Catalyzed Click Chemistry Research Articles

Synthesis, characterization, optical and electrochemical properties and antifungal and anticancer activities of ferrocenyl conjugated novel dendrimers

A new class of triazoloferrocenyl conjugates was prepared by copper(i) catalyzed click chemistry, which shows good antifungal activity against fungal pathogens, and also shows excellent anticancer activity against MCF-7 cells.

Novel pyrimidine-2,4-dione–1,2,3-triazole and furo[2,3-d]pyrimidine-2-one–1,2,3-triazole hybrids as potential anti-cancer agents: Synthesis, computational and X-ray analysis and biological evaluation

Regioselective 1,4-disubstituted 1,2,3-triazole tethered pyrimidine-2,4-dione derivatives (5–23) were successfully prepared by the copper(I)-catalyzed click chemistry. While known palladium/copper-cocatalyzed method based on Sonogashira cross-coupling followed by the intramolecular 5-endo-dig ring closure generated novel 6-alkylfuro[2,3-d]pyrimidine-2-one–1,2,3-triazole hybrids (24b–37b), a small library of their 5-alkylethynyl analogs (24a–37a) was synthesized and described for the first time by tandem terminal alkyne dimerization and subsequent 5-endo-trig cyclization, which was additionally corroborated with computational and X-ray crystal structure analyses. The nature of substituents on alkynes and thereof homocoupled 1,3-diynes predominantly influenced the ratio of the formed products in both pathways. In vitro antiproliferative activity of prepared compounds evaluated on five human cancer cell lines revealed that N,N-1,3-bis-(1,2,3-triazole)-5-bromouracil (5–7) and 5,6-disubstituted furo[2,3-d]pyrimidine-2-one-1,2,3-triazole 34a hybrids exhibited the most pronounced cytostatic acitivities against hepatocellular carcinoma (HepG2) and cervical carcinoma (HeLa) cells with higher potencies than the reference drug 5-fluorouracil. Cytostatic effect of pyrimidine-2,4-dione-1,2,3-triazole hybrid 7 in HepG2 cells could be attributed to the Wee-1 kinase inhibition and abolishment of sphingolipid signaling mediated by acid ceramidase and sphingosine kinase 1. Importantly, 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.

A new click-derived tripodal receptor for fluorescence recognition of Ni2+ in aqueous solution

A new click-derived tripodal receptor, tris[(9-anthryl benzyl-1H-1,2,3-triazole-4-yl)methyl]amine (1), was synthesized from tripropargylamine and anthracene azide by Cu(I)-catalyzed click chemistry. In acetonitrile/Tris-HCl (1:1, v/v, pH=7.2) buffer solutions, 1 showed exclusive fluorescence turn-off response to Ni2+ over other metal ions. The detection limit for Ni2+ is 7.1×10−7M.

Surface functionalization with redox active molecule-based imidazolium via click chemistry

In this study, the redox active molecule N-ferrocenylmethyl-N-propargylimidazolium bromide was immobilized onto the surface of an electrode. The surface modification was performed by coupling the electrochemical reduction of the 4-azidophenyldiazonium generated in situ with a copper(I) catalyzed click chemistry reaction. Surface and electrochemical investigations suggest the attachment of a monolayer of redox active molecules containing an ionic liquid framework onto the electrode surface. Furthermore, scanning electrochemical microscopy studies revealed the conductive behavior of the attached ferrocenyl moieties on the ITO surface.

ChemInform Abstract: When CuAAC ′Click Chemistry′ Goes Heterogeneous

AbstractReview: 281 refs.

Measuring and Suppressing the Oxidative Damage to DNA During Cu(I)-Catalyzed Azide-Alkyne Cycloaddition.

We have used the quantitative polymerase chain reaction (qPCR) to measure the extent of oxidative DNA damage under varying reaction conditions used for copper(I)-catalyzed click chemistry. We systematically studied how the damage depends on a number of key reaction parameters, including the amounts of copper, ascorbate, and ligand used, and found that the damage is significant under nearly all conditions tested, including those commonly used for bioconjugation. Furthermore, we discovered that the addition of dimethyl sulfoxide, a known radical scavenger, into the aqueous mixture dramatically suppresses DNA damage during the reaction. We also measured the efficiency of cross-linking two short synthetic oligonucleotides via click chemistry, and found that the reaction could proceed reasonably efficiently even with DMSO present. This approach for screening both DNA damage and reactivity under a range of reaction conditions will be valuable for improving the biocompatibility of click chemistry, and should help to extend this powerful synthetic tool for both in vitro and in vivo applications.

Synthesis of newer 1,2,3-triazole linked chalcone and flavone hybrid compounds and evaluation of their antimicrobial and cytotoxic activities

The present study was carried out in an attempt to synthesize a new class of antimicrobial and antiplasmodial agents by copper catalyzed click chemistry to afford 25 compounds 10–14(a–e) of 1,4-disubstituted-1,2,3-triazole derivatives of chalcones and flavones. The structures of the newly synthesized compounds were established by elemental analysis, IR, 1H NMR, 13C NMR and Mass spectral data. The newly synthesized compounds were evaluated for their antibacterial activity against Gram positive bacteria (Staphylococcus aureus, Enterococcus faecalis), Gram negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Shigella boydii, Klebsiella pneumoniae) and antifungal activity against (Candida albicans, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Dermatophyte) as well as molds (Aspergillus niger, Aspergillus fumigatus). The antiplasmodial and cytotoxic activities of these compounds were also evaluated against human malaria parasite Plasmodium falciparum strain 3D7 and human hepato-cellular carcinoma cells (Huh-7), respectively. Compounds 10a, 10c, 10d, 12c and 14e showed promising antibacterial activity while compounds 10e, 11d, 11e, 12c, 13a, 13b, 13e, 14a and 14d showed good antifungal activity as compared to the corresponding standard drugs. Compound 10b was found to be the most active against Plasmodium falciparum while the remaining compounds showed moderate to weak antiplasmodial activity. However, cytotoxic activities of all compounds were found ineffective against Huh-7 cells.

Cu-Catalyzed Click Reaction in Carbohydrate Chemistry.

Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC), popularly known as the "click reaction", serves as the most potent and highly dependable tool for facile construction of simple to complex architectures at the molecular level. Click-knitted threads of two exclusively different molecular entities have created some really interesting structures for more than 15 years with a broad spectrum of applicability, including in the fascinating fields of synthetic chemistry, medicinal science, biochemistry, pharmacology, material science, and catalysis. The unique properties of the carbohydrate moiety and the advantages of highly chemo- and regioselective click chemistry, such as mild reaction conditions, efficient performance with a wide range of solvents, and compatibility with different functionalities, together produce miraculous neoglycoconjugates and neoglycopolymers with various synthetic, biological, and pharmaceutical applications. In this review we highlight the successful advancement of Cu(I)-catalyzed click chemistry in glycoscience and its applications as well as future scope in different streams of applied sciences.

Combination of photoinduced copper(i) catalyzed click chemistry and photosol–gel reaction for the synthesis of hybrid materials

We investigate in this work a novel one-step methodology for preparing hybrid materials by combining photoinduced sol–gel polymerization and light-induced CuAAC reaction.

Click Chemistry Finds Its Way in Constructing an Ionic Highway in Anion-Exchange Membrane.

To find the way to construct an ionic highway in anion-exchange membranes (AEMs), a series of side-chain-type alkaline polymer electrolytes (APEs) based on poly(2,6-dimethyl-1,4-phenylene oxide) (PPO) polymer backbones were synthesized via Cu(I)-catalyzed click chemistry. The resulting triazole groups and quaternary ammonium (QA) groups facilitate the formation of a continuous hydrogen bond network, which will lead to high hydroxide conductivity according to Grotthuss-type mechanism. Microphase separation induced by long alkyl side chains contributes at the same time to further improving the hydroxide conductivity of the resultant AEMs. Hydroxide conductivity as high as 52.8 mS/cm is obtained for membrane TA-14C-1.21 (IEC = 1.21 mmol/g) with the longest pendant chain at 30 °C, and the conductivity can be increased to 140 mS/cm when the temperature was increased to 80 °C. Moreover, the corresponding water uptake is only 8.6 wt % at 30 °C. In the meantime, the membrane properties can be tuned by precisely regulating the hydrophilic/hydrophobic ratio in the cationic head groups. Compared with AEMs containing triazole and quaternized trimethylammonium head groups, enhanced dimensional stability and mechanical properties are obtained by tuning side-chain chemistry. However, the alkaline stability of the membrane is not as stable as anticipated, probably because of the existence of the triazole ring. Further study will be focused on increasing the alkali stability of the membrane. We envisage that the side-chain-type APEs meditated by click chemistry bearing long hydrophobic side chains pendant to the cationic head groups hold promise as a novel AEMs material.

Capturing the Direct Binding of CFTR Correctors to CFTR by Using Click Chemistry.

Cystic fibrosis (CF) is a lethal genetic disease caused by the loss or dysfunction of the CF transmembrane conductance regulator (CFTR) channel. F508del is the most prevalent mutation of the CFTR gene and encodes a protein defective in folding and processing. VX-809 has been reported to facilitate the folding and trafficking of F508del-CFTR and augment its channel function. The mechanism of action of VX-809 has been poorly understood. In this study, we sought to answer a fundamental question underlying the mechanism of VX-809: does it bind CFTR directly in order to exert its action? We synthesized two VX-809 derivatives, ALK-809 and SUL-809, that possess an alkyne group and retain the rescue capacity of VX-809. By using Cu(I) -catalyzed click chemistry, we provide evidence that the VX-809 derivatives bind CFTR directly in vitro and in cells. Our findings will contribute to the elucidation of the mechanism of action of CFTR correctors and the design of more potent therapeutics to combat CF.

Hairpin DNA‐Dependent Click Conjugation of Oligonucleotides for Electrochemical Monitoring of Copper(II)

AbstractA new electrochemical sensing platform was designed for sensitive detection of copper(II) (Cu2+) based on click conjugation of two short oligonucleotides by using methylene blue‐functionalized hairpin DNA as the template. The analyte (Cu2+) was in situ reduced to Cu+ by sodium ascorbate, which catalyzed the click conjugation between two single‐stranded oligonucleotides one was labelled with a 5′‐alkyne and the other with 3′‐azide group via the Cu+‐catalyzed azide‐alkyne cycloaddition. The newly formed long‐chain oligonucleotide induced the conformational change of hairpin DNA to open the hairpin, resulting in methylene blue far away from the electrode for the decrease of redox current. Under optimal conditions, the decrease in the electronic signal was directly proportional to target Cu2+ concentration, and allowed the detection of Cu2+ at a concentration as low as 1.23 nM. Our strategy also displayed high selectivity for Cu2+ against other metal ions owing to the highly specific Cu+‐catalyzed click chemistry reaction, and was applicable for monitoring of Cu2+ in drinking water with satisfactory results.

Bioorthogonal mimetics of palmitoyl-CoA and myristoyl-CoA and their subsequent isolation by click chemistry and characterization by mass spectrometry reveal novel acylated host-proteins modified by HIV-1 infection.

Protein acylation plays a critical role in protein localization and function. Acylation is essential for human immunodeficiency virus 1 (HIV-1) assembly and budding of HIV-1 from the plasma membrane in lipid raft microdomains and is mediated by myristoylation of the Gag polyprotein and the copackaging of the envelope protein is facilitated by colocalization mediated by palmitoylation. Since the viral accessory protein NEF has been shown to alter the substrate specificity of myristoyl transferases, and alter cargo trafficking lipid rafts, we hypothesized that HIV-1 infection may alter protein acylation globally. To test this hypothesis, we labeled HIV-1 infected cells with biomimetics of acyl azides, which are incorporated in a manner analogous to natural acyl-Co-A. A terminal azide group allowed us to use a copper catalyzed click chemistry to conjugate the incorporated modifications to a number of substrates to carry out SDS-PAGE, fluorescence microscopy, and enrichment for LC-MS/MS. Using LC-MS/MS, we identified 103 and 174 proteins from the myristic and palmitic azide enrichments, with 27 and 45 proteins respectively that differentiated HIV-1 infected from uninfected cells. This approach has provided us with important insights into HIV-1 biology and is widely applicable to many virological systems.

Amilorides bind to the quinone binding pocket of bovine mitochondrial complex I.

Amilorides, well-known inhibitors of Na(+)/H(+) antiporters, were previously shown to inhibit bacterial and mitochondrial NADH-quinone oxidoreductase (complex I) but were markedly less active for complex I. Because membrane subunits ND2, ND4, and ND5 of bovine complex I are homologous to Na(+)/H(+) antiporters, amilorides have been thought to bind to any or all of the antiporter-like subunits; however, there is currently no direct experimental evidence that supports this notion. To identify the binding site of amilorides in bovine complex I, we synthesized two photoreactive amilorides (PRA1 and PRA2), which have a photoreactive azido (-N3) group and terminal alkyne (-C≡CH) group at the opposite ends of the molecules, respectively, and conducted photoaffinity labeling with bovine heart submitochondrial particles. The terminal alkyne group allows various molecular tags to covalently attach to it via Cu(+)-catalyzed click chemistry, thereby allowing purification and/or detection of the labeled peptides. Proteomic analyses revealed that PRA1 and PRA2 label none of the antiporter-like subunits; they specifically label the accessory subunit B14.5a and core subunit 49 kDa (N-terminal region of Thr25-Glu115), respectively. Suppressive effects of ordinary inhibitors (bullatacin, fenpyroximate, and quinazoline), which bind to the putative quinone binding pocket, on labeling were fairly different between the B14.5a and 49 kDa subunits probably because the binding positions of the three inhibitors differ within the pocket. The results of this study clearly demonstrate that amilorides inhibit complex I activity by occupying the quinone binding pocket rather than directly blocking translocation of protons through the antiporter-like subunits (ND2, ND4, and ND5). The accessory subunit B14.5a may be located adjacent to the N-terminal region of the 49 kDa subunits. The structural features of the quinone binding pocket in bovine complex I were discussed on the basis of these results.

Evaluating Relative Chain Orientation of Amylose and Poly(l‐lactide) in Inclusion Complexes Formed by Vine‐Twining Polymerization Using Primer–Guest Conjugates

The relative chain orientation of amylose and poly(l‐lactide) (PLLA) in inclusion complexes formed by phosphorylase‐catalyzed enzymatic polymerization is made clear, by using primer–guest conjugates according to a vine‐twining polymerization manner. The conjugates, which have a maltoheptaosyl moiety at COOH‐ or OH‐terminus of poly(l‐ and d‐lactide)s, are synthesized by copper(I)‐catalyzed click chemistry using propargyl‐terminated polylactides (PLAs) and maltoheptaosyl azide. The cavity of amylose includes PLLA, regardless of the chain orientation, when the conjugates composed of PLLA are used on the vine‐twining polymerization. On the other hand, amylose–poly(d‐lactide) (PDLA) diblock copolymers, which are noninclusion products, are produced when the conjugates composed of PDLA are used. X‐ray diffraction (XRD) patterns of products and gel permeation chromatography (GPC) analyses of their alkaline hydrolysates strongly support that the amylose‐PLLA inclusion supramolecular polymers are produced, probably owing to the same helical direction of amylose as that of PLLA, which is responsibly induced by its chirality, regardless of the chain orientation on complexation. image

One-pot click synthesis of 1,2,3-triazole-embedded unsaturated uracil derivatives and hybrids of 1,5- and 2,5-disubstituted tetrazoles and pyrimidines

Novel conformationally restricted pyrimidine derivatives with a 1,2,3-triazolyl scaffold bound via Z- and E-2-butenyl spacers were prepared by Cu(I)-catalyzed click chemistry via a one-pot, multi-step reaction under microwave irradiation, while 1,5- and 2,5-disubstituted tetrazoles were synthesized by convenient, environmentally friendly click synthesis and subsequently by N-alkylation of 5-substituted 1H-tetrazoles. Among all the tested compounds, the N-1,N-3-disubstituted olefinic uracil derivative showed the highest antiproliferative effects.

A simple lateral flow biosensor for the rapid detection of copper(ii) ions based on click chemistry

A simple and enzyme-free lateral flow biosensor for the rapid detection of Cu2+ based on copper(i) ion (Cu+)-catalyzed click chemistry has been constructed for the first time.

Click chemistry for the conservation of cellular structures and fluorescent proteins: ClickOx

Reactive oxygen species (ROS), including hydrogen peroxide, are known to cause structural damage not only in living, but also in fixed, cells. Copper-catalyzed azide-alkyne cycloaddition (click chemistry) is known to produce ROS. Therefore, fluorescence imaging of cellular structures, such as the actin cytoskeleton, remains challenging when combined with click chemistry protocols. In addition, the production of ROS substantially weakens the fluorescence signal of fluorescent proteins. This led us to develop ClickOx, which is a new click chemistry protocol for improved conservation of the actin structure and better conservation of the fluorescence signal of green fluorescent protein (GFP)-fusion proteins. Herein we demonstrate that efficient oxygen removal by addition of an enzymatic oxygen scavenger system (ClickOx) considerably reduces ROS-associated damage during labeling of nascent DNA with ATTO 488 azide by Cu(I)-catalyzed click chemistry. Standard confocal and super-resolution fluorescence images of phalloidin-labeled actin filaments and GFP/yellow fluorescent protein-labeled cells verify the conservation of the cytoskeleton microstructure and fluorescence intensity, respectively. Thus, ClickOx can be used advantageously for structure preservation in conventional and most notably in super-resolution microscopy methods.

Design, synthesis and evaluation of 1,2,3-triazole-adamantylacetamide hybrids as potent inhibitors of Mycobacterium tuberculosis

A series of novel 1,2,3-triazole-adamantylacetamide hybrids 5a–u, designed by combining bioactive fragments from antitubercular I-A09 and substituted adamantyl urea, were synthesized using copper catalyzed click chemistry. N-(1-Adamantyl)-2-azido acetamide 3 prepared from 1-adamantylamine was reacted with a series of alkyl/aryl acetylenes in the presence of copper sulfate and sodium ascorbate to give new analogues 5a–u in very good yields. Evaluation of all new compounds for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv (ATCC27294), resulted N-(1-adamantan-1-yl)-2-(4-(phenanthren-2-yl)-1H-1,2,3-triazol-1-yl)acetamide (5t) as most promising lead MIC: 3.12μg/mL) with selectivity index >15.

Synthesis and adhesive property study of polyoxetanes grafted with catechols via Cu(I)-catalyzed click chemistry

Mussel-inspired catechol-containing polymers have drawn great attention due to their outstanding adhesive properties. Catechol-containing polyethylene glycol (cPEG) is a well-studied catechol-containing polymer used for tissue repair. Nevertheless, catechols can only be attached to the chain ends of polyethylene glycols thus the bonding strength of the resulting polymers is limited. Aiming at solving the problem, a series of clickable polyoxetane copolymers with grafted catechol moieties were synthesized in an efficient manner. Upon addition of FeCl3 as the cross-linker, strong bonding strength of the adhesive was achieved. Polymer containing 15.5 molar percent of catechol showed the strongest bonding strength up to 5.59 MPa on sanded stainless steel. It was found that the triazole groups also contributed to the overall adhesive performance. This polyoxetane-based adhesive also displayed strong bonding ability to a variety of other substrates including porcine skin.