gene Our findings broadened the modification strategies of specific G-quadruplex stabilizers
TL;DR: It is concluded that the method based on metabolic glycoengineering and bioorthogonal copper-free click chemistry can stably label stem cells with diverse imageable nanoparticles representing great potential as new stem cell imaging technology.
TL;DR: This study reports on the noncovalent association of a maleimide-containing catechol (dopa-MAL) surface anchor onto the rGO, which is an attractive platform for various applications.
Abstract: Materials based on reduced graphene oxide (rGO) have shown to be amenable to noncovalent functionalization through hydrophobic interactions. The scaffold, however, does not provide sufficient covalent linkage given the low number of reactive carboxyl and alcohol groups typically available on the rGO. The integration of clickable groups, particularly the ones that can undergo efficient conjugation without any metal catalyst, would allow facile functionalization of these materials. This study reports on the noncovalent association of a maleimide-containing catechol (dopa-MAL) surface anchor onto the rGO. Thiol–maleimide chemistry allows thereafter the facile attachment of thiol-containing molecules under ambient metal-free conditions. Although the attachment of glutathione and 6-(ferrocenyl)hexanethiol was used as model thiols, the attachment of a cancer cell targeting cyclic peptide, c(RGDfC), opened the possibility of using the dopa-MAL-modified rGO as a targeted drug delivery system for doxorubicin (DOX)...
TL;DR: A facile novel strategy is developed for the preparation of 4-mercapto-phenylboronic acid functionalized silica nanoparticle-graphene oxide composite via thiol-yne click reaction to design environmentally friendly and more efficient adsorbents for the isolation and enrichment of glycoprotein from complex biological samples.
TL;DR: Under the optimized reaction conditions, a broad range of azides and alkynes were found to participate in this transformation, thus affording 3-trifluoromethyl-substituted 1,2,4-triazinones in moderate to excellent yields.
Abstract: A copper(I)-catalyzed interrupted click reaction in the presence of trifluoroacetic anhydride has been developed, wherein an N-trifluoroacetyl group is used to accelerate the ring-opening of the putative 5-copper(I) triazolide intermediate. Under the optimized reaction conditions, a broad range of azides and alkynes were found to participate in this transformation, thus affording 3-trifluoromethyl-substituted 1,2,4-triazinones in moderate to excellent yields. The reaction has proven to be compatible with a variety of electron-withdrawing and electron-donating groups, halogens, and nitrogen- and sulfur-containing heterocycles, as well as pharmaceutically relevant molecules.
TL;DR: A Cu(I)-catalyzed interrupted click reaction is described, using TMSCF3 as a nucleophilic CF3 source, to synthesize 5-trifluoromethyl 1,2,3-triazoles in one step from readily available terminal alkynes and azides.
TL;DR: Results showed that silyl ether could be used to control release rates of drugs from MSNs under acid environment, which could be useful in clinical treatments requiring controlled drug release.