Cycloaddition Of Azides Research Articles

Targeted delivery and enhanced gene-silencing activity of centrally modified folic acid-siRNA conjugates.

One of the major hurdles in RNAi research has been the development of safe and effective delivery systems for siRNAs. Although various chemical modifications have been proposed to improve their pharmacokinetic behaviour, their delivery to target cells and tissues presents many challenges. In this work, we implemented a receptor-targeting strategy to selectively deliver siRNAs to cancer cells using folic acid as a ligand. Folic acid is capable of binding to cell-surface folate receptors with high affinity. These receptors have become important molecular targets for cancer research as they are overexpressed in numerous cancers despite being expressed at low levels in normal tissues. Employing a post-column copper-catalyzed alkyne–azide cycloaddition (CuAAC), we report the synthesis of siRNAs bearing folic acid modifications at different positions within the sense strand. In the absence of a transfection carrier, these siRNAs were selectively taken up by cancer cells expressing folate receptors. We show that centrally modified folic acid–siRNAs display enhanced gene-silencing activity against an exogenous gene target (∼80% knockdown after 0.75 μM treatment) and low cytotoxicity. In addition, these siRNAs achieved potent dose-dependent knockdown of endogenous Bcl-2, an important anti-apoptotic gene.

One-Pot Synthesis of [1,2,3]Triazolo[1,5-a]quinoxalin-4(5H)-ones by a Metal-Free Sequential Ugi-4CR/Alkyne–Azide Cycloaddition Reaction

A convenient and one-pot approach to prepare [1,2,3]triazolo[1,5-a]quinoxalin-4(5H)-ones by a metal-free sequential Ugi-4CR/alkyne–azide cycloaddition reaction has been developed. The reaction of 2-azidobenzenamines, aldehydes, propiolic acids, and isocyanides produced the Ugi adducts, which were transformed to the [1,2,3]triazolo[1,5-a]quinoxalin-4(5H)-ones in moderate to good yields via alkyne–azide cycloaddition reaction.

Formation of octaalkylated rctt tetranaphthyl-resorcinarene derivatives containing biologically active components

Derivatives containing eight easily transformable ester (2) or alkynyl (3) groups were prepared by the alkylation of rctt ortho-methyl-tetra-C-naphthyl-resorcinarene 1 with ethyl 2-bromoacetate and propargyl bromide. Amination of compound 2 gave conjugates (5, 6) of resorcinarenes with biologically active benzyl- and phenethylamines. The reactions proceeded most efficiently in a microwave reactor. The catalytic cycloaddition of benzyl azide or ethyl azidoacetate to octaalkynyl-resorcinarene 3 was used to prepare rctt resorcinarenes (7, 8) conjugated to eight triazole moieties. Resorcinarene 2 is easily converted to octacarboxy derivative (4), which reacts with ethanolamine and phenethylamine to give water-soluble salts (9, 10), whereas reactions with benzylamine and tryptamine result in the formation of complexes (11, 12) containing several amine groups arranged in space in different ways.

Anti-inflammatory activity of polyamide dendrimers bearing bile acid termini synthesized via SPAAC

Inflammation is a general pathomechanism associated with numerous diseases of global impact such as many cancers, metabolic disorders, and neurodegenerative and autoimmune diseases. The development of drugs that can treat chronic inflammation, in an effective way and that are well tolerated by the patients, is an active research area that pursues the treatment for hundreds of diseases. Dendrimers recently appeared as a convenient starting point for the design of anti-inflammatory drugs due to its nanosize, well-defined branched structure, multivalency, and versatility. In this work, polyamide dendrimers with 1 ➔ 3 connectivity were synthesized and functionalized with three types of bile acids (BAs): cholic acid (CA), ursodeoxycholic acid (UDCA), and chenodeoxycholic acid (CDCA). Functionalization was carried out through strain-promoted alkyne–azide cycloaddition (SPAAC) between an azide dendrimer and cyclooctyne derivatives of bile acids. The cell viability and the anti-inflammatory potential of the bile acid dendrimers were evaluated in vitro and compared with those of the pure BAs. The bile acid dendrimers and pure BAs did not show significant cytotoxicity at the concentrations tested (0.78–5.00 × 104 nM) against THP-1 cells. Chenodeoxycholic acid (CDCA) and the corresponding dendrimer dendri-(CDCA)18 (polyamide dendrimer bearing 18 CDCA moieties) presented the highest anti-inflammatory activity, showing LPS-induced IL-8 release inhibition of 45.3% at 0.78 nM CDCA and 35.5% at 0.43 nM dendri-(CDCA)18.

Effect of Dipolar Interactions on the Assembly Process of Iron Oxide Nanoparticles Promoted by the CuAAC “Click” Chemistry Reaction

Nanoparticle assemblies are very attractive because they allow the fine-tuning of magnetic properties by taking advantage of collective behavior ruled by interparticle interactions. Nevertheless, great efforts to control the spatial arrangement of nanoparticles still have to be developed in order to integrate such nanomaterials in devices for applications in fields such as sensors and recording media. Herein, we report on the assembly of iron oxide magnetic nanoparticles promoted by copper-catalyzed alkyne–azide cycloaddition (CuAAC) “click” reaction. Azido-terminated nanoparticles were assembled onto alkyne-terminated gold substrates. The assembly mechanism was investigated by monitoring the density of nanoparticles as a function of their size and concentration. The kinetics of the assembly process is exponential and is favored by the increase of the nanoparticle size and of the concentration. We show that the assembly of nanoparticles is controlled by the random sequential adsorption (RSA) mechanism below a critical size. In contrast, large nanoparticles allow strong dipolar interactions which participate actively in the assembly process, thus they avoid the RSA pathway. These two different mechanism pathways have a significant influence on the spatial arrangement of nanoparticles. The RSA results in rather isolated small nanoparticles at the earliest reaction times which become gradually a discontinuous monolayer. In contrast, the dipolar interaction assisted RSA mechanism (DIA-RSA) favors linear or 2D small assemblies which quickly grow in tight-packed monolayers of nanoparticles. Finally, the magnetic collective properties of these assemblies are markedly favored by the increase of the nanoparticle size.

Some Aspects of the Azide-Alkyne 1,3-Dipolar Cycloaddition Reaction

Some peculiar features of two most commonly used catalytic systems (Cul and CuSOVsodium ascorbate) controlling the regioselectivity of 1,3-dipolar cycloaddition of azides to terminal alkynes have been studied. Their potentialities, main disadvantages, and limitations have been demonstrated by a number of examples, including reactions of low-molecular-weight azides and alkynes containing heterocyclic substituents. The possibility of using novel reagents in click reactions is discussed.

Synthesis of Highly Efficient Multivalent Disaccharide/[60]Fullerene Nanoballs for Emergent Viruses.

After the last epidemic of the Zika virus (ZIKV) in Brazil that peaked in 2016, growing evidence has been demonstrated of the link between this teratogenic flavivirus and microcephaly cases. However, no vaccine or antiviral drug has been approved yet. ZIKV and Dengue viruses (DENV) entry to the host cell takes place through several receptors, including dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), so that the blockade of this receptor through multivalent glycoconjugates supposes a promising biological target to inhibit the infection process. In order to get enhanced multivalency in biocompatible systems, tridecafullerenes appended with up to 360 1,2-mannobiosides have been synthesized using a strain-promoted cycloaddition of azides to alkynes (SPAAC) strategy. These systems have been tested against ZIKV and DENV infection, showing an outstanding activity in the picomolar range.

Water as a solvent for Ru‐catalyzed click reaction: Highly efficient recyclable catalytic system for triazolocoumarins synthesis

A new family of Ru (III) complexes has been synthesized, characterized and their catalytic performance has been tested for alkyne–azide cycloaddition (AAC) in water under ultrasonic irradiation conditions. These complexes are found to be effective heterogeneous catalysts for the regioselective synthesis of 1,4‐disubstituted‐1,2,3‐triazoles giving access to these products in excellent yields. The catalyst system is equally active for one‐pot multi‐component protocol of the AAC reactions. Also, successive sequencing of Huisgen reaction with Knoevenagel condensation reaction results in the effective assembly of a diversified hitherto unreported 1,2,3‐triazolyl coumarin frameworks. In present strategy, the catalyst could be easily isolated by simple filtration and reused up to eight consecutive cycles without significant drop in the reaction yields. During the leaching experiment, there is no leaching amount of the catalyst was detected, suggesting true heterogeneity in the catalytic system. The results of gram‐scale reaction and green metrics calculations also confirmed the sustainability and industrial applicability of the current catalytic protocol.

Highly Efficient [3 + 2] Cycloaddition: Click Synthesis of Novel 1H‐indol‐3‐yl‐benzo[d]imidazole Bis‐triazoles

A series of novel 1‐((1H‐1,2,3‐triazol‐4‐yl)methyl)‐2‐(1‐((1H‐1,2,3‐triazol‐4‐yl)methyl)‐5‐substituted‐1H‐indol‐3‐yl)‐6‐substituted‐1H‐benzo[d]imidazoles 5a–i have been prepared using click chemistry as an ideal strategy where [3 + 2] cycloaddition of azides with terminal alkynes has been developed as the target compounds. In route‐II, 5‐substituted‐1H‐indole‐3‐carbaldehydes 1a–c react with 5‐substituted orthophenylenediamine 8 to give desired products, that is, 6‐substituted‐2‐(5‐substituted‐1H‐indol‐3‐yl)‐1H‐benzo[d]imidazole 6a–i. Here, 6a–i react with 2 equiv of propargylbromide 7 to give novel 6‐substituted 2‐(5‐substituted‐1‐(prop‐2‐yn‐1‐yl)‐1H‐indol‐3‐yl)‐1‐(prop‐2‐yn‐1‐yl)‐1H‐benzo[d]imidazole 4a–i. 4a–i were reacted with 2 equiv of NaN3 in t‐butanol/water (1:2) and add catalytic amount of CuSO4.5H2O. Stir the reaction mixture at room temperature to get the target products 5a–i. Here, obtained products contain four rings, that is, one indole, two triazoles, and one benzimidazole. The main advantages of this method are short reaction times, easy workup, higher yields (88–92%), and no by‐products formation.

Kinetic Study of the Polyaddition of Azide-Alkyne AB<sub>2</sub> Monomers in Nonisotermic Conditions

Nowadays, hyperbranched polymers (HBP) are obtained by different polycondensation and polyaddition reactions [1]. Almost interest is the reaction of 1,3-dipolar cycloaddition of azides to alkynes (1,3-DCA) [2, 3]. There is a series of papers dedicated to the preparation of triazine-triazole HBPs [4, 5, 6]. These polymers were obtained by the reaction of azido-acetylene AB2 monomers polyaddition: 2-azido-4,6-bis (propyne-2-yloxy) -1,3,5-triazine (ABPOT) and 2,4-diazido-6- (propine-2-yloxy) -1,3,5-triazine (DAPOT) (Fig. 1).

Development of carbohydrate functionalized magnetic nanoparticles for aminoglycosides magnetic solid phase extraction

Magnetic nanoparticles decorated with d-galactose and galactitol (Fe3O4@SiN-galactose and Fe3O4@SiN-galactitol) were synthesized and employed as sorbent in a magnetic solid phase extraction (MSPE) procedure prior the analysis of aminoglycosides (AGs) in honey samples by LC-MS/MS. AGs are broad spectrum antibiotics, characterized by aminosugars, widespread used in therapeutic and veterinary applications. AGs can be found in the environment and food of animal origin. Fe3O4@SiN-galactose and Fe3O4@SiN-galactitol were synthesized via copper catalyzed alkyne azide cycloaddition and the synthesis was efficiently followed by infrared spectroscopy. They were characterized by electron microscopy, thermogravimetric analysis and magnetization curves. The nature of the loading (acetonitrile:water, 50:50 v/v) and elution solution (formic acid 190 mM) were studied in order to optimize the MSPE. Quantitative difference between MSPE with Fe3O4@SiN-galactose and MSPE with Fe3O4@SiN-galactitol in terms of recovery was found. The final optimized method using Fe3O4@SiN-galactose and Fe3O4@SiN-galactitol was applied in the determination of AGs in honey. The MSPE performance of Fe3O4@SiN-galactitol was found to be superior to that of MSPE with Fe3O4@SiN-galactose. The limits of quantification were between 2 and 19 μg kg−1 for amikacin, dihydrostreptomycin, tobramicyn and gentamycin. A good correlation between predicted and nominal values of AGs in honey was found (trueness from 84% to 109%). This MSPE procedure not only requires a minimum amount of sorbent (1 mg) and sample (0.2 g), but it can also be accomplish in a rather short time.

Divergent synthesis of chiral cyclic azides via asymmetric cycloaddition reactions of vinyl azides

Vinyl azides, bearing conjugated azide and alkene functional groups, have been recognized as versatile building blocks in organic synthesis. In general vinyl azides act as 3-atom (CCN) synthons through the fast release of molecular nitrogen and have been extensively utilized in the construction of structurally diverse N-heterocycles. Keeping the azide moiety intact in organic transformations to synthesis chiral azides is an important but challenging task. Herein, we report an enantioselective copper(II)/BOX-catalyzed cycloaddition of vinyl azides, generating diverse chiral cyclic azides. α-Aryl substituted vinyl azides react with unsaturated keto esters through an inverse-electron-demand hetero-Diels-Alder reaction to afford chiral azido dihydropyrans with excellent enatioselectivities. In contrast, cyclohexenyl azides undergo a diastereo- and enantio-selective Diels-Alder reaction giving important azido octahydronaphthalenes with three continuous stereogenic centers. Notable features of these reactions include a very broad scope, mild reaction conditions and 100% atom economy.

Dibenzocyclooctynes: Effect of Aryl Substitution on Their Reactivity toward Strain-Promoted Alkyne-Azide Cycloaddition.

Five new dibenzocyclooctynes bearing different substituents on their aryl moieties were synthesized and evaluated for their reactivity toward strain-promoted alkyne-azide cycloaddition (SPAAC). The dinaphthylcyclooctynes proved to be poorly reactive with azides, and the formation of triazole required many days compared to a few hours for the other cyclooctynes. Fluoride atoms and methoxy groups were also introduced to the aryl rings, leading to more active compounds. Oxidation of the alcohol on the cyclooctyne ring also increased the reaction rates by 3.5- to 6-fold. 3,9-Difluoro-4,8-dimethoxy-dibenzocyclooctyne-1-one thus displayed a SPAAC kinetic rate of 3.5 M-1 s-1, which is one of the highest rates ever described. Furthermore, the dibenzocyclooctyn-1-one displayed fluorescence properties that have allowed their detection in the protozoan parasites Plasmodium falciparum and Trypanosoma brucei by microscopy imaging, proving that they can cross cell membranes and that they are stable enough in biological media.

Synthesis of (1,2,3-triazol-4-yl)methyl Phosphinates and (1,2,3-Triazol-4-yl)methyl Phosphates by Copper-Catalyzed Azide-Alkyne Cycloaddition.

An efficient and practical method was developed for the synthesis of new (1,2,3-triazol-4-yl)methyl phosphinates and (1,2,3-triazol-4-yl)methyl phosphates by the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) of organic azides and prop-2-ynyl phosphinate or prop-2-ynyl phosphate. The synthesis of (1-benzyl-1H-1,2,3-triazol-4-yl)methyl diphenylphosphinate was optimized with respect to the reaction parameters, such as the temperature, reaction time, and catalyst loading. The approach was applied to a range of organic azides, which confirmed the wide scope and the substituent tolerance of the process. The method elaborated represents a novel approach for the synthesis of the target compounds.

Synthesis of 5‐Carboxamidotriazoles via Azide‐Alkyne Cycloaddition–Aminocarbonylation Sequence

Abstract5‐Carboxamidotriazoles were prepared in the palladium‐catalyzed aminocarbonylation of the corresponding iodotriazole using various amines as N‐nucleophiles under mild reaction conditions. The iodoheteroarene substrates were obtained in good yields in copper‐catalysed azide‐alkyne cycloaddition of iodoalkynes (2′‐iodophenylacetylene and ethyl iodopropiolate) and benzyl azide.

Copper-Catalyzed Alkyne–Azide Cycloaddition by Kinetic Resolution

Copper-Catalyzed Alkyne–Azide Cycloaddition by Kinetic Resolution

NHC copper complexes functionalized with sulfoxide and sulfone moieties

A series of N‐heterocyclic copper carbene complexes bearing sulfoxide and sulfone moieties have been prepared. In case of new copper compounds with sulfone ligand, the solid‐state structures were determined using X‐Ray crystallography. Obtained complexes were investigated as catalysts in such transformations as: 1,3‐dipolar cycloaddition of alkynes and azides (CuAAC), A3 coupling reaction and β‐hydroboration and compared with standard copper catalytic systems.

Amplified Photoacoustic Imaging of Tumor through In Situ Cycloaddition

AbstractPhotoacoustic (PA) imaging has received great attention in the field of biomedical applications due to the combination advantages of the high contrast of optical imaging and the high spatial resolution of ultrasound. The limited targeting property of PA contrast agents is restricted to elaborate its advantage. To overcome this point, a pretargeting strategy is developed to amplify the targeting property and PA imaging of a model dye in vivo. As a proof of concept, the dibenzyl cyclootyne (DBCO)‐modified Fe@Fe3O4 nanoparticles (NPs) (Fe@Fe3O4/DBCO) and azide‐modified Cy7.5 (Cy7.5‐N3) are adopted as the pretargeting and PA contrast agents, respectively. Fe@Fe3O4/DBCO NPs are first targeted into tumors by the enhanced permeability and retention effect, and then Cy7.5‐N3 is conjugated to the pretargeted Fe@Fe3O4/DBCO labeled tumor cells via strain‐promoted alkyne azide cycloaddition reaction after intravenous injection, which results in an obvious increase of the accumulated dose and PA signal of Cy7.5 in tumor, and simultaneously extends its residence time. This signal amplification strategy should have an important guiding significance for the clinical application in cancer theranostics.

Synthesis and properties of a P3HT-based ABA triblock copolymer containing a perfluoropolyether central segment

A poly(3-hexylthiophene)-block-perfluoropolyether-block-poly(3-hexylthiophene) (P3HT-b-PFPE-b-P3HT) triblock copolymer was synthesized by copper(I)-catalyzed alkyne–azide cycloaddition (CuAAC) in 95% yield. The copolymer was unequivocally characterized by size exclusion chromatography reaching 27 000 g mol−1 and nuclear magnetic resonance (NMR). As expected, diffusion-ordered spectroscopy NMR experiment revealed a lower diffusion coefficient (2.56 × 10-10 m2 s−1) for the P3HT-b-PFPE-b-P3HT triblock copolymer than the ethynyl end-functionalized P3HT (2.83 × 10-10 m2 s−1). Such a triblock copolymer exhibits i) a good thermal stability with no significant weight loss until 320 °C under air, ii) a glass transition of -50 °C due to the soft PFPE segment and iii) a melting peak arising from P3HT at 236 °C. The UV–vis absorption spectrum exhibits a similar absorption profile to that of pure P3HT with a vibronic structure. Analysis of terpolymer thin films by atomic force microscopy imaging and grazing incidence wide-angle X-ray scattering reveals the formation of P3HT crystallites and an “edge-on” orientation of the polymer chains towards the substrate. Preliminary photovoltaic studies on blends of this triblock copolymer combined with a fullerene derivative indicate that the devices using P3HT-b-PFPE-b-P3HT show an almost similar power conversion efficiency to commercial P3HT.

Ag2CO3-catalyzed cycloaddition of organic azides onto terminal alkynes: A green and sustainable protocol accelerated by aqueous micelles of CPyCl

Using catalytic amount of Ag2CO3 a simple, efficient and copper free green protocol has been developed to synthesize 1,4-disubstituted 1,2,3-triazoles regioselectively. Here, the cationic surfactant, cetylpyridinium chloride (CPyCl) in water provides a micellar media and accelerates the subsequent Ag(I)-catalysed azide-alkyne cycloaddition (AgAAC) reaction by increasing the concentration of reactants in the micellar pseudophase. Our method is found to be environmentally friendly from E-factor measurement. The surfactant, CPyCl is found to be nontoxic.