Catalyzed Click Reaction Research Articles

Alkynylated and Dendronized 5-Aza-7-deazaguanine Nucleosides: Cross-Coupling with Tripropargylamine and Linear Alkynes, Click Functionalization, and Fluorescence of Pyrene Adducts†.

The change of the recognition face of 5-aza-7-deazaguanine bridgehead nucleosides with respect to purine nucleosides permits the construction of new purine-purine or purine-pyrimidine base pairs in DNA and RNA. Clickable derivatives of 5-aza-7-deazaguanine were synthesized by introducing ethynyl, 1,7-octadiynyl, and tripropargylamino side chains in the 7-position of the 5-aza-7-deazapurine moiety by Sonogashira cross-coupling. Click reactions were performed with 1-azidomethylpyrene by the copper-catalyzed azide-alkyne cycloaddition. The copper(I)-catalyzed click reaction on the tripropargylamino nucleoside was significantly faster and higher yielding than that for nucleosides carrying linear alkynyl chains. Also, this reaction could be performed with copper(II) as the catalyst. An autocatalyzed cycle was suggested in which the click product acts as a catalyst. Pyrene click adducts of linear alkynylated nucleosides showed pyrene monomer emission, while tripropargylamino adducts showed monomer and excimer fluorescence. The fluorescence intensities of the 5-aza-7-deazaguanine nucleosides were higher than those of their 7-deazaguanine counterparts. The reported clickable nucleosides can be utilized to functionalize or to cross-link monomeric nucleosides or DNA for diagnostic or imaging purposes and other applications in nucleic acid chemistry and biotechnology.

Click Synthesis of 1,2,3‐Triazoles‐Linked 1,2,4‐Triazino[5,6‐b]indole, Antibacterial Activities and Molecular Docking Studies

AbstractThe reaction of 4,5‐dihydro‐3H‐1,2,4‐triazino[5,6‐b]indole‐3‐thion with propargyl bromide, in EtOH at 80 °C, produces mono‐propargylated 3‐(prop‐2‐one‐1‐ylthio)‐5H‐1,2,4‐triazino[5,6‐b]indole. Further reaction of this compound with propargyl bromide, in DMF in the presence of K2CO3 at room temperature, produced successfully double‐propargylated 5‐(prop‐2‐one‐1‐yl)‐3‐(prop‐2‐one‐1‐ylthio)‐5H‐1,2,4‐triazino[5,6‐b]indole. The Cu(I)‐catalyzed click reaction of these propargylated compounds with different aromatic azides at room temperature, afforded new derivatives of 1,2,3‐triazoles‐linked 1,2,4‐triazino[5,6‐b]indole with high yields. The in vitro antibacterial activities of the novel 1,2,3‐triazoles were screened. The binding modes of these compounds to three enzyme active sites were determined by a molecular docking study. Docking studies demonstrated the most potent compounds; and binding maps revealed that the activities might be attributed to the hydrophobic interactions, hydrogen bonds, cation‐π and π‐π contacts with the active sites.

A glutathione-responsive photosensitizer with fluorescence resonance energy transfer characteristics for imaging-guided targeting photodynamic therapy

Here, we have synthesized and characterized a novel activatable photosensitizer (PS) 8a in which two well-designed boron dipyrromethene (BODIPY) derivatives are utilized as the photosensitizing fluorophore and quencher respectively, which are connected by a disulfide linker via two successive Cu (І) catalyzed click reactions. The fluorescence emission and singlet oxygen production of 8a are suppressed via intramolecular fluorescence resonance energy transfer (FRET) from the excited BODIPY-based PS part to quencher unit, but both of them can be simultaneously switched on by cancer-related biothiol glutathione (GSH) in phosphate buffered saline (PBS) solution with 0.05% Tween 80 as a result of cleavage of disulfide. Also, 8a exhibits a bright fluorescence image and a substantial ROS production in A549 human lung adenocarcinoma, HeLa human cervical carcinoma and H22 mouse hepatoma cells having a relatively high concentration of GSH, thereby leading to a significant photocytotoxicity, with IC50 values as low as 0.44 μM, 0.67 μM and 0.48 μM, respectively. In addition, the photosensitizer can be effectively activated and imaged in H22 transplanted hepatoma tumors of mice and shows a strong inhibition on tumor growth. All these results suggest that such a GSH-responsive photosensitizer based on FRET mechanism may provide a new strategy for tumor-targeted and fluorescence imaging-guided cancer therapy.

Microwave-assisted synthesis, biological evaluation and molecular docking studies of new coumarin-based 1,2,3-triazoles.

Coumarin-based 1,4-disubstituted 1,2,3-triazole derivatives were synthesized using a highly efficient, eco-friendly protocol via a copper(i)-catalyzed click reaction between various substituted arylazides and terminal alkynes. The synthetic route was easy to access and gave excellent yields under microwave irradiation conditions compared to the conventional heating route. The structures of all the compounds were characterized by IR, 1H NMR, 13C NMR spectroscopy and mass spectrometry. All the synthesized compounds were screened for their in vitro antimicrobial, antioxidant and anti-inflammatory activities; among all compounds, 8a, 8j, 8k and 8l exhibited better results with respect to standard drugs. Furthermore, molecular docking studies have been carried out with PDB IDs 2VCX (anti-inflammatory), 3VXI (antioxidant), 4GEE (antimicrobial) and 2XFH (antifungal) using the Glide module of the Schrödinger suite. The final compounds 8d, 8e, 8h, and 8k showed the highest hydrogen bond interactions with His-88 and Val-191 proteins and with water in all the proteins.

Cu(ii), Ir(i) and CuO nanocatalyzed mild synthesis of luminescent symmetrical and unsymmetrical bis(triazolylmethyl)quinoxalines: biocompatibility, cytotoxicity, live cell imaging and biomolecular interaction

A microwave induced Cu(ii) and Ir(i) catalysed click reaction for the synthesis of anticancer symmetrical and unsymmetrical triazoles.

Rotaxanation as a sequestering template to preclude incidental metal insertion in complex oligochromophores

The high yielding CuI-mediated click reaction is an effective procedure for the preparation of oligoporphyrinoid conjugates. However, the CuI catalyst leads to the adventitious and usually undesirable insertion of Cu ions into any non-metalated porphyrinoid centers during reaction. Here we report a "sacrificial rotaxane" strategy for the multifunctionalization of porphyrins with free base corroles without incidental copper insertion. This strategy can be considered a general method for implementing CuI-mediated click reactions with metal cation sequestration to avoid detrimental effects caused by the presence of copper cations.

Synthesis and characterization of 1,2,3-triazoles-linked urea hybrid sensor for selective sensing of fluoride ion

Two urea-linked 1,2,3-triazole based sensors (5a and 5b) have been synthesized by 1,3-dipolar cycloaddition between 1-(4-fluorophenyl)-3-(prop-2-yn-1-yl)urea (2) and phenyl azides (4a-4b) via copper(I)-catalyzed click reaction. The synthesized sensors 5a and 5b have been evaluated for their sensing ability towards anions (F−, Br−, Cl−, I−, H2PO4− and AcO−) and cations (Cu2+, Zn2+, Ca2+, Co2+, Cd2+, Hg2+, Pb2+ and Ni2+) through UV–Visible, fluorescence and NMR spectral techniques. It was observed that sensor 5a exhibited selective sensing for F− ion with a bathochromic shift in absorption spectrum and showed fluorescence “turn-on” behaviour in the emission spectroscopy. The UV–Visible experiments exhibited that 5a interact with F− ion with a stability constant (K) of 2.058 × 104 M−1 and detection limit of 5a for F− ions was found to be 65.76 ± 0.45 μM. Furthermore, these results were also supported by density functional theory (DFT) calculations.

Synthesis, Structure and In Vitro Cytotoxic Activity of Novel Cinchona-Chalcone Hybrids with 1,4-Disubstituted- and 1,5-Disubstituted 1,2,3-Triazole Linkers.

By means of copper(I)-and ruthenium(II)-catalyzed click reactions of quinine- and quinidine-derived alkynes with azide-substituted chalcones a systematic series of novel cinchona-chalcone hybrid compounds, containing 1,4-disubstituted- and 1,5-disubstituted 1,2,3-triazole linkers, were synthesized and evaluated for their cytotoxic activity on four human malignant cell lines (PANC-1, COLO-205, A2058 and EBC-1). In most cases, the cyclization reactions were accompanied by the transition-metal-catalyzed epimerization of the C9-stereogenic centre in the cinchona fragment. The results of the in vitro assays disclosed that all the prepared hybrids exhibit marked cytotoxicity in concentrations of low micromolar range, while the C9-epimerized model comprising quinidine- and (E)-1-(4-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)phenyl) fragments, connected by 1,5-disubstituted 1,2,3-triazole linker, and can be regarded as the most potent lead of which activity is probably associated with a limited conformational space allowing for the adoption of a relatively rigid well-defined conformation identified by DFT modelling. The mechanism of action of this hybrid along with that of a model with markedly decreased activity were approached by comparative cell-cycle analyses in PANC-1 cells. These studies disclosed that the hybrid of enhanced antiproliferative activity exerts significantly more extensive inhibitory effects in subG1, S and G2/M phases than does the less cytotoxic counterpart.

Recovery of palladium from acidic nitrate media with triazole type extractants in ionic liquid

A series of ligands with triazole ring were synthesized via a facile, safe, high yielding Cu(I)-catalysed click reaction, which was used for the first time to recovery Pd(II) from HNO3 medium, wherein ligands 2-[1-(Pyridin-2-ylmethyl)-1H-1,2,3-triazol-4-yl]pyridine (Tz1) and 1,1′-Bis(pyridin-2-ylmethyl)-1H,1′H-4,4′-bi-1,2,3-triazole (Tz2) had excellent extraction efficiency and selectivity. Extraction performance of such two ligands in ionic liquid vs. a classical solvent (chloroform) was compared. Their extraction ability in ionic liquid was four times better than that in chloroform. The mechanism of extraction was investigated by exploring the effects of different parameters such as HNO3, NaNO3 and ligand concentrations on extraction efficiency. It revealed the nature of the extracted species was [Pd(NO3)2·Tz)] confirmed by Electrospray Ionization Mass Spectrometry data. The coordination properties between palladium and the ligand were examined by the structure-activity relationship and the Fourier transform infrared spectra. More than 95% of palladium could be obtained after three times stripping. The Tz/ionic liquid system showed remarkable separation efficiency towards palladium in a simulated mixed metal solution.

Click synthesis of N1-(β-D-ribofuranosyl)-C4-(coumarin-4″-yl)-1,2,3-triazoles

A series of eight N1-(β-D-ribofuranosyl)-C4-(coumarin-4′′-yl)-1,2,3-triazoles have been synthesized by Cu(I)-catalyzed click reaction of 1-azido-1-deoxy-2,3,5-tri-O-benzoyl-β-D-ribofuranose with differently substituted 4-ethynylcoumarins followed by debenzoylation of the resulted N1-(2′,3′,5′-tri-O-benzoyl-β-D-ribofuranosyl)-C4-(coumarin-4″-yl)-1,2,3-triazoles in 71 to 89% overall yields. The structures of all the synthesized compounds were established on the basis of their spectral data analysis that was further confirmed by X-ray data analysis of one of the model benzoylated compounds, i.e. N1-(2′,3′,5′-tri-O-benzoyl-β-D-ribofuranosyl)-C4-(7″-isopropoxycoumarin-4″-yl)-1,2,3-triazole.

Fluorometric detection of copper ions using click chemistry and the target-induced conjunction of split DNAzyme fragments

ABSTRACTThis study aimed to develop a fluorescence assay for Cu2+ monitoring with cascade signal amplification using split Mg2+-dependent DNAzyme subunits as the sensing system and fluorescence as the signal reporter. A subunit of DNAzyme can be formed through a Cu2+-catalysed click reaction between azide- and alkyne-modified short sequences immobilized on magnetic beads, eliminating the washing steps of conventional assays. The immobilized subunit recruits the assisting oligonucleotides to form an autocatalytic DNAzyme as the signal amplifier and a caged fluorescent molecule as the signal reporter. This assay is ultrasensitive, enabling the detection of trace levels of Cu2+ as low as 2 nM, which enhances the detection sensitivity by approximately 100-fold. In addition, the whole reaction process does not require a long manipulation time or a complicated procedure, making the system simple and cost-effective. This method is robust and can be applied to the determination of spiked Cu2+ in water samples with satisfactory recovery. The combination of click chemistry with fluorescent DNAzyme for a simple on-site detection assay can be used for the rapid and sensitive screening of Cu2+.

Synthesis of Multicompartment Nanoparticles of ABC Miktoarm Star Polymers by Seeded RAFT Dispersion Polymerization.

Polymeric multicompartment nanoparticles (MCNs) of μ-ABC miktoarm star polymers composed of poly(N,N-dimethylacrylamide) (PDMA), poly(butyl methacrylate) (PBMA), and polystyrene (PS) were synthesized by Cu(I)-catalyzed click reaction and seeded RAFT dispersion polymerization. The synthesized MCNs have a solvophobic PBMA core with separate segregated PS microdomains and a solvophilic PDMA corona. The size and/or morphology of MCNs are correlative to the length of PDMA, PBMA, and PS segments. Ascribed to the characteristic structure, MCNs of μ-DBS can decrease interfacial tension in n-hexane/water, which is much superior to linear diblock copolymer nanoassemblies.

Efficient synthesis, antitubercular and antimicrobial evaluation of 1,4-disubstituted 1,2,3-triazoles with amide functionality

A series of 21 amide linked 1,4-disubstituted-1,2,3-triazoles were achieved via one-pot synthesis through Cu(I) catalyzed click reaction between terminal alkynes and 2-azido-N-substituted acetamides. Newly formed triazoles were characterized by various spectroscopic techniques (FT-IR, 1H NMR, 13C NMR spectroscopy, and HRMS) and investigated for in vitro antitubercular evaluation against bacteria, i.e., Mycobacterium tuberculosis and antimicrobial evaluation against Bacillus subtilis, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa, Candida albicans, and Aspergillus niger. Some of the synthesized triazole derivatives were found to exhibit moderate inhibitory activity against the tested antitubercular strain, whereas one compound displayed a significant inhibitory activity against most of the tested microbial strains.

Nanopore-Based Strategy for Sensing of Copper(II) Ion and Real-Time Monitoring of a Click Reaction.

A straightforward yet efficient, nanopore-based strategy that enables the sensitive detection of copper(II) ion (Cu2+) and real-time monitoring of a click reaction is provided. Two single-stranded DNAs (ssDNAs) are designed to act as the preprobes, one being modified with an azide and the other an alkyne. The presence of Cu2+ induces the ligation of two ssDNAs via click reaction, leading to the formation of a forked DNA which can quantitatively generate characteristic current signatures when interacts with α-hemolysin (α-HL) nanopore. The assay facilitates a highly selective and sensitive measurement of Cu2+ without the need for labels or signal amplification. More importantly, this nanopore platform exhibits excellent performance in real-time monitoring of a copper(I) ion (Cu+)-catalyzed click reaction at the single-molecule level, by recording the current signals of the forked DNA generated by click chemistry. The proposed strategy is believed to play an important role in both nanopore sensing and characterization of chemistry reactions, especially coupling reactions.

Carbohydrate-functionalized polythiophene biointerface: design, fabrication, characterization and application for protein analysis

In this study, a general method for fabricating glycosylated conductive polymer (CP) biointerface was demonstrated for a label-free electrochemical biosensor. A 3-(3-azidopropoxy) thiophene monomer was designed and synthesized. By electrochemically polymerizing this monomer in ionic liquid [Bmim][BF4], a unique conductive polymer was formed, allowing grafting of lactose or ferrocene via post-polymerization Cu(I)-catalyzed click reaction. X-ray photoelectron spectra validated the covalent 1, 2, 3-triazole ring formation during this click functionalization. SEM study showed an increasing of the crystallinity of the CPs after click functionalization with lactose or ferrocene. The binding of the fabricated lactosylated polythiophene biointerface with Erythrina Cristagalli lectin (ECL) was characterized with differential pulse voltammetry, showing excellent sensitivity and selectivity for ECL analysis. This study illustrated a new glycosylated CP biointerface design and fabrication method that can be applied for developing real-time and label-free electrochemical biosensor to study protein-carbohydrate interactions for protein analysis.

Triazolyl C-nucleosides via the intermediacy of β-1′-ethynyl-2′-deoxyribose derived from a Nicholas reaction: Synthesis, photophysical properties and interaction with BSA

We report the design and synthesis of triazolyl donor/acceptor unnatural C-nucleosides via alkyne (sugar)—azide (aromatic) 1, 3-dipolar cyclo-addition reaction as a key step and studies on their photophysical properties. We have chosen β-1′-ethynyl-2′-deoxyribose as a precursor to synthesize triazolyl-C-nucleosides. Overcoming the difficulties, we obtain β-1′-ethynyl-2′-deoxyribose as a major product following a Co2(CO)8 catalyzed intramolecular Nicholas reaction. The 1,3-diaxial interaction is the driving force for the α to β-anomeric conversion while performing cobalt complexation followed by oxidation to afford β-1′- ethynyl-2′-deoxyribose as the major product. A Cu(I)-catalyzed click reaction between different aromatic donor/acceptor azides and β-1′- ethynyl-2′-deoxyribose generates the desired unnatural triazolyl donor-acceptor aromatic C-nucleosides (cTBDo/Ac) within 30 min. Single crystal X-ray structure shows the puckered conformation of sugar as C3′-exo. Studies on the photophysical properties suggests good fluorophoric as well as solvatochromic characteristics of these nucleosides. Two of the synthesised nucleosides, cTAnthBDo and cTPyBDo, are found to interact with BSA as the only tested protein with quenching of fluorescence signal. The designed bases, thus, might find applications in stabilizing a DNA and in the biophysical study thereof, if a pair of such donor acceptor C-nucleosides could be incorporated into a DNA sequence.

A Click-Chemistry Linked 2'3'-cGAMP Analogue.

2'3'-cGAMP is an uncanonical cyclic dinucleotide where one A and one G base are connected via a 3'-5' and a unique 2'-5' linkage. The molecule is produced by the cyclase cGAS in response to cytosolic DNA binding. cGAMP activates STING and hence one of the most powerful pathways of innate immunity. cGAMP analogues with uncharged linkages that feature better cellular penetrability are currently highly desired. Here, the synthesis of a cGAMP analogue with one amide and one triazole linkage is reported. The molecule is best prepared via a first CuI -catalyzed click reaction, which establishes the triazole, while the cyclization is achieved by macrolactamization.

CuI/l-proline catalyzed click reaction in glycerol for the synthesis of 1,2,3-triazoles

Despite the apparent simplicity of the copper(I) iodide catalyzed CuAAC reaction, the conversion of the catalytic species, i.e. Cu(I) to thermodynamically more stable Cu(II), via aerial oxidation or disproportionation is a major issue. To stabilize the Cu(I) species, the reaction is ideally carried out under an inert atmosphere in the presence of additives such as alcohols, amines, thiols, and aldehydes. Herein, we report the first CuI catalyzed click reaction without an inert atmosphere by employing the CuI/l-proline system in glycerol. The method showed remarkable stability towards sensitive functional groups such as acetonides and 1,2,4-trioxanes.

Medium Rings Bearing Bitriazolyls: Easily Accessible Structures with Superior Performance as Cu Catalyst Ligands

Benefiting from their unique properties, the development of structurally novel and easily accessible medium rings is of significant interest in the pharmaceutical industry and academic research. However, synthetic access to medium-ring scaffolds is very difficult due to their rigid skeleton and large-angle strains. In this paper, a new class of medium rings bearing bitriazolyls (MRBTs) was designed, synthesized, identified as a promising new skeleton ligand for the Cu(I)-catalyzed click reaction, and used in site-special modification of protein. One of the MRBTs, 3aa, exhibited a turnover number (TON) as high as 55 000 and dramatic accelerating effects ( kobs = 1.95 M-1 s-1) and ranked among the most efficient ligands for copper-catalyzed alkyne and azide cycloaddition. Unlike the difficult access to other known medium rings, these 7-12-membered MRBTs can be prepared in straightforward, one-step manner from structurally diverse linear terminal diynes and azides. The unique accessibility and intriguing properties therefore imply their broad application perspectives.

Synthesis of 1,2,3-triazolyl analog of Neisseria meningitidis A capsular polysaccharide

Towards constructing a stable, non-hydrolyzable linkage for Neisseria meningitidis type A (MenA) polysaccharide, the phosphate bridge of its (1→6)-linked 2-acetamido-2-deoxy-α-D-mannopyranosyl phosphate repeating unit was replaced by a triazolyl analog using Cu(I) catalyzed click reaction. The synthesis involved anomeric azidation of N-acetyl-D-mannosamine derivative from its acetate precursor using stoichiometric amount of FeCl3 and one-pot synthesis of precursors for di- and tri- triazolyl saccharides with an azidoethyl spacer at the reducing end for bioconjugation.