Showing papers on "Click chemistry published in 2011"

Click Chemistry: 1,2,3‐Triazoles as Pharmacophores

Abstract: The copper(I)-catalyzed 1,2,3-triazole-forming reaction between azides and terminal alkynes has become the gold standard of 'click chemistry' due to its reliability, specificity, and biocompatibility. Applications of click chemistry are increasingly found in all aspects of drug discovery; they range from lead finding through combinatorial chemistry and target-templated in vitro chemistry, to proteomics and DNA research by using bioconjugation reactions. The triazole products are more than just passive linkers; they readily associate with biological targets, through hydrogen-bonding and dipole interactions. The present review will focus mainly on the recent literature for applications of this reaction in the field of medicinal chemistry, in particular on use of the 1,2,3-triazole moiety as pharmacophore.

From mechanism to mouse: a tale of two bioorthogonal reactions.

Abstract: Bioorthogonal reactions are chemical reactions that neither interact with nor interfere with a biological system. The participating functional groups must be inert to biological moieties, must selectively reactive with each other under biocompatible conditions, and, for in vivo applications, must be nontoxic to cells and organisms. Additionally, it is helpful if one reactive group is small and therefore minimally perturbing of a biomolecule into which it has been introduced either chemically or biosynthetically. Examples from the past decade suggest that a promising strategy for bioorthogonal reaction development begins with an analysis of functional group and reactivity space outside those defined by Nature. Issues such as stability of reactants and products (particularly in water), kinetics, and unwanted side reactivity with biofunctionalities must be addressed, ideally guided by detailed mechanistic studies. Finally, the reaction must be tested in a variety of environments, escalating from aqueous medi...

Water‐Soluble Poly(N‐isopropylacrylamide)–Graphene Sheets Synthesized via Click Chemistry for Drug Delivery

Abstract: Covalently functionalized graphene sheets are prepared by grafting a well-defined thermo-responsive poly(N-isopropylacrylamide) (PNIPAM) via click chemistry. The PNIPAM-grafted graphene sheets (PNIPAM-GS) consist of about 50% polymer, which endows the sheets with a good solubility and stability in physiological solutions. The PNIPAM-GS exhibits a hydrophilic to hydrophobic phase transition at 33 °C, which is relatively lower than that of a PNIPAM homopolymer because of the interaction between graphene sheets and grafted PNIPAM. Moreover, through π–π stacking and hydrophobic interaction between PNIPAM-GS and an aromatic drug, the PNIPAM-GS is able to load a water-insoluble anticancer drug, camptothecin (CPT), with a superior loading capacity of 15.6 wt-% (0.185 g CPT per g PNIPAM-GS). The in vitro drug release behavior of the PNIPAM-GS-CPT complex is examined both in water and PBS at 37 °C. More importantly, the PNIPAM-GS does not exhibit a practical toxicity and the PNIPAM-GS-CPT complex shows a high potency of killing cancer cells in vitro. The PNIPAM-GS is demonstrated to be an effective vehicle for anticancer drug delivery.

Increasing the efficacy of bioorthogonal click reactions for bioconjugation: a comparative study.

Abstract: Raising the bar: the efficacy of bioorthogonal reactions for bioconjugation has been thoroughly evaluated in four different biological settings. Powered by the development of new biocompatible ligands, the copper-catalyzed azide-alkyne cycloaddition has brought about unsurpassed bioconjugation efficiency, and thus it holds great promise as a highly potent and adaptive tool for a broader spectrum of biological applications.

Chemical sensors that incorporate click-derived triazoles.

Abstract: Since the advent of click chemistry in 2001, the 1,4-disubstituted triazole has become an increasingly common motif in chemical sensors. Although these click-derived triazoles are generally used as a convenient method of ligation, their prevalence in chemosensors can be attributed to their ability to bind both cations and anions. In this critical review, we present an overview of the wide range of chemosensors that contain click-derived triazoles, with a particular focus on those cases where the triazole plays a functional, rather than merely a structural, role. Examples are categorised based on method of detection and key structural features, providing a complete picture of the current state of click-based chemosensors, as well as potential future directions for sensor design. (140 references)

Spatial and temporal control of the alkyne–azide cycloaddition by photoinitiated Cu(II) reduction

Abstract: The click reaction paradigm is focused on the development and implementation of reactions that are simple to perform while being robust and providing exquisite control of the reaction and its products. Arguably the most prolific and powerful of these reactions, the copper-catalysed alkyne-azide reaction (CuAAC) is highly efficient and ubiquitous in an ever increasing number of synthetic methodologies and applications, including bioconjugation, labelling, surface functionalization, dendrimer synthesis, polymer synthesis and polymer modification. Unfortunately, as the Cu(I) catalyst is typically generated by the chemical reduction of Cu(II) to Cu(I), or added as a Cu(I) salt, temporal and spatial control of the CuAAC reaction is not readily achieved. Here, we demonstrate catalysis of the CuAAC reaction via the photochemical reduction of Cu(II) to Cu(I), affording comprehensive spatial and temporal control of the CuAAC reaction using standard photolithographic techniques. Results reveal the diverse capability of this technique in small molecule synthesis, patterned material fabrication and patterned chemical modification.

Surface functionalization of porous coordination nanocages via click chemistry and their application in drug delivery.

Abstract: The discrete coordination-driven self assemblies have received continuous attention due to their molecular architecture esthetics and applications in recognition, catalysis, storage, etc. [ 1 ] Among these self assemblies, one species that has emerged recently is the porous coordination nanocages formed between carboxylate ligands and metal clusters, which are also known as metal-organic polyhedra (MOP). [ 2 ] Due to the robust porous structure and versatile functionality, they have found applications as plasticizer, gas sponge, ion channel, coatings, and building units. [ 3 ] Presumably, the porous shell and uniform yet tunable cavity make them good candidates for drug delivery purpose. However, almost all the coordination nanocages reported so far are hydrophobic, which greatly limits their applications in aqueous condition. We hypothesize this problem can be circumvented by turning these nanocages into colloids through surface functionalization with hydrophilic polymers. In this Communication, we report a porous coordination nanocage covered with alkyne groups and its surface functionalization by grafting with azide-terminated polyethylene glycol (PEG) through “click chemistry”. In addition, its drug load and release capacity has been evaluated using an anticancer drug 5-fl uorouracil as a model. The metal-organic cuboctahedron was chosen as the prototype of nanocage in this study. [ 2a , 2c ] It is composed of 12 dicopper paddlewheel clusters and 24 isophthalate moieties, with 8 triangular and 6 square windows that are roughly 8 and 12 Å across, respectively. The internal cavity has a diameter of around 15 Å. The 5-position of isophthalate moieties would be the reaction site for surface functionalization. The Cu(I)catalyzed Huisgen cycloaddition between azide and alkyne, a so-called “click reaction”, was chosen as the synthetic tool in

Copper-Catalyzed Azide–Alkyne Click Chemistry for Bioconjugation

Abstract: The copper-catalyzed azide-alkyne cycloaddition reaction is widely used for the connection of molecular entities of all sizes. A protocol is provided here for the process with biomolecules. Ascorbate is used as reducing agent to maintain the required cuprous oxidation state. Since these convenient conditions produce reactive oxygen species, five equivalents of a copper-binding ligand is used with respect to metal. The ligand both accelerates the reaction and serves as a sacrificial reductant, protecting the biomolecules from oxidation. A procedure is also described for testing the efficiency of the reaction under desired conditions for purposes of optimization, before expensive biological reagents are used.

High-order multiblock copolymers via iterative Cu(0)-mediated radical polymerizations (SET-LRP): toward biological precision.

Abstract: We report a new approach for the facile synthesis of high-order multiblock copolymers comprising very short blocks. The approach entails sequential addition of different monomers via an iterative single electron transfer–living radical polymerization technique, allowing nearly perfect control of the copolymer microstructure. It is possible to synthesize high-order multiblock copolymers with unprecedented control, i.e., A-B-C-D-E-etc., without any need for purification between iterative 24 h block formation steps. To illustrate this concept, we report the synthesis of model P(MA-b-MA...) homopolymer and P(MA-b-nBuA-b-EA-b-2EHA-b-EA-b-nBuA) copolymer in extremely high yield. Finally, the halide end-group can be modified via “click chemistry”, including thiol–bromide click chemistry, sodium methanethiosulfonate nucleophilic substitution, and atom transfer radical nitroxide coupling reaction, to yield functional, structurally complex macromolecules.

Reliable and Efficient Procedures for the Conjugation of Biomolecules through Huisgen Azide–Alkyne Cycloadditions

Abstract: The Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) has been established as a powerful coupling technology for the conjugation of proteins, nucleic acids, and polysaccharides. Nevertheless, several shortcomings related to the presence of Cu, mainly oxidative degradation by reactive oxygen species and sample contamination by Cu, have been pointed out. This Minireview discusses key aspects found in the development of the efficient and benign functionalization of biomacromolecules through CuAAC, as well as the Cu-free strain-promoted azide-alkyne cycloaddition (SPAAC).

Genetically encoded copper-free click chemistry.

Abstract: The ability to visualize biomolecules within living specimen by engineered fluorescence tags has become a major tool in modern biotechnology and cell biology. Encoding fusion proteins with comparatively large fluorescent proteins (FPs) as originally developed by the Chalfie and Tsien groups is currently the most widely applied technique.[1] As synthetic dyes typically offer better photophysical properties than FPs, alternative strategies have been developed based on genetically encoding unique tags such as Halo and SNAP tags, which offer high specificity but are still fairly large.[2] Small tags like multi-histidine[3] or multi-cysteine motifs[4] may be used to recognize smaller fluorophores, but within the cellular environment they frequently suffer from poor specificity as their basic recognition element is built from native amino acid side chains. Such drawbacks may be overcome by utilizing bioorthogonal chemistry that relies on coupling exogenous moieties of non-biological origin under mild physiological conditions. A powerful chemistry that fulfils these requirements is the Huisgen type (3+2) cycloaddition between azides and alkynes (a form of click chemistry[5]). By utilizing supplementation-based incorporation techniques and click reactions Beatty et al. coupled azide derivatized dyes to Escherichia coli expressing proteins bearing linear alkynes.[6] However, this azide–alkyne cycloaddition required copper(I) as a catalyst (CuAAC), which strongly reduces biocompatibility (but see Ref. [7]). This limitation has been overcome by Bertozzi and co-workers, who showed that the “click” reaction readily proceeds when utilizing ring-strained alkynes as a substrate[8] and since then this strain-promoted azide–alkyne cycloaddition (SPAAC) has found increasing applications in labeling, for example, carbohydrates,[9] nucleotides,[10] and lipids.[11] Further expanding the potential of this approach, Ting and co-workers engineered a lipolic acid ligase which ligates a small genetically encoded recognition peptide to a cylcooctyne-containing substrate. In a second step the incorporated cyclooctyne moiety then functioned as a specific site for labeling in cells.[12]

One-pot multistep reactions based on thiolactones: extending the realm of thiol-ene chemistry in polymer synthesis.

Abstract: The in situ generation of thiols by nucleophilic ring-opening of a thiolactone with amines, followed by a UV-initiated radical thiol-ene reaction in a one-pot fashion, has been evaluated as an accelerated and versatile protocol for the synthesis of several types of polymeric architectures. After elaboration of a model amine-thiol-ene conjugation reaction, a number of routes based on readily available thiolactone-containing structures have been developed to successfully assemble functional, linear polymers and networks via a mild and facile radical photopolymerization process.

Copper-Free Sonogashira Cross-Coupling for Functionalization of Alkyne-Encoded Proteins in Aqueous Medium and in Bacterial Cells

Abstract: Bioorthogonal reactions suitable for functionalization of genetically or metabolically encoded alkynes, for example, copper-catalyzed azide-alkyne cycloaddition reaction ("click chemistry"), have provided chemical tools to study biomolecular dynamics and function in living systems. Despite its prominence in organic synthesis, copper-free Sonogashira cross-coupling reaction suitable for biological applications has not been reported. In this work, we report the discovery of a robust aminopyrimidine-palladium(II) complex for copper-free Sonogashira cross-coupling that enables selective functionalization of a homopropargylglycine (HPG)-encoded ubiquitin protein in aqueous medium. A wide range of aromatic groups including fluorophores and fluorinated aromatic compounds can be readily introduced into the HPG-containing ubiquitin under mild conditions with good to excellent yields. The suitability of this reaction for functionalization of HPG-encoded ubiquitin in Escherichia coli was also demonstrated. The high efficiency of this new catalytic system should greatly enhance the utility of Sonogashira cross-coupling in bioorthogonal chemistry.

Click Chemistry on Solution-Dispersed Graphene and Monolayer CVD Graphene

Abstract: Graphene from two different preparative routes was successfully functionalized with 4-propargyloxybenzenediazonium tetrafluoroborate in order to study a subsequent attachment by click chemistry (1,3-dipolar azide–alkyne cycloaddition) of a short chain polyethylene glycol with terminal carboxylic end group (PEG-COOH). The reaction steps were studied by FTIR and Raman spectroscopies, as well as zeta-potential and surface tension measurements. In the first route, pristine graphene was surfactant dispersed from a stage controlled expanded graphite before reaction, resulting in colloidally stable dispersions after dialysis removal of the surfactant following the two functionalization steps. The chemistry was shown to increase the zeta-potential from −45.3 to −54.6 mV and increase the surface tension from 48.5 to 63.0 mN/m compared to those of the precursor solution. The magnitudes of the zeta-potential and the resulting solution concentration were shown to increase with grafting density up to 14.2 μg/mL. A col...

Thiol-ene click reaction as a general route to functional trialkoxysilanes for surface coating applications.

Abstract: Functionalized trialkoxysilanes are widely used to modify the surface properties of materials and devices. It will be shown that the photoinitiated radical-based thiol–ene “click” reaction provides a simple and efficient route to diverse trialkoxysilanes. A total of 15 trialkoxysilanes were synthesized by reacting either alkenes with 3-mercaptopropyltrialkoxysilane or thiols with allyltrialkoxysilanes in the presence of a photoinitiator. The functionalized trialkoxysilanes were obtained in quantitative to near-quantitative yields with high purity. The photochemical reactions can be run neat in standard borosilicate glassware using a low power 15-W blacklight. A wide range of functional groups is tolerated in this approach, and even complex alkenes click with the silane precursors. To demonstrate that these silanes can be used as surface coating agents, several were reacted with iron oxide superparamagnetic nanoparticles and the loadings quantified. The photoinitiated thiol–ene reaction thus offers a facil...

Click Chemistry for Rapid Labeling and Ligation of RNA

Abstract: The copper(I)-promoted azide-alkyne cycloaddition reaction (click chemistry) is shown to be compatible with RNA (with free 2'-hydroxyl groups) in spite of the intrinsic lability of RNA. RNA degradation is minimized through stabilization of the Cu(I) in aqueous buffer with acetonitrile as cosolvent and no other ligand; this suggests the general possibility of "ligandless" click chemistry. With the viability of click chemistry validated on synthetic RNA bearing "click"-reactive alkynes, the scope of the reaction is extended to in-vitro-transcribed or, indeed, any RNA, as a click-reactive azide is incorporated enzymatically. Once clickable groups are installed on RNA, they can be rapidly click labeled or conjugated together in click ligations, which may be either templated or nontemplated. In click ligations the resultant unnatural triazole-linked RNA backbone is not detrimental to RNA function, thus suggesting a broad applicability of click chemistry in RNA biological studies.

Click-chemistry for nanoparticle-modification

Abstract: Both function and use of nanoparticles (NPs) to a great extent are dominated by interfacial energies, which in turn can be addressed by chemical modifications. This article focuses exclusively on the use of ‘click’-chemistry for NP-surface modification, also putting a major focus on the application of the resulting NPs in bio- and nanoscience. As ‘click’-chemistry is a universal method to link reaction partners in high efficiency, solvent insensitivity and at moderate reaction conditions, its use for engineering NP surfaces has become widespread. The basic approach of Cu(I)-catalyzed azide/alkyne-‘click’ (CuAAC) chemistry for NP-science is elucidated in this article, together with the applications of the resulting surface modified NPs in medicine, nanotechnology and bioassay-science.

Click chemistry from organic halides, diazonium salts and anilines in water catalysed by copper nanoparticles on activated carbon

Abstract: An easy-to-prepare, reusable and versatile catalyst consisting of oxidised copper nanoparticles on activated carbon has been fully characterised and found to effectively promote the multicomponent synthesis of 1,2,3-triazoles from organic halides, diazonium salts, and aromatic amines in water at a low copper loading.

Highly efficient and straightforward functionalization of cellulose films with thiol-ene click chemistry

Abstract: Three efficient and straightforward chemical pathways have been studied to functionalize solid cellulose substrates, involving for the first time alkoxysilane chemistry coupled with the photochemical version of the thiol-ene reaction. The success of the reactions was confirmed using FTIR-ATR spectroscopy and XPS analysis, but different grafting efficiencies were observed depending on the combination used. In a first route, ene-functionalized cellulose films were synthesized using vinyltrimethoxysilane as coupling agent, and were photochemically coupled with methylthioglycolate (MeGlySH). A very fast reaction rate was observed for this reaction during the first 5 min. In a second route, the opposite reaction was envisaged by clicking allylbutyrate on a thiol-functionalized cellulose surface, previously synthesized using 3-mercaptopryltrimethoxysilane as coupling agent. The success of the reaction was highlighted, but lower modification rates were observed. In a third route, a novel approach was successfully proposed for the grafting of thiol molecules on cellulose, based on the click derivatization of the molecule with alkoxysilane functions. Through this study, we expand the modular and versatile character of click chemistry to natural cellulosic substrates. But most importantly, these modification routes can be envisaged for the functionalization of other surfaces (i.e., metal alkoxides for instance) where alkoxysilane chemistry can be employed.

The first well-defined silver(I)-complex-catalyzed cycloaddition of azides onto terminal alkynes at room temperature.

Abstract: The copper(I)-catalyzed Huisgen dipolar cycloaddition of terminal alkynes 1 with azides 2 to yield 1,4and 1,4,5-substituted 1,2,3-triazoles 3 (azide–alkyne cycloaddition; AAC reaction) has been transformed in recent years, since its description as the prototype “click” reaction, to become a general process with applications in diverse areas ranging from functional materials to biological chemistry. The generally accepted mechanism for the reaction, outlined in Scheme 1, involves a stepwise process initiated through generation of a copper(I) acetylide complex I, which complexes to the azide 2, undergoes the cycloaddition, generating a metalated triazole III, which is then protonated to yield the product 3, regenerating the catalyst.