Copper-mediated Azide-alkyne Cycloaddition Research Articles

New Analogues of the Nicotinamide Phosphoribosyltransferase Inhibitor FK866 as Potential Anti-Pancreatic Cancer Agents

Background: During the past two decades, many nicotinamide phosphoribosyltransferase (NAMPT) inhibitors were prepared and tested because this enzyme is overexpressed in pancreatic cancer. Although FK866 is a well-known, strong NAMPT inhibitor, it suffers severe drawbacks. background: During the past two decades, many nicotinamide phosphoribosyltransferase (NAMPT) inhibitors were prepared and tested because this enzyme is overexpressed in pancreatic cancer. Although FK866 is a well-known, strong NAMPT inhibitor, it suffers from severe drawbacks. Objective: Our work aimed to synthesize efficient NAMPT inhibitors featuring better pharmacokinetic properties than the pyridine-containing FK866. To this aim, the new anticancer agents were based on benzene, pyridazine, or benzothiazole moieties as a cap group instead of the pyridine unit found in FK866 and other NAMPT inhibitors. Methods: The new compounds, prepared exploiting standard heterocycle chemistry and coupling reactions (e.g., formation of amides, ureas, and cyanoguanidines, copper-mediated azide-alkyne cycloaddition), have been fully characterized using NMR and HRMS analyses. Their activity has been evaluated using cytotoxicity and intracellular NAD depletion assays in the human pancreatic cancer cell line MiaPaCa-2. Results: Among the 14 products obtained, compound 28, bearing a pyridazine unit as the cap group and a thiophene moiety as the tail group, showed 6.7 nanomolar inhibition activity in the intracellular NAD depletion assay and 43 nanomolar inhibition in the MiaPaCa-2 cells cytotoxicity assay, comparable to that observed for FK866. result: Among the 14 products obtained, one showed nanomolar inhibition activity in both biological assays, comparable to that observed for FK866. Conclusion: The positive results observed for some newly synthesized molecules, particularly those carrying a thiophene unit as a tail group, indicate that they could act as in vivo anti-pancreatic cancer agents.

Biocompatible photoinduced CuAAC using sodium pyruvate.

Sodium pyruvate, a natural intermediate produced during cellular metabolism, is commonly used in buffer solutions and media for biochemical applications. Here we show the use of sodium pyruvate (SP) as a reducing agent in a biocompatible aqueous photoinduced azide-alkyne cycloaddition (CuAAC) reaction. This copper(I)-catalyzed 1,3-dipolar cycloaddition is triggered by SP under UV light irradiation, exhibits oxygen tolerance and temporal control, and provides a convenient alternative to current CuAAC systems, particularly for biomolecular conjugations.

Polymeric "Clickase" Accelerates the Copper Click Reaction of Small Molecules, Proteins, and Cells.

Recent work has shown that polymeric catalysts can mimic some of the remarkable features of metalloenzymes by binding substrates in proximity to a bound metal center. We report here an unexpected role for the polymer: multivalent, reversible, and adaptive binding to protein surfaces allowing for accelerated catalytic modification of proteins. The catalysts studied are a group of copper-containing single-chain polymeric nanoparticles (CuI-SCNP) that exhibit enzyme-like catalysis of the copper-mediated azide-alkyne cycloaddition reaction. The CuI-SCNP use a previously observed "uptake mode", binding small-molecule alkynes and azides inside a water-soluble amphiphilic polymer and proximal to copper catalytic sites, but with unprecedented rates. Remarkably, a combined experimental and computational study shows that the same CuI-SCNP perform a more efficient click reaction on modified protein surfaces and cell surface glycans than do small-molecule catalysts. The catalysis occurs through an "attach mode" where the SCNPs reversibly bind protein surfaces through multiple hydrophobic and electrostatic contacts. The results more broadly point to a wider capability for polymeric catalysts as artificial metalloenzymes, especially as it relates to bioapplications.

Chemical Waltz of Organic Molecules "On Water": Saline-Assisted Sustainable Regioselective Synthesis of Fluorogenic Heterobioconjugates via Click Reaction.

A new sustainable green protocol for obtaining highly fluorogenic heterobioconjugates by a well-known copper-mediated azide–alkyne cycloaddition click reaction of nonfluorescent 3-azidocoumarins/benzyl azides (2a–f) and terminal alkynes (1a–e) using aqueous NaCl as a cheap and nontoxic salting-out agent under ultrasonication at ambient temperature is described. The presence of aqueous NaCl significantly influences the reaction by disturbing the water kosmotropes and augments the hydrophobic interaction of water-insoluble reactants, thus making the reaction feasible in water at neutral pH. The “beauty” of the presented ecofriendly approach is further boosted up by recycling the aqueous filtrate of the reaction mixture without further addition of NaCl, CuSO4·5H2O, and Na ascorbate up to seven cycles, resulting in effectively low copper loading (100 ppm) with excellent turn-over number (4850) and turn-over frequency (88.18 min–1). A gram-scale synthesis was also successfully achieved with 92% yield, further elaborating the scope of this methodology.

Heteromultivalent Glycooligomers as Mimetics of Blood Group Antigens.

Precision glycomacromolecules have proven to be important tools for the investigation of multivalent carbohydrate-lectin interactions by presenting multiple glycan epitopes on a highly-defined synthetic scaffold. Herein, we present a new strategy for the versatile assembly of heteromultivalent glycomacromolecules that contain different carbohydrate motifs in proximity within the side chains. A new building block suitable for the solid-phase polymer synthesis of precision glycomacromolecules was developed with a branching point in the side chain that bears a free alkyne and a TIPS-protected alkyne moiety, which enables the subsequent attachment of different carbohydrate motifs by on-resin copper-mediated azide-alkyne cycloaddition reactions. Applying this synthetic strategy, heteromultivalent glycooligomers presenting fragments of histo-blood group antigens and human milk oligosaccharides were synthesized and tested for their binding behavior towards bacterial lectin LecB.

Surface Engineering of Chemically Exfoliated MoS2 in a “Click”: How To Generate Versatile Multifunctional Transition Metal Dichalcogenides-Based Platforms

The interest for transition metal dichalcogenides (TMDs) as two-dimensional (2D) analogues of graphene is steadily growing along with the need of efficient and easy tunable protocols for their surface functionalization. This latter aspect holds a key role in the widespread application of TMDs in various technological fields and it represents the missing step to bridge the gap between the more popular C sp2-based networks and their inorganic counterparts. Although significant steps forward have already been made in the field of TMDs functionalization (particularly for MoS2), a rational approach to their surface engineering for the generation of 2D organic–inorganic hybrids capable to accommodate various molecules featured by orthogonal groups has not been reported yet. The paper paves the way toward a new frontier for “click” chemistry in material science. It describes the post-synthetic modification (PSM) of covalently decorated MoS2 nanosheets with phenylazido pendant arms and the successful application of CuAAC chemistry (copper-mediated azide–alkyne cycloaddition) towards the generation of highly homo- and hetero-decorated MoS2 platforms. This contribution goes beyond the proof of evidence of the chemical grafting of organic groups to the surface of exfoliated MoS2 flakes through covalent C–S bonds. It also demonstrates the versatility of the hybrid samples to undergo post-synthetic modifications thus imparting multimodality to these 2D materials. Several physico-chemical [SEM microscopy, fluorescence lifetime imaging (FLIM)], spectroscopic (IR, Raman, XPS, UV–vis), and analytical tools have been combined together for the hybrids’ characterization as well as for the estimation of their functionalization loading.

Versatile Ring-Opening Copolymerization and Postprinting Functionalization of Lactone and Poly(propylene fumarate) Block Copolymers: Resorbable Building Blocks for Additive Manufacturing

Additive manufacturing has the potential to change medicine, but clinical applications are limited by a lack of resorbable, printable materials. Herein, we report the first synthesis of polylactone and poly(propylene fumarate) (PPF) block copolymers with well-defined molecular masses and molecular mass distributions using sequential, ring-opening polymerization and ring-opening copolymerization methods. These new copolymers represent a diverse platform of resorbable printable materials. Furthermore, these polymers open a previously unexplored range of accessible properties among stereolithographically printable materials, which we demonstrate by printing a polymer with a molecular mass nearly 4 times that of the largest PPF homopolymer previously printed. To further demonstrate the potential of these materials in regenerative medicine, we report the postprinting “click” functionalization of the material using a copper-mediated azide–alkyne cycloaddition.

A one-pot protocol for copper-mediated azide–alkyne cycloaddition using alkenyl triflate precursors

On the basis of the mild transformation of alkenyl triflates into alkynes promoted by LiCl, a one-pot protocol using alkenyl triflate precursors was developed for copper-mediated azide–alkyne cycloaddition. This protocol may provide an opportunity of sequentially click reactions for the construction of bifunctional probes in chemical biology studies.

Copper-Mediated Late-Stage Iodination and 123I-Labelling of Triazole-benzimidazole Bioactives

The copper-mediated azide-alkyne cycloaddition has been studied to achieve late-stage introduction of iodine onto novel triazole-benzimidazole Gonadotropin Releasing Hormone (GnRH)-receptor antagonists. Moreover, the reaction conditions can affect a direct regioselective C–H iodination of the benzimidazole, leading to a range of novel iodo-analogues. The methodologies are powerful strategies for late-stage 123I-labelling of complex bioactives. Our investigations have generated two highly promising 123I-labelled radiotracer candidates that retain high affinities for the GnRH-receptor.

Split‐and‐Combine Approach Towards Branched Precision Glycomacromolecules and Their Lectin Binding Behavior

Previously, monodisperse and sequence-controlled oligo(amidoamine) scaffolds were synthesized based on the step-wise assembly of tailor-made building blocks on a solid support that allow for the multivalent presentation of sugar ligands. Here, we extend on this concept using a split-and-combine approach to gain access to a small library of linear and branched glycomacromolecules. Azide side chains were introduced in the scaffold by the use of a novel building block allowing for copper-mediated azide-alkyne cycloaddition (CuAAC) of readily available propargyl-functionalized glycans. In the first stage, after assembly of the linear scaffold on solid support, the batch was divided into two. One part of the resin-bound oligomers was end-capped and further used as backbone and the other part was functionalized with propargylated α-d-mannopyranoside in the sidechain, end capped with an alkyne functionality and finally cleaved from solid support to give the branching arm. In the second stage, the linear, glycosylated and alkynylated arms were then coupled to the end capped backbone via CuAAC. In this way, branched glycomacromolecules with two and three branches, respectively, have been synthesized carrying from two to six sugar residues per molecule. Both, linear arms and branched glycomacromolecules were then subjected to a lectin binding assay using surface plasmon resonance (SPR) and model lectin Concanavalin A (Con A) showing the effect of branching as well as valency on the binding kinetics.

Functionalization of polyfluorene-wrapped carbon nanotubes via copper-mediated azide–alkyne cycloaddition

Copper-mediated azide–alkyne cycloaddition enables quantitative functionalization of polymer-nanotube complexes containing azide moieties in the polymer side chains.

Magnesium Catalyzed Polymerization of End Functionalized Poly(propylene maleate) and Poly(propylene fumarate) for 3D Printing of Bioactive Scaffolds.

The ring-opening copolymerization of maleic anhydride and propylene oxide, using a functionalized primary alcohol initiator and magnesium 2,6-di-tert-butyl phenoxide as a catalyst, was investigated in order to produce high end-group fidelity poly(propylene maleate). Subsequent isomerization of the material into 3D printable poly(propylene fumarate) was utilized to produce thin films and scaffolds possessing groups that can be modified with bioactive groups postpolymerization and postprinting. The surface concentration of these modifiable groups was determined to be 30.0 ± 3.3 pmol·cm-2, and copper-mediated azide-alkyne cycloaddition was used to attach a small molecule dye and cell adhesive GRGDS peptides to the surface as a model system. The films were then studied for cytotoxicity and found to have high cell viability before and after surface modification.

Poly(N-alkyl-3,6-carbazole)s via Suzuki–Miyaura Polymerization: From Macrocyclization toward End Functionalization

The metal-catalyzed polymerization of 3,6-carbazoles is explored with emphasis of end-group fidelity of the telechelic polymers. The Suzuki–Miyaura coupling polymerization using asymmetric bifunctional (AB-type) monomers was selected to circumvent the inherent polycondensation character of symmetric (AA/BB-type) monomers. Common synthetic protocols were screened to facilitate the chain growth vs step growth character during the polymerization, e.g., several activation reagents for the boronic ester and various catalytic systems and their associated reaction conditions. The reactions were analyzed in detail by size exclusion chromatography (SEC), 1H NMR spectroscopy, and mass spectrometry including isotope analysis for end-group determination. It was found that the intermediate oligomers are susceptible for macrocycle formation, particularly at low concentration, while longer polymer chains continue to polymerize. The synthetic methodology was extended to utilize functionalized precatalysts and functional terminating agents in order to explore the scope of chain growth vs step growth. The concomitant formation of macrocycles was observed, which indicates the catalyst dissociation and, thus, also the polycondensation pathway. Importantly, the applied low concentration leads to trapping of the undesired nonfunctionalized chains as macrocycles, which can be readily removed from the telechelic linear polymer. In summary, the developed protocols demonstrate the versatility to prepare telechelic poly(3,6-carbazole)s via Suzuki–Miyaura coupling. The azide-decorated poly(carbazole) exemplifies the potential to serve as building blocks for further copper-mediated azide–alkyne cycloaddition reactions.

Flash cationic polymerization followed by bis-end-functionalization. A new approach to linear-dendritic hybrid polymers

Cationic polymerization of vinyl ethers using a multifunctional dendritic initiator and multifunctional terminators in a flow microreactor system gave polymers having multiple functionalities on both ends. Subsequent transformation of the resulting polymers through Suzuki-Miyaura coupling and/or copper-mediated azide-alkyne cycloaddition gave linear-dendritic hybrid polymers.

A modular synthesis of 1,4,5-trisubstituted 1,2,3-triazoles with ferrocene moieties

Regioselective synthesis of 1,2,3-triazoles with ferrocenyl moieties in positions 1, 4, and 5 was carried out in a two-step reaction sequence: a copper-mediated azide–alkyne cycloaddition followed by a palladium-catalyzed cross-coupling. A new route towards 5-iodo-1,2,3-triazoles was developed using N-iodomorpholine hydrogen iodide, instead of the corrosive and toxic ICl, as the I+ source. The novel methodology together with a consecutive Suzuki or Sonogashira reaction was shown to be a useful procedure for the synthesis of a wide range of ferrocenyl 1,2,3-triazoles with di- and triferrocenyl derivatives among them.

The Rise of Azide–Alkyne 1,3-Dipolar 'Click' Cycloaddition and its Application to Polymer Science and Surface Modification

New methods to synthesize and functionalize polymers are of constant interest to the polymer scientist. The 1,3-dipolar cycloaddition between an azide and terminal alkyne has received much attention since the reports that copper(i) provides high yields and regioselective synthesis of 1,4-substituted 1,2,3-triazoles. This coupling chemistry has been rapidly adopted by polymer scientists in the synthesis and post-polymerization modification of polymers. This Review will provide the historical context of the recent development of the copper-mediated azide–alkyne cycloaddition and its use in polymer science, particularly in dendrimer synthesis/functionalization, surface immobilization/modification, orthogonally functionalizing polymers, and its integration with ATRP (atom transfer radical polymerization).