Click Strategy Research Articles

Synthesis of Tetravalent Thio- and Selenogalactoside-Presenting Galactoclusters and Their Interactions with Bacterial Lectin PA-IL from Pseudomonas aeruginosa.

Synthesis of tetravalent thio- and selenogalactopyranoside-containing glycoclusters using azide-alkyne click strategy is presented. Prepared compounds are potential ligands of Pseudomonas aeruginosa lectin PA-IL. P. aeruginosa is an opportunistic human pathogen associated with cystic fibrosis, and PA-IL is one of its virulence factors. The interactions of PA-IL and tetravalent glycoconjugates were investigated using hemagglutination inhibition assay and compared with mono- and divalent galactosides (propargyl 1-thio- and 1-seleno-β-d-galactopyranoside, digalactosyl diselenide and digalactosyl disulfide). The lectin-carbohydrate interactions were also studied by saturation transfer difference NMR technique. Both thio- and seleno-tetravalent glycoconjugates were able to inhibit PA-IL significantly better than simple d-galactose or their intermediate compounds from the synthesis.

Customer perception and expectations towards the services of organised retail outlets: an empirical study in the twin cities of Hyderabad and Secunderabad - a review

Retailing is vending unswervingly to the end users for their personal use, offline and online modes that is brick and click strategies are used to have a better space felt in the market. The service expectations of the customers help in development and sustainable growth, therefore understanding the buying behaviour paradigms has become necessity of the marketer for its survival. Customer expectations are based on how the customers do selective attention, distortion and retention, for perceptions. Retail store services depend on various factors; in this paper the researcher has tried to identify these. The FDI policy has increased the competition for the local market and opened a new door to the global marketers, simultaneously changing the buying pattern, opening better service options and service providers. Customer takes the product for trial, repeat it if they like and gets delighted when they are satisfied, the findings of this study provide important guidelines for framing marketing strategies and identifying factors to get the word WOW from the customer. Emerging as the most dynamic and fast paced expected to reach US$120 billion by 2020.

“Thiol–ene” click synthesis of chiral covalent organic frameworks for gas chromatography

A facile “thiol–ene” click strategy was reported to construct novel chiral COFs for gas chromatographic separation.

Further Insights on Structural Modifications of Muramyl Dipeptides to Study the Human NOD2 Stimulating Activity.

A series of muramyl dipeptide (MDP) analogues with structural modifications at the C4 position of MurNAc and on the d-iso-glutamine (isoGln) residue of the peptide part were synthesized. The C4-diversification of MurNAc was conveniently achieved by using CuAAC click strategy to conjugate an azido muramyl dipeptide precursor with structurally diverse alkynes. d-Glutamic acid (Glu), replaced with isoGln, was applied for the structural diversity through esterification or amidation of the carboxylic acid. In total, 26 MDP analogues were synthesized and bio-evaluated for the study of human NOD2 stimulation activity in the innate immune response. Interestingly, MDP derivatives with an ester moiety are found to be more potent than reference compound MDP itself or MDP analogues containing an amide moiety. Among the varied lengths of the alkyl chain in ester derivatives, the MDP analogue bearing the d-glutamate dodecyl (C12) ester moiety showed the best NOD2 stimulation potency.

Synthesis and antiproliferative activity of Daidzein bridged bis-[1,2,3]-triazole derivatives: Double click strategy

A series of unsymmetrical bis-[1,2,3]-triazole-daidzein hybrid derivatives have been synthesized from natural isoflavone, Diadzein through terminal alkyne tethered intermediate using double click strategy, Cu(I) catalyzed azide-alkyne 1,3-dipolar cycloaddition. All the synthesized derivatives were evaluated for their in vitro anti-proliferative activity against three human cancer cell lines A549 (lung), HeLa (cervical), and MDA-MB-231 (breast). Among the tested thirteen hybrid compounds, 5d, e, g, h, i, j, k, l and m derivatives showed potent anti-proliferative activity with GI 50 values range of 0.14 (>) 0.88 μM against all the three cancer cell lines, particularly compounds 5j and k showed significant activity against HeLa and MDA-MB-231 cell lines and compounds 5d, e and i showed selective potency against A549 cancer cell line. The test results revealed that the compound 5l has very close GI 50 value 0.14 μM as compared with positive control, Nocodazole reference, against breast cancer cell line (MDA-MB-231), it could be further optimized to develop promising future anticancer drug candidate.

Thiol-yne Click Post-Modification for the Synthesis of Chiral Microporous Organic Networks for Chiral Gas Chromatography.

Microporous organic networks (MONs) have shown great potential in diverse domains recently. However, the application of MONs in chiral separation or catalysis has been largely lagged due to the lack of chiral MONs and the challenge to synthesize chiral MONs. Here we report a facile thiol-yne click strategy to post-synthesize chiral MONs for the first application in chiral gas chromatography. Three chiral MONs with different chiral centers were rationally designed and synthesized to fabricate their capillary columns for gas chromatographic resolution of various chiral compounds with better resolution than three commercial chiral capillary columns. These results show the great potential of the thiol-yne click strategy for constructing newly chiral MONs and their application in chiral separation.

Strategies for conjugating iridium(III) anticancer complexes to targeting peptides via copper-free click chemistry

We report the synthesis and characterization of novel pentamethylcyclopentadienyl (Cp*) iridium(III) complexes [(Cp*)Ir(4-methyl-4′-carboxy-2,2′-bipyridine)Cl]PF6 (Ir-I), the product (Ir-II) from amide coupling of Ir-I to dibenzocyclooctyne-amine, and its conjugate (Ir-CP) with the cyclic nona-peptide c(CRWYDENAC). The familiar three-legged ‘piano-stool’ configuration for complex Ir-I was confirmed by its single crystal X-ray structure. Significantly, copper-free click strategy has been developed for site-specific conjugation of the parent complex Ir-I to the tumour targeting nona-cyclic peptide. The approach consisted of two steps: (i) the carboxylic acid group of the bipyridine ligand in complex Ir-I was first attached to an amine functionalized dibenzocyclooctyne group via amide formation to generate complex Ir-II; and (ii) the alkyne bond of dibenzocyclooctyne in complex Ir-II underwent a subsequent strain-promoted copper-free cycloaddition with the azide group of the modified peptide. Interestingly, while complex Ir-I was inactive towards A2780 human ovarian cancer cells, complex Ir-II exhibited moderate cytotoxic activity. Targeted complexes such as Ir-CP offer scope for enhanced activity and selectivity of this class of anticancer complexes.

Thiol-Ene Click Synthesis of Phenylboronic Acid-Functionalized Covalent Organic Framework for Selective Catechol Removal from Aqueous Medium.

We report a thiol-ene click strategy for the preparation of a novel phenylboronic acid-functionalized covalent organic framework (COF) for selective removal of catechol in aqueous solution. Vinyl-functionalized 2,5-diallyloxyterephthalaldehyde (Da-V) was prepared as a building ligand. Da-V was then condensed with 1,3,5-tris(4-aminophenyl)benzene (Tab) to give a vinyl-functionalized COF DhaTab-V. Subsequently, 4-mercaptophenylboronic acid (4-MPBA) was covalently linked on DhaTab-V via thiol-ene click reaction to give phenylboronic acid-functionalized COF DhaTab-PBA. The adsorption isotherms, energetics and kinetics, and reusability of DhaTab-PBA for the adsorption and removal of catechol from aqueous solution were investigated in detail. This phenylboronic acid-functionalized COF is promising as sorbent for selective removal of catechol from aqueous medium with large adsorption capacity and good reusability.

Click multiwalled carbon nanotubes: A novel method for preparation of carboxyl groups functionalized carbon quantum dots.

As potential alternatives to conventional semiconductor quantum dots, fluorescent carbon quantum dots (CQDs) have received increasing research attention in biomedical fields owing to their splendid advantages of low cytotoxicity, strong fluorescence and excellent water dispersion. However, the preparation procedures of CQDs with designable chemical properties and functions are complicated and low efficient. In this work, we developed a facile, economical and straightforward strategy to prepare CQDs by a one-step thiol-ene click reaction between multiwalled carbon nanotubes (CNTs) and thiomalic acid (TA). The successful synthesis of CQDs was confirmed by a series of characterization data. The results manifested that CQDs were well combined with TA through surface thiol-ene click chemistry. In addition, the optical property is also desirable, the maximum emission wavelength was located in 500 nm and CQDs still could emit strong blue fluorescent light after irradiation with UV irradiation for 3 h. Besides, the pH value makes no significant changes for fluorescence emission wavelength of CQDs and CQDs can emit strongest fluorescence in weak acid solution. Furthermore, CQDs could be internalized by cells and show great cell dyeing performance and low cytotoxicity. All these features imply that TA functionalized CQDs possess great potential for biological imaging. The one-step thiol-ene click strategy provided a novel tool to prepare functionalized CQDs with great potential for biomedical applications.

Synthesis, Molecular Modeling, and Antiviral Activity of Novel Triazole Nucleosides and Their Analogs

Two new pharmacophoric models incorporating 1,2,3-triazole glycosides have been synthesized in good yields via 1,3-dipolar cycloaddition reaction based on the click strategy. Copper catalyzed click dipolar cycloaddition of the acetylenic centers with azido compounds leads to the targeted compounds. Docking of the designed structures into Influenza virus neuraminidase (NA) active site is studied. Three molecular structures exhibit good fitting inside the binding site of the protein molecule. Antiviral activity against H5N1 avian influenza virus strain A/Egypt/M7217B/2013 is tested, and a number of compounds demonstrate high inhibition activity.

Alternative computer mouse trigger designs in computerized physician order entry (CPOE) system to reduce clinicians’ drop-down menu selection errors

BackgroundExtended daily computer use and overload of clinicians has been associated with a reported increase of prescription error. New mouse activity designs offer alternative strategies to potentially decrease drop-down menu selection error in computerized physician order entry (CPOE) prescription. ObjectiveThis study aimed to evaluate the use of alternative computer mouse trigger designs by clinicians during a prescription task. Data related to mouse activities and prescription error were collected in order to better understand the mouse trigger impact and interaction with level of urgency for physician to prescribe orders in CPOE. Materials and methodsThirty healthy, right-handed clinicians (16 female; 14 male) participated in this study. All participants completed eight prescription trials in which three factors were manipulated: mouse click strategies (single-click vs. double-click), mouse release strategies (down vs. up) and level of urgency (urgent vs. non-urgent). Human performance in terms of drop-down menu selection error was captured for each mouse design. Multiple aspects of participants’ behavior related to prescribing medication were measured in conditions simulating prescription of medication. ResultsThere were significant main effects for mouse click strategies and urgency (F (1, 20) = 11.03, P = 0.002; F (1, 20) = 14.24, P = 0.001), and no significant main effects for mouse release strategies (F (1, 20) = 2.39, P = 0.134) on drop-down menu selection error. A significant interaction, mouse click strategies × urgency, was revealed (F (1, 20) = 5.44, P = 0.027). There was a significant change found in error rate associated with mouse click strategy changes (adjusted OR = 2.38, 95% CI 1.57 to 3.61, P < 0.001) and urgent condition changes (adjusted OR = 0.56, 95% CI 0.37 to 0.83, P = 0.004). ConclusionWhen clinicians input physician orders into CPOE, regardless of mouse release strategy, double clicks were associated with lower error rates than single-click strategy. In urgent situations, double clicks also were associated with a lower error rate compared with single-click strategy. These findings may have wide-ranging applications, and computer engineers may consider adopting a double-click strategy in CPOE to reduce medical error, especially in urgent situations.

Genome-wide identification of protein binding sites on RNAs in mammalian cells

RNA-binding proteins (RBPs) are proteins that bind to the RNA and participate in forming ribonucleoprotein complexes. They have crucial roles in various biological processes such as RNA splicing, editing, transport, maintenance, degradation, intracellular localization and translation. The RBPs bind RNA with different RNA-sequence specificities and affinities, thus, identification of protein binding sites on RNAs (R-PBSs) will deeper our understanding of RNA-protein interactions. Currently, high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP, also known as CLIP-Seq) is one of the most powerful methods to map RNA-protein binding sites or RNA modification sites. However, this method is only used for identification of single known RBPs and antibodies for RBPs are required. Here we developed a novel method, called capture of protein binding sites on RNAs (RPBS-Cap) to identify genome-wide protein binding sites on RNAs without using antibodies. Double click strategy is used for the RPBS-Cap assay. Proteins and RNAs are UV-crosslinked in vivo first, then the proteins are crosslinked to the magnetic beads. The RNA elements associated with proteins are captured, reverse transcribed and sequenced. Our approach has potential applications for studying genome-wide RNA-protein interactions.

Heaviside's dolphins (Cephalorhynchus heavisidii) relax acoustic crypsis to increase communication range.

The costs of predation may exert significant pressure on the mode of communication used by an animal, and many species balance the benefits of communication (e.g. mate attraction) against the potential risk of predation. Four groups of toothed whales have independently evolved narrowband high-frequency (NBHF) echolocation signals. These signals help NBHF species avoid predation through acoustic crypsis by echolocating and communicating at frequencies inaudible to predators such as mammal-eating killer whales. Heaviside's dolphins (Cephalorhynchus heavisidii) are thought to exclusively produce NBHF echolocation clicks with a centroid frequency around 125 kHz and little to no energy below 100 kHz. To test this, we recorded wild Heaviside's dolphins in a sheltered bay in Namibia. We demonstrate that Heaviside's dolphins produce a second type of click with lower frequency and broader bandwidth in a frequency range that is audible to killer whales. These clicks are used in burst-pulses and occasional click series but not foraging buzzes. We evaluate three different hypotheses and conclude that the most likely benefit of these clicks is to decrease transmission directivity and increase conspecific communication range. The expected increase in active space depends on background noise but ranges from 2.5 (Wenz Sea State 6) to 5 times (Wenz Sea State 1) the active space of NBHF signals. This dual click strategy therefore allows these social dolphins to maintain acoustic crypsis during navigation and foraging, and to selectively relax their crypsis to facilitate communication with conspecifics.

Controlled decoration of boron-doped diamond electrodes by electrochemical click reaction (e−CLICK)

Controlled surface functionalization of electrode materials is an important technique in various fields such as analytical chemistry, molecular electronics, and molecular recognition in biological systems. In this work, we report the control decoration of boron-doped diamond (BDD) electrodes by electrochemically driven copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition of alkyne and azide (e−CLICK) in which the catalyst is produced by electroreduction of copper(II) species. As the e−CLICK strategy enabled to tune the produced amount of the copper(I) catalyst electrochemically, the alkyne-terminated BDD electrodes were decorated with azide-terminated ferrocene in a controlled manner.

Multiple epitope presentation and surface density control enabled by chemoselective immobilization lead to enhanced performance in IgE-binding fingerprinting on peptide microarrays

Multiple ligand presentation is a powerful strategy to enhance the affinity of a probe for its corresponding target. A promising application of this concept lies in the analytical field, where surface immobilized probes interact with their corresponding targets in the context of complex biological samples. Here we investigate the effect of multiple epitope presentation (MEP) in the challenging context of IgE-detection in serum samples using peptide microarrays, and evaluate the influence of probes surface density on the assay results. Using the milk allergen alpha-lactalbumin as a model, we have synthesized three immunoreactive epitope sequences in a linear, branched and tandem form and exploited a chemoselective click strategy (CuAAC) for their immobilization on the surface of two biosensors, a microarray and an SPR chip both modified with the same clickable polymeric coating. We first demonstrated that a fine tuning of the surface peptide density plays a crucial role to fully exploit the potential of oriented and multiple peptide display. We then compared the three multiple epitope presentations in a microarray assay using sera samples from milk allergic patients, confirming that a multiple presentation, in particular that of the tandem construct, allows for a more efficient characterization of IgE-binding fingerprints at a statistically significant level. To gain insights on the binding parameters that characterize antibody/epitopes affinity, we selected the most reactive epitope of the series (LAC1) and performed a Surface Plasmon Resonance Imaging (SPRi) analysis comparing different epitope architectures (linear versus branched versus tandem). We demonstrated that the tandem peptide provides an approximately twofold increased binding capacity with respect to the linear and branched peptides, that could be attributed to a lower rate of dissociation (Kd).

Click strategy using disodium salts of amino acids improves the water solubility of plinabulin and KPU-300

Plinabulin and KPU-300 are promising anti-microtubule agents; however, the low water solubility of these compounds (<0.1µg/mL) has limited their pharmaceutical advantages. Here, we developed five water-soluble derivatives of plinabulin and KPU-300 with a click strategy using disodium salts of amino acids. The mother skeleton, diketopiperazine (DKP), was transformed into a monolactim-type alkyne and a copper-catalyzed alkyne azide cycloaddition (CuAAC) combined azides that was derived from amino acids as a water-solubilizing moiety. The conversion of carboxyl groups into disodium salts greatly improved the water solubility by 0.8 million times compared to the solubility of the parent molecules. In addition, the α-amino acid side chains of the water-solubilizing moieties affected both the water solubility and the half-lives of the compounds during enzymatic hydrolysis. Our effort to develop a variety of water-soluble derivatives using the click strategy has revealed that the replaceable water-solubilizing moieties can alter molecular solubility and stability under enzymatic hydrolysis. With this flexibility, we are approaching to the in vivo study using water-soluble derivative.

Highly reactive “RIKEN click” probe for glycoconjugation on lysines

One pot double click strategy containing strain-promoted click-reaction followed by 6π-azaelectrocyclization (RIKEN click reaction) has worked well in the synthesis of multivalent homogeneous and heterogeneous N-glycoalbumins. We have slightly changed the structure of linker unsaturated aldehyde used in this method. As a result it can be easily synthesized from commercially available material and furthermore, the enhancement of its reactivity towards both click-reactions was observed. The data described in this Communications facilitate the usage of the double click strategy as a general method for the synthesis of a variety of neo-N-glycoproteins.

Modulation of electrostatic interactions to improve controlled drug delivery from nanogels

The synthesis of nanogels as devices capable to maintain the drug level within a desired range for a long and sustained period of time is a leading strategy in controlled drug delivery. However, with respect to the good results obtained with antibodies and peptides there are a lot of problems related to the quick and uncontrolled diffusion of small hydrophilic molecules through polymeric network pores. For these reasons research community is pointing toward the use of click strategies to reduce release rates of the linked drugs to the polymer chains. Here we propose an alternative method that considers the electrostatic interactions between polymeric chains and drugs to tune the release kinetics from nanogel network. The main advantage of these systems lies in the fact that the carried drugs are not modified and no chemical reactions take place during their loading and release. In this work we synthesized PEG-PEI based nanogels with different protonation degrees and the release kinetics with charged and uncharged drug mimetics (sodium fluorescein, SF, and rhodamine B, RhB) were studied. Moreover, also the effect of counterion used to induce protonation was taken into account in order to build a tunable drug delivery system able to provide multiple release rates with the same device.

ChemInform Abstract: “Click‐fluors”: Triazole‐Linked Saccharide Sensors.

AbstractUsing the CuAAC click strategy, several boronic acid‐containing saccharide receptors with triazole‐linked fluorophores are synthesized.

Determinants of Attitude toward the Public Health Spending and Its Relationship with Voting Behavior in the 2012 South Korean Presidential Election.

This study aimed to identify the factors influencing South Korean voters’ attitudes towards increasing public expenditure on health and to identify whether the issue of healthcare expenditure influenced candidate choice in the 2012 Korean presidential election. The study used the data from a survey conducted by the Institute of Korean Politics at Seoul National University immediately following the 2012 presidential election. The survey was completed by a nationwide sample of 1,200 people aged 19 or over using a face-to-face interview method and proportional quota sampling based on sex, age, and region. About 44.3% of respondents had a positive attitude toward increasing public health expenditure. There was no significant difference by the candidate they supported (conservative Park Geun-hye or liberal Moon Jae-in). In particular, even 44.9% of conservative supporters agreed with more spending. Politically neutral respondents (OR = 1.76, 90% CI 1.22–2.54) and strong conservative party supporters (OR = 1.53, 90% CI 1.05–2.25) were more likely to support public health expenditure increase compared to strong liberal party supporters. Also, respondents who believed that the economic gap in the country was widening were 1.91 times more likely to support an increase in public health expenditures. However, the issue of health expenditure had no influence on voters’ choice of presidential candidates, and in particular no negative effect of choice of the ruling (conservative) party’s candidate. Our results should be interpreted with care; one possible reason for this lack of effect might be that constituents voted along partisan lines regardless of their attitude to the welfare issue; another possible explanation might be the success of the “left click strategy” of the conservative party. That is, the conservatives did not reject economic democratization or social welfare expansion. Further research should be done to explain why attitudes to health spending did not directly affect choice of candidate.