Click Chemistry Approach Research Articles

A Library of Multipurpose Supramolecular Supergelators: Fabrication of Structured Silica, Porous Plastics, and Fluorescent Gels.

Supramolecular gels find applications in various fields. Usually, a specific gelator is useful only for a specific application. This one-gelator-one-application format is one factor that limits the usefulness of supramolecular gels. We report the synthesis of a library of gelators from a common core by using a click-chemistry approach. Thus, the click reaction of β-azido-4,6-O-benzylidene-galactopyranoside (1) with various alkynes gave 11 different gelators having varying gelation abilities. Whereas gelators having alkyl-chain substituents congealed alkanes and tetraethylorthosilicate (TEOS), the gelators having aromatic substituents congealed aromatic solvents. We exploited this difference in gelling behavior in the templated synthesis of silica rods and porous plastics. The styrene gel of gelator 2 j was polymerized, and the gelator was removed by washing to obtain porous polystyrene. The TEOS gel of gelator 2 b was polymerized to silica, and the gelator template was removed by calcination to give microstructured silica rods. We also developed fluorescent gelator 2 f by this method, which might find applications by virtue of its fluorescence in the assembled state.

Boron-containing phenolic–siloxane hybrid polymers through facile click chemistry route

Realization of easily processable, tough phenolic functional polymer materials is of high demand for composite applications. Herein, we report the synthesis of boron-containing phenolic–siloxane hybrid polymers through a facile copper-catalysed azide–alkyne click chemistry (CuAAC) approach. For this, phenolic resoles incorporated with boron (PFB) was propargyl-derivatized and then bridged through triazole moieties using telechelic α, ω azidated polydimethylsiloxane (AZ-PDMS). The propargylated boronated PF (PFBPr) resins exhibited high heat of reaction during thermal cure due to the prevalence of multiple reactions. PFBPr-siloxane hybrid co-polymers exhibited glass transitions in the ranges – 100 to – 75 °C and at 25–35 °C corresponding to soft segment and hard segments. Pyrolysed PFBPr-siloxane products showed mixed phase heterogeneous systems of B and SiC. Introduction of boron and silicon improved the degree of graphitization and reduced the graphite crystallite size of the carbonization products. The pyrolysed compounds of silicon and boron formed during high temperature were conducive for creating a layer of void-free graphitic ordered carbon that improved with boron and silicon content, as revealed by SEM images.

Synthesis and antimicrobial activity of triazolyl analogs of diosgenin

Novel and diverse triazoles of steroidal sapogenin-diosgenin were prepared using click chemistry approach. All the derivatives were subjected to antimicrobial screening to check their antibacterial and antifungal potential. All the tested analogs were inactive towards the tested bacterial strains, while as, some analogs displayed better activity towards the tested fungal strains. Of the synthesized analogs, Dgn-3 and Dgn-6 exhibited antifungal activity against Candida albicans with MICs of 12 and 16 µg/ml respectively, while as, Dgn-8 and Dgn-9 showed potency towards both the tested fungal strains: Candida albicans and Aspergillus fumigatus. The other derivatives showed almost comparable activity with that of the parent molecule. The structure-activity relationship (SAR) revealed that the analogs with electron withdrawing substituents (-NO2 and -CN) at meta position in R moieties along with analogs bearing bromo substituted R moieties seem to have beneficial impact on the antifungal activity.

Click functionalization of magnetite nanoparticles: A new magnetically recoverable catalyst for the selective epoxidation of olefins

A new magnetically recoverable heterogeneous molybdenum catalyst was developed by means of a click chemistry approach. First, silica‐coated magnetite nanoparticles were functionalized using a bidentate ligand via thiol–ene click reaction of mercaptopropyl‐modified magnetite nanoparticles with acrylic acid. Then, a molybdenum complex was covalently supported on the surface of the clicked silica‐coated magnetite nanoparticles. The prepared catalyst was characterized using Fourier transform infrared and inductively coupled plasma optical emission spectroscopies, X‐ray diffraction, vibrating sample magnetometry and transmission electron microscopy. The catalytic performance of the prepared heterogeneous catalyst was investigated in the epoxidation of olefins with tert‐butyl hydroperoxide as oxidant. This catalyst could be reused for five runs without significant loss of activity and selectivity.

Synthesis and antimicrobial screening of novel 9-{2-[(1H-1,2,3-triazol-4-yl)methoxy]phenyl}-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione derivatives

A series of novel 9-{2-[(1H-1,2,3-triazol-4-yl)methoxy]phenyl}-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione derivatives were synthesized by a click chemistry approach. The structures of all the newly synthesized compounds were characterized by IR, MASS, 1H and 13C NMR spectral data. The final analogues showed good to excellent antibacterial and antifungal activities in an agar well diffusion assay. Compounds 6i and 6f were the most active against all the test bacterial and fungal strains.

Expeditious microwave-assisted synthesis and bio-evaluation of novel bis (trifluoromethyl) phenyl-triazole-pyridine hybrid analogues by the click chemistry approach

A series of novel 1,2,3-triazole-2,4-bis(trifluoromethyl) phenyl pyridine hybrids 7a–n were efficiently synthesized by the click chemistry approach. The precursor 6-(3,5-bis(trifluoromethyl)phenyl)pyridin-3-ol 3 was obtained by palladium catalyzed cross coupling between 6-bromo-3-pyridinol (2) and (3,5-bis (trifluoromethyl) phenyl) boronic acid (1) in a microwave under nitrogen conditions, which was further alkylated with propargyl bromide 4 in DMF in the presence of K2CO3 and a catalytic amount of TBAI to get 5. All products obtained in each step were well characterized by various spectral studies and found consistent with expected structure. The triazole derivatives 7a–n were evaluated against human bacterial pathogens, namely, Escherichia coli, Salmonella typhimurium and Staphylococcus aureus and fungal strains Aspergillus niger, Fusarium solani and Penicillium notatum for in vitro activity. Among them, 7e and 7m emerged as potential compounds comparable with the standard drug Ciprofloxacin against tested bacteria, and it is worthwhile to notice that compound 7k emerged more potent than the standard Griseofulvin against fungi.

Triazole tethered isatin-coumarin based molecular hybrids as novel antitubulin agents: Design, synthesis, biological investigation and docking studies

In an attempt to develop potent anti-tubulin agents against most dreadful disease cancer, a library of 28 novel triazole tethered isatin-coumarin hybrids were synthesized by click chemistry approach. Synthesized hybrids were characterized and evaluated against a panel of human cancer cell lines viz. THP-1, COLO-205, HCT-116 and PC-3. Biological assay unveiled that, compounds A-1 to A-6, B-1 to B-4 and C-1 to C-3 displayed significant inhibitory potential against THP-1, COLO-205 and HCT-116 cell lines which were more sensitive towards the designed hybrids. PC-3 among these cell lines was found to be almost resistant. Established SAR revealed marked dependence of the cytotoxic activity on the type of substituent on isatin and the length of carbon-bridge connecting isatin moiety with triazole ring. Unsubstituted isatin and two carbon-bridge were found to be crucial for cytotoxicity. Three most potent hybrids (A-1, A-2 and B-1) were further tested for tubulin polymerization inhibition. Among these three compounds, A-1 found to be endowed with most prominent tubulin polymerization inhibition potential with IC50 value of 1.06µM which was further confirmed by using confocal microscopy. Possible binding interactions between the most potent hybrid molecule A-1 and tubulin were also divulged by molecular modeling studies.

Auric Chloride Induced Micellization on Fractal Patterned Dicationic Amphiphiles and Stabilization of Gold Nanoparticles.

The present article reports the development of sunlight-mediated rapid synthesis of bile acid derived dicationic amphiphiles, namely, dicationic cysteamine-conjugated cholic acid (DCaC), dicationic cysteamine-conjugated deoxycholic acid (DCaDC), and dicationic cysteamine-conjugated lithocholic acid (DCaLC) by adopting thiol–yne click chemistry approach. The auric chloride (AuHCl4) induced micellization of amphiphiles from fractal pattern to chainlike aggregates was examined by critical micelle concentration measurements, quenching studies, field emission scanning electron microscopy, and optical microscopy techniques. The micelles thus formed act as ideal templates for the stabilization of gold nanoparticles (AuNPs) and exhibit good stability for more than 6 months. The synthesized AuNPs were characterized using UV–visible spectroscopy, high-resolution transmission electron microscopy, DLS, zeta potential, and contact angle measurements. These NPs showed high salt tolerance, and the levels were found to be 420, 460, and 580 mM for DCaC-, DCaDC-, and DCaLC-capped AuNPs, respectively.

Clicked graphene oxide supported venturello catalyst: A new hybrid nanomaterial as catalyst for the selective epoxidation of olefins

A new peroxopolyoxotungstate-graphene oxide hybrid nanomaterial was developed by means of click chemistry approach. Graphene oxide (GO) was modified by cysteamine hydrochloride as linking agent via thiol-ene click reaction. Then, Venturello anion, {PO4·[WO2(O2)2]4}3-, was supported on the surface of clicked graphene oxide through the electrostatic interaction with ammonium groups. The prepared material was characterized by Fourier transform infrared (FT-IR) and inductively coupled plasma-optical emission spectroscopies (ICP-OES), X-ray diffraction (XRD), N2 adsorption–desorption analysis, transmission electron microscopy (TEM), and thermogravimetric (TGA-DTA) analyses. ICP-OES analysis showed 0.041 mmol g−1 of peroxopolyoxotungstate in the hybrid nanomaterial. The catalytic performance and turnover frequencies (TOFs) of the prepared hybrid nanomaterials as heterogeneous catalyst were investigated in the epoxidation of olefins and allylic alcohols with H2O2 as oxidant. This catalyst could be reused for five runs without significant loss of the activity and stability.

Abstract 2864: Tumor targeting and imaging using 64Cu labeled cyclic RGD conjugated human serum albumin via click chemistry

Abstract PURPOSE: The RGD specifically recognizes the integrin αvβ3 which is overexpressed on various malignant tumors. One major drawback of small peptide such as RGD, however, is short half-life in the blood, which greatly compromises their targeting efficacy. To improve blood circulation time and targeting efficacy, we developed cyclic RGDyK (cRGDyK) conjugated human serum albumin (HSA) using click chemistry reaction. METHODS: HSA was conjugated with DBCO-NHS (dibenzyl cyclooctyne) under physiologically favorable reaction condition for the preparation of strain promoted azide-alkyne reaction. Using this reaction group, DBCO-HSA was conjugated with N3-c RGDyK (azido cRGDyK) for integrin αvβ3 targeting, N3-FNR648 for fluorescence labeling and 64Cu labeled N3-NOTA (3-azidopropyl-NOTA) for radiolabeling. Cell binding of cRGDyK-HSA were analyzed with FNR648 labeled probes. Cellular uptake of 64Cu-cRGDyK-HSA were tested for integrin αvβ3 specific binding at cell level. PET images were acquired after tail vein injection of 64Cu-HSA, 64Cu-cRGDyK-HSA in integrin αvβ3 positive tumor (SK-OV3, ovarian cancer cell line) bearing BALB/c nude mice. PET signals were quantitatively analyzed with PET image analysis program, AMIDE. RESULTS: The number of cRGDyK on DBCO-HSA conjugates was confirmed using MALDI-TOF MS. cRGDyK-HSA was successfully conjugated with 64Cu labeled N3-NOTA. Integrin αvβ3 mRNA and protein was highly expressed in SK-OV3 cell line. At fluorescence labeled probes were treated in SK-OV3, cRGDyK-HSA were highly bound to cell membrane and this pattern were decreased with pre-treatment of excess cRGDyK. When compared to cellular uptake level, 64Cu-cRGDyK-HSA were more accumulated at integrin αvβ3 positive cells (SK-OV3) than integrin αvβ3 negative cells (P < 0.05) and there were no difference in 64Cu-HSA. Serial PET images were acquired 0, 4, 24, 48 hours after tail vein injection of 64Cu-cRGDyK-HSA. Radioactivity of 64Cu-cRGDyK-HSA in SK-OV3 tumor was higher than that of 64Cu-HSA. 64Cu-labeled-cRGDyK-HSA can be observed at 48 hours after injection, which shows longer circulation time in mice. CONCLUSION: We successfully conjugated cyclic RGDyK to HSA using click chemistry approach. We demonstrated that cRGDyK-HSA specifically bind to integrin αvβ3 in in vitro and in vivo model. And in animal model, 64Cu-labeled-cRGDyK-HSA can be observed at 48 hours after injection, which shows longer circulation time. Our results indicated that cRGDyK-HSA have a potential to diagnosis and therapy response monitoring of tumor expressing integrin αvβ3. Citation Format: Cho Rong Park, Myung Geun Song, Ji-Yong Park, Hyewon Youn, June-Key Chung, Jae Min Jeong, Yun-Sang Lee, Keon Wook Kang. Tumor targeting and imaging using 64Cu labeled cyclic RGD conjugated human serum albumin via click chemistry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2864. doi:10.1158/1538-7445.AM2017-2864

Molecular recognition of a carboxy pyridostatin toward G-quadruplex structures: Why does it prefer RNA?

The pyridostatin (PDS) represents the lead compound of a family of G-quadruplex (G4) stabilizing synthetic small molecules based on a N,N'-bis(quinolinyl)pyridine-2,6-dicarboxamide scaffold. Its mechanism of action involves the induction of telomere dysfunction by competing for binding with telomere-associated proteins, such as human POT1. Recently, through a template-directed "in situ" click chemistry approach, a PDS derivative, the carboxypyridostatin (cPDS), was discovered. It has the peculiarity to exhibit high molecular specificity for RNA over DNA G4, while PDS is a good generic RNA and DNA G4-interacting small molecule. Structural data on the binding modes of these compounds are not available, and the selectivity mode of cPDS toward TERRA G4 is unknown too. Therefore, this work is aimed at rationalizing the selectivity of cPDS versus TERRA G4 by means of molecular dynamics and docking simulations, coupled to better understand the binding mode of these compounds to telomeric G4 structures. The comprehensive analysis of cPDS binding mode and its conformational behavior demonstrates the importance of the ligand conformation properties coupled with a remarkable solvation contribution. This work is expected to provide valuable clues for further rational design of novel and selective TERRA G4 binders.

Conjugation of hemin to G-quadruplex forming oligonucleotide using click chemistry

Peroxidase-mimicking DNAzyme is one of the systems that recently gained a great interest. It has been successfully applied for designing numerous bioassays. The success of this system is connected to its advantages over a protein enzyme, horseradish peroxidase. Promising strategy for further improvement of performance of DNAzyme with peroxidase-like activity was proposed recently. It was based on the covalent attachment of hemin moiety to the G-quadruplex scaffold. We report here the first attempt of conjugating hemin to the G-quadruplex DNA using click chemistry approach. We modified hemin molecule through attachment of an azide-terminated linker to the porphyrin carboxylic group. Two click chemistry approaches were examined to conjugate the azide-modified hemin to a G-quadruplex oligonucleotide: copper-catalyzed and Cu-free cycloaddition reactions. Using Cu-free click reaction, we successfully synthesized G-quadruplex-hemin conjugate that exhibited promising peroxidase activity.

1-(4-(6-Fluorobenzo [d] isoxazol-3-yl) piperidin-1-yl)-2-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl) ethanone: Synthesis, spectroscopic characterization, Hirshfeld surface analysis, cytotoxic studies and docking studies

Compound 1-(4-(6-fluorobenzo[d] isoxazol-3-yl) piperidin-1-yl)-2-(4-(hydroxymethyl)-1H-1, 2,3-triazol-1-yl) ethanone was synthesized in good yield by using click chemistry approach with 2-azido-1-(4-(6-flurobenzo[d]isooxazol-3-yl)piperidin-1-yl)ethanone as a starting material. The synthesized compound was characterized using IR, NMR and MS studies. Thermal stability of the compound was analyzed by using TGA and DSC technique. The single crystal XRD analysis was taken part, to confirm the structure of the compound. The intercontacts in the crystal structure are analyzed using Hirshfeld surfaces computational method. Cytotoxicity of the synthesized compound was evaluated and the results were reported. The binding analysis carried out between the newly synthesized molecule with human serum albumin using fluorescence spectroscopy technique to understand the pharmacokinetics nature of the compound for further biological application. The molecular docking studies were evaluated for the compound to elucidate insights of new molecules in carrier protein.

Click-PEGylation – A mobility shift approach to assess the redox state of cysteines in candidate proteins

The redox state of cysteine thiols is critical for protein function. Whereas cysteines play an important role in the maintenance of protein structure through the formation of internal disulfides, their nucleophilic thiol groups can become oxidatively modified in response to diverse redox challenges and thereby function in signalling and antioxidant defences. These oxidative modifications occur in response to a range of agents and stimuli, and can lead to the existence of multiple redox states for a given protein. To assess the role(s) of a protein in redox signalling and antioxidant defence, it is thus vital to be able to assess which of the multiple thiol redox states are present and to investigate how these alter under different conditions. While this can be done by a range of mass spectrometric-based methods, these are time-consuming, costly, and best suited to study abundant proteins or to perform an unbiased proteomic screen. One approach that can facilitate a targeted assessment of candidate proteins, as well as proteins that are low in abundance or proteomically challenging, is by electrophoretic mobility shift assays. Redox-modified cysteine residues are selectively tagged with a large group, such as a polyethylene glycol (PEG) polymer, and then the proteins are separated by electrophoresis followed by immunoblotting, which allows the inference of redox changes based on band shifts. However, the applicability of this method has been impaired by the difficulty of cleanly modifying protein thiols by large PEG reagents. To establish a more robust method for redox-selective PEGylation, we have utilised a Click chemistry approach, where free thiol groups are first labelled with a reagent modified to contain an alkyne moiety, which is subsequently Click-reacted with a PEG molecule containing a complementary azide function. This strategy can be adapted to study reversibly reduced or oxidised cysteines. Separation of the thiol labelling step from the PEG conjugation greatly facilitates the fidelity and flexibility of this approach. Here we show how the Click-PEGylation technique can be used to interrogate the redox state of proteins.

Click chemistry approach for the regioselective synthesis of iso-indoline-1,3-dione-linked 1,4 and 1,5 coumarinyl 1,2,3-triazoles and their photophysical properties

ABSTRACTCopper-catalyzed reaction of N-propargyl isoindoline-1,3-dione and 4-azidomethyl coumarins / 4-azidomethyl-1-aza coumarins under click chemistry conditions afforded 1,4-disubstituted 1,2,3-triazoles, whereas ruthenium catalysis yielded isomeric 1,5-disubstituted 1,2,3-triazoles. The two regioisomers have been distinguished by NOE studies. UV absorption for a given pair of isomers exhibited similar trend, whereas fluorescence measurements showed considerable differences. Photo physical studies on the interaction of azides with copper and ruthenium have also been performed.

Click-chemistry approach to study mycoloylated proteins: Evidence for PorB and PorC porins mycoloylation in Corynebacterium glutamicum.

Protein mycoloylation is a recently identified, new form of protein acylation. This post-translational modification consists in the covalent attachment of mycolic acids residues to serine. Mycolic acids are long chain, α-branched, β-hydroxylated fatty acids that are exclusively found in the cell envelope of Corynebacteriales, a bacterial order that includes important genera such as Mycobacterium, Nocardia or Corynebacterium. So far, only 3 mycoloylated proteins have been identified: PorA, PorH and ProtX from C. glutamicum. Whereas the identity and function of ProtX is unknown, PorH and PorA associate to form a membrane channel, the activity of which is dependent upon PorA mycoloylation. However, the exact role of mycoloylation and the generality of this phenomenon are still unknown. In particular, the identity of other mycoloylated proteins, if any, needs to be determined together with establishing whether such modification occurs in Corynebacteriales genera other than Corynebacterium. Here, we tested whether a metabolic labeling and click-chemistry approach could be used to detect mycoloylated proteins. Using a fatty acid alkyne analogue, we could indeed label PorA, PorH and ProtX and determine ProtX mycoloylation site. Importantly, we also show that two other porins from C. glutamicum, PorB and PorC are mycoloylated.

Synthesis and antimicrobial activity of some novel benzofuran based 1,2,3-triazoles

In the present study, a series of novel {6-[(1H-1,2,3-triazol-4-yl)methoxy]-3-methylbenzofuran-2-yl}(phenyl)methanones (7a–7o) have been synthesized using click chemistry approach. The structures of all newly synthesized compounds were characterized by FT-IR, 1H and 13C NMR, and MASS spectral data. Most of products demonstrated high antimicrobial activity.

Synthesis and anti-inflammatory activity of novel triazole hybrids of (+)-usnic acid, the major dibenzofuran metabolite of the lichen Usnea longissima.

(+)-Usnic acid ((R)-2,6-diacetyl-7,9-dihydroxy-8,9b-dimethyl-1,3(2H,9bH)-dibenzo-furandione), a dibenzofuran isolated from the lichen Usnea longissima, has been chemically transformed to synthesize a series of sixteen novel triazole analogs by click chemistry approach. The synthesized compounds were tested for their anti-inflammatory potential against the cytokines TNF-[Formula: see text] and IL-1[Formula: see text] in U937 cell lines. The bromo enamines (2a, 2b), azido enamines (3a, 3b) and triazole analogs (4f, 4g, 4h, 5f, 5g and 5h) exhibited promising anti-inflammatory activity against TNF-[Formula: see text] with [Formula: see text] values ranging from 1.40 to 5.70 [Formula: see text]M. Most significantly, the [Formula: see text] values of compounds 5f (1.40 [Formula: see text]M) and 5h (1.88 [Formula: see text]M) are the lowest among the compounds tested and found close to that of standard prednisolone. Hence, these two compounds can be considered as lead molecules for further fine tuning to make highly potent anti-inflammatory therapeutic agents.

Synthesis and biological evaluation of novel 7-hydroxy-4-phenylchromen-2-one–linked to triazole moieties as potent cytotoxic agents

A new series of novel 7-hydroxy-4-phenylchromen-2-one (1a)–linked 1,2,4-triazoles were synthesised using a click chemistry approach. All derivatives were subjected to 3-(4,5-dimethylthiazol-yl)-diphenyl tetrazolium bromide (MTT) cytotoxicity screening against a panel of six different human cancer cell lines (AGS, MGC-803, HCT-116, A-549, HepG2, and HeLa) to assess their cytotoxic potential. Among the tested molecules, some of the analogues showed better cytotoxic activity than that shown by the 7-hydroxy-4-phenylchromen-2-one (1a). Of the synthesised 1,2,4-triazoles,the 7-((4-(4-Chlorophenyl)-4H-1,2,4-triazol-3-yl)methoxy)-4-phenyl-2H-chromen-2-one (4d) showed the best activity, with an IC50 of 2.63 ± 0.17 µM against AGS cells. Further flow cytometry assays demonstrated that compound 4d exerts its antiproliferative effects by arresting cells in the G2/M phase of the cell cycle and by inducing apoptosis. Collectively, our results indicate that the 1,2,4-triazole derivatives have a significantly stronger antitumour activity than 1,2,3-triazole derivatives. Most of the compounds exhibited better antitumour activity than the positive control drug 5-fluorouracil.

Synthesis, photophysical and electrochemical properties and DSSC applications of triphenylamine chalcone dendrimers via click chemistry

Fluorene-cored dendrimers containing a triphenylamine chalcone unit at the periphery have been synthesized by click chemistry approach, and their photophysical and electrochemical properties have been investigated.