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A new trehalose-grafted poly(2-hydroxyethyl methacrylate) (HEMA) glycopolymer was synthesized via the perfluorophenyl azide (PFPA)-mediated Staudinger reaction between poly(HEMA

Silver nanoparticles (AgNPs) are potent antimicrobial agents, but their utility is limited due to their relatively high cytotoxicity. In this work, we used trehalose as the ligand to reduce the cytotoxicity of AgNPs without affecting their antimicrobial activities. Trehalose is a disaccharide that is unique to mycobacteria. We showed that trehalose-functionalized AgNPs, AgNP-Tre, drastically increased the viability of A549 cells, especially at high concentrations, for example, from 4% for AgNPs to 67% for AgNP-Tre at 64

The Diels-Alder (DA) reaction, a classic cycloaddition reaction involving a diene and a dienophile to form a cyclohexene, is among the most versatile organic reactions. Theories have predicted thermodynamically unfavorable DA reactions on pristine graphene owing to its low chemical reactivity. We hypothesized that metals like Ni could enhance the reactivity of graphene towards DA reactions through charge transfer. The results indeed showed that metal substrates enhanced the reactivity of graphene in the DA reactions with a diene, 2,3-dimethoxy butadiene (DMBD), and a dienophile, maleic anhydride (MAH), with the activity enhancement in the order of NiCu, and both are more reactive than graphene supported on silicon wafer. The rate constants were estimated to be two times higher for graphene supported on Ni than on silicon wafer. The computational results support the experimentally obtained rate trend of NiCu, both predicted to be greater than unsupported graphene, which is explained by the enhanced graphene-substrate interaction reflected in charge transfer effects with the strongly interacting Ni. This study opens up a new avenue for enhancing the chemical reactivity of pristine graphene through substrate selection.

A fluorescence turn-on probe, an azide-masked and trehalose-derivatized carbazole (Tre-Cz), was developed to image mycobacteria. The fluorescence turn-on is achieved by photoactivation of the aryl azide generating a fluorescent product through an efficient intramolecular C-H insertion reaction. The probe is highly specific for mycobacteria and could image mycobacteria in the presence of other Gram-positive and Gram-negative bacteria. Both the photoactivation and detection can be achieved using a handheld UV lamp, and bacteria of 103 CFU/mL or higher can be seen by the naked eye. The probe was also able to image mycobacteria spiked in sputum samples, although the detection sensitivity was lower. Studies using heat-killed, stationary phase and isoniazid-treated mycobacteria showed that metabolically active bacteria are required for the uptake of Tre-Cz. The uptake decreased in the presence of trehalose in a concentration dependent manner, indicating that Tre-Cz hijacks the trehalose uptake pathway. Mechanistic studies revealed that the trehalose recycling transporter LpqY-SugABC is the primary pathway for the uptake of Tre-Cz. The uptake was mostly diminished in the LpqY-SugABC deletion mutants ΔlpqY, ΔsugA and ΔsugB. For the mycolyl transferase antigen 85 complex (Ag85), however, only a slight reduction of uptake was observed in the Ag85 deletion mutant ΔAg85C, and no incorporation of Tre-Cz into the mycomembrane was observed.

Pristine graphene is fairly inert chemically, and as such, most application-driven studies use graphene oxide, or reduced graphene oxide. Using substrates to modulate the reactivity of graphene represents a unique strategy in the covalent functionalization of this otherwise fairly inert material. It was found that the reactivity of pristine graphene towards perfluorophenyl azide (PFPA) can be enhanced by a metal substrate on which graphene is supported. Results on the extent of functionalization, defect density, and reaction kinetics all show that graphene supported on Ni (G/Ni) has the highest reactivity toward PFPA, followed by G/Cu and then G/silicon wafer. DFT calculations suggest that the metal substrate stabilizes the physisorbed nitrene through enhanced electron transfer to the singlet nitrene from the graphene surface assisted by the electron rich metal substrate. The G/Ni substantially stabilizes the singlet nitrene relative to G/Cu and the free-standing graphene. The product structure is also predicted to be substrate dependent. These findings open up opportunities to enhance the reactivity of pristine graphene simply through the selection of the substrate. This also represents a new and powerful approach to increasing the reactivity of singlet nitrenes through direct electronic communication with graphene.

This review discusses the present knowledge and recent advances in the techniques used to analyze nanomaterial surfaces, including traditional techniques that are easily accessible to researchers as well as advanced techniques and recent developments. Each technique will only be discussed in the context of its utility in nanomaterial surface characterization. We highlight both advantages and drawbacks of the techniques, and review examples from literature with the focus on recent publications. The following topics will be discussed: (1) ligand structure and conformation, (2) ligand density, (3) surface charge, (4) hydrophobicity, (5) ligand shell thickness, (6) binding affinity, and (7) surface morphology. This list is by no means complete, but rather serves as a discussion platform to draw attention to this important yet challenging field of nanomaterial surface characterization. Techniques that can provide quantitative information on the nanomaterial surfaces will be discussed whenever possible. As most nanomaterials are in the form of nanoparticles, both terms will be used interchangeably throughout the text.

Water-soluble gold nanoclusters (AuNCs) are popular in biomedical applications such as bioimaging, labelling, drug delivery, and biosensing. Despite their widespread applications, the synthesis of water-soluble phosphine-capped AuNCs is not as straightforward as their organic-soluble equivalents. Organic soluble phosphine-passivated [Au(9)(L)(8)](3+) are 6-electron closed-shell AuNCs that are generally prepared via the reduction of phosphine-Au(I) complex by NaBH(4). A similar approach attempted for the water-soluble ligand triphenylphosphine monosulfonate (TPPMS) using [AuTPPMS]Cl resulted in a mixture of cluster sizes that required gel electrophoresis or fractional precipitation to isolate the Au(9) product. In this work, we report the synthesis of water-soluble [Au(9)(L)(8)](3+) nanoclusters in high yield through the biphasic ligand exchange of [Au(11)(PPh(3))(8)Cl(2)]Cl with water-soluble phosphines such as TPPMS and 4-(diphenylphosphino)benzoic acid (DPPBA). The small molecule byproducts can be completely removed by size-based separation methods, like size exclusion chromatography or dialysis, as confirmed by (31)P and (1)H nuclear magnetic resonance (NMR) as well as diffusion ordered spectroscopy (DOSY). Furthermore, [Au(9)(DPPBA)(8)]Cl(3) underwent a visible pH- and temperature-induced isomerization in ethanol between the ‘crown’ and ‘butterfly’ isomers of [Au(9)(L)(8)](3+) that has not been previously reported. Cytotoxicity evaluation of these water-soluble nanoclusters gave CC(50) of 36 μg/mL and 70 μg/mL against A549 human alveolar epithelial cells, and 30 μg/mL and 40 μg/mL against NIH/3T3 mouse fibroblast cells for [Au(9)(TPPMS)(8)]Cl(3) and [Au(9)(DPPBA)(8)]Cl(3), respectively. For comparison, auranofin, an FDA-approved gold drug, is more than an order of magnitude more toxic with a CC(50) of 7.7 μg/mL against A549 cells.

In this work we show that biological inactive gold nanoclusters (AuNCs) capped with D-maltose can be converted to antimicrobial AuI species by the addition of thiourea (TU). The antimicrobial activity mainly arises from the reaction of AuNCs with TU generating [Au(TU)2]Cl and small Au nanoclusters. Excess TU also maintains the oxidation state as AuI (vs. AuIII) which is key in maintaining activity. The AuNCs/TU combination was a powerful bactericidal agent against resistant bacteria, including multidrug-resistant (MDR) clinical isolates of Pseudomonas aeruginosa, and could eradicate S. epidermidis biofilm. It is unaffected by the efflux or bacterial outer membrane. The modes of action are multiple, including inhibition of thioredoxin reductase, CuI regulation interference and depletion of ATP. The formulation was 30-60 times less toxic on mammalian cells. This represents a new strategy enabling the antimicrobial activity of otherwise inactive AuNCs against the most difficult to treat MDR bacteria.

Chemical vapor deposition (CVD) is among the most utilized techniques to fabricate single-layer graphene on a large substrate. However, the substrate is limited to very few transition metals like copper. On the other hand, many applications involving graphene require technologically relevant substrates like semiconductors and metal oxide, and therefore, a subsequent process is often needed to transfer CVD to the new substrate. As graphene is fragile, a supporting material such as a polymer film, is introduced during the transfer process. This brings unexpected challenges, the biggest of which is the complete removal of this support material without contaminating graphene. Numerous methods have been developed, each having advantages and drawbacks. This review will first introduce the classic transfer method using poly(methyl methacrylate) (PMMA) as the support material. The operating procedure and issues of PMMA residuals will be discussed. Methods to minimize/eliminate contamination will be presented, together with alternative approaches that do not require the use of PMMA.

The nitroaldol reaction is demonstrated as an efficient dynamic covalent reaction in phosphate buffers at neutral pH. Rapid equilibration was recorded with pyridine-based aldehydes, and dynamic oligomerization could be achieved, leading to nitroaldol dynamers of up to 17 repeating units. The dynamers were applied in a coherent stimuli-responsive molecular system in which larger dynamers transiently existed out-of-equilibrium in a neutral aqueous system rich in formaldehyde, controlled by nitromethane.

Carbohydrate-mediated interactions are involved in many cellular activities including immune responses and infections. These interactions are relatively weak, and as such, cells employ multivalency, i.e., the presentation of multiple monovalent carbohydrate ligands within a close proximity, for cooperative binding thus drastically enhanced binding affinity. In the past two decades, the field of glyconanomaterials has emerged where nanomaterials are used as multivalent scaffolds to present multiple copies of carbohydrate ligands on the nanomaterial surface. At the core of glyconanomaterial research is the ability to control and modulate multivalency through ligand display. For the quantitative evaluation of multivalency, the binding affinity must be determined. Quantification of the binding parameters provides insights for not only the fundamental glyconanomaterial – lectin interactions, but also the rational design of effective diagnostics and therapeutics. Several methods have been developed to determine the binding affinity of glyconanomaterials with lectins, including fluorescence competitive assays in solution or on microarrays, Förster resonance energy transfer, fluorescence quenching, isothermal titration calorimetry, surface plasmon resonance spectroscopy, quartz crystal microbalance and dynamic light scattering. This Feature Article discusses each of these techniques, as well as how each technique is applied to determine the binding affinity of glyconanomaterials with lectins, and the data analysis. Although the results differed depending on the specific method used, collectively, they showed that nanomaterials as multivalent scaffolds could amplify the binding affinity of carbohydrate-lectin interactions by several orders of magnitude, the extent of which depending on the structure of the carbohydrate ligand, the ligand density, the linker length and the particle size.

The excellent physical and chemical properties of graphene make it an attractive nanomaterial and a component in high-performance nanocomposite materials. To prepare graphene-based nanocomposite materials, chemical functionalization is often necessary. Water-soluble ligands such as carbohydrates not only make the functionalized graphene compatible with aqueous media, but also introduce biorecognition, which is important for graphene to be used in biotechnology. In this study, we report the derivatization of few-layer graphene (FLG) with carbohydrates through microwave-assisted reaction of perfluorophenyl azide (PFPA). FLG was first treated with PFPA under microwave radiation. Subsequent conjugation with glycosyl amine gave carbohydrate-presenting FLG. Thermogravimetric analysis showed that microwave radiation gave a higher degree of functionalization compared to conventional heating, with higher weight losses for both PFPA and Man ligands. The carbohydrates (mannose and galactose) retained their bioactivity, as demonstrated by the lectin binding assays. Higher degree of binding toward lectins was obtained for the carbohydrate-functionalized FLG prepared by microwave radiation than the conventional heating. Copyright © 2018 American Chemical Society.

Liposomes, a nanoscale drug delivery system, are well known for their ability to improve pharmacokinetics and reduce drug toxicity. In this work, maltoheptaose (G7)-presenting glycoliposomes were synthesized and evaluated in the delivery of the antibiotic rifampicin. Two types of liposomes were prepared: nonfluid liposomes from l-α-phosphatidylcholine (PC) and cholesterol, and fluid liposomes from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-dimyristoyl-sn-glycero-3-phospho-(1′-rac-glycerol). G7-derivatized glycolipid, G7-DPPE (DPPE: 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine), was incorporated into the liposomes at 21 and 14 μmol/mg to form nanoparticles of 75 ± 12 and 146 ± 14 nm for the nonfluid and fluid G7-glycoliposomes, respectively. The multivalent G7-glycoliposomes were characterized by lectin binding with concanavalin A (Con A). The dissociation constant K(d) between Con A and the nonfluid or fluid G7-glycoliposomes was 0.93 or 0.51 μM, which represented ~900- or 1600-fold stronger affinity than the binding between Con A and G7. The G7-glycoliposomes were loaded with rifampicin at 6.6 and 16 wt % encapsulation for the nonfluid and fluid G7-glycoliposomes, respectively. Introducing a carbohydrate in the liposomes slowed down the release of rifampicin, with the G7-glycoliposomes having the slowest release rate and the lowest permeability coefficient among the liposome formulations. The fluid G7-glycoliposomes lowered the minimal inhibitory concentration (MIC) of rifampicin against E. coli ORN208 by about 3 times, whereas liposomes without G7 or Man (d-mannose)-glycoliposomes showed no improvement in MIC. The rifampicin-loaded fluid G7-glycoliposomes demonstrated the best sustained antibacterial activity against E. coli, with up to 2 log reduction in the colony forming units at 4 × MIC after 24 h. Fluorescence resonance energy transfer and confocal fluorescence microscopy revealed stronger interactions of the bacterium with the fluid G7-glycoliposomes than other liposome formulations.

Molecules, capable of fluorescence turn-on by light, are highly sought-after in spatio-temporal labeling, surface patterning, monitoring cellular and molecular events, and high-resolution fluorescence imaging. In this work, we report a fluorescence turn-on system based on photoinitiated intramolecular C-H insertion of azide into the neighboring aromatic ring. The azide-masked fluorogens were efficiently synthesized via a cascade nucleophilic aromatic substitution of perfluoroaryl azides with carbazoles. The scaffold also allows for derivatization with biological ligands, as exemplified with d-mannose in this study. This photoinitiated intramolecular transformation led to high yields, high photo-conversion efficiency, and well-separated wavelengths for photoactivation and fluorescence excitation. The mannose-derivatized structure enabled spatio-temporal activation and showed high contrast and signal amplification. Live cell imaging suggested that the mannose-tagged fluorogen was transported to the lysosomes.

Helicobacter pylori (H. pylori) infection poses a worldwide public health crisis, as chronic infection is rampant and can lead to gastric ulcers, gastritis, and gastric cancer. Unfortunately, frontline therapies cause harmful side effects and are often ineffective due to antibiotic resistance. The FDA-approved drug auranofin is a gold complex with a Au(I) core coordinated with triethylphosphine and peracetylated thioglucose as the ligands. Auranofin is used for the treatment of rheumatoid arthritis and also displays potent activity against H. pylori. One of auranofin's modes of action involves cell death by disrupting cellular thiol-redox balance maintained by thioredoxin reductase (TrxR), but this disruption leads to unwanted side effects due to mammalian cell toxicity. Here, we developed and tested sugar-modified analogs of auranofin as potential antibiotics against H. pylori, with the rationale that modulating the sugar moiety would bias uptake by targeting bacterial cells and mitigating mammalian cell toxicity. Sugar-modified auranofin analogs displayed micromolar minimum inhibitory concentrations against H. pylori, maintained nanomolar inhibitory activity against the target enzyme TrxR, and caused reduced toxicity to mammalian cells. Taken together, our results suggest that structurally modifying the sugar component of auranofin has the potential to yield superior antibiotics for the treatment of H. pylori infection. Broadly, glyco-tailoring is an attractive approach for repurposing approved drugs.

Auranofin, an FDA-approved arthritis drug, has recently been repurposed as a potential antimicrobial agent; it performed well against many Gram-positive bacteria, including multidrug resistant strains. It is, however, inactive toward Gramnegative bacteria, for which we are in dire need of new therapies. In this work, 40 auranofin analogues were synthesized by varying the structures of the thiol and phosphine ligands, and their activities were tested against ESKAPE pathogens. The study identified compounds that exhibited bacterial inhibition (MIC) and killing (MBC) activities up to 65 folds higher than that of auranofin, making them effective against Gram-negative pathogens. Both thiol and the phosphine structures influence the activities of the analogues. The trimethylphosphine and triethylphosphine ligands gave the highest activities against Gramnegative and Gram-positive bacteria, respectively. Our SAR study revealed that the thiol ligand is also very important, the structure of which can modulate the activities of the Au(I) complexes for both Gram-negative and Gram-positive bacteria. Moreover, these analogues had mammalian cell toxicities either similar to or lower than that of auranofin.

AAsymmetric synthesis of N-aryloxazolidinones via dynamic kinetic resolution was developed. A ruthenium-based catalyst was used in the racemization of beta-anilino alcohols, while Candida antarctic ...

Auranofin, a gold(I)-complex with tetraacetylated thioglucose and triethylphosphine ligands, is an FDA-approved drug used as an anti-inflammatory aid in the treatment of rheumatoid arthritis. In repurposing auranofin for other diseases, it was found that the drug showed significant activity against Gram-positive bacteria but was inactive against Gram-negative bacteria. Herein, we report the design and synthesis of gold nanoclusters (AuNCs) based on the structural motif of auranofin. Phosphine-capped AuNCs were synthesized and glycosylated, yielding auranofin AuNC analogues with mixed phosphine/thioglucose ligand shells. These AuNCs were active against both Gram-negative and Gram-positive bacteria, including a panel of resistant ESKAPE pathogens. Notably, an auranofin analogue, a mixed-ligand 1.6 nm AuNC (4b) was ~4 times more active than auranofin against Pseudomonas aeruginosa, while exhibiting 24 times lower toxicity against human A549 cells. The enhanced antibacterial activity of these AuNCs was characterized by a greater uptake of Au by the bacteria compared to AuI-complexes (20% for AuNC 4b). Additional factors include increased oxidative stress, moderate inhibition of thioredoxin reductase (TrxR), and DNA damage. Most intriguingly, the AuNCs were not affected by the bacterial outer membrane (OM) barrier or by extracellular proteins. This contrasts with AuI-complexes like auranofin that are susceptible to protein binding and hindered by the OM barrier.

Misfolding proteins could form oligomers or amyloid fibers, which can cause a variety of amyloid-associated diseases. Thus, the inhibition of protein misfolding and fibrillation is a promising way to prevent and treat these diseases. Captopril (CAP) is an angiotensin-converting enzyme inhibitor (ACEI) that is widely used to treat diseases such as hypertension and heart failure. In this study, we found that CAP inhibits human lysozyme (HL) fibrillation through the combination techniques of biophysics and biochemistry. The data obtained by thioflavin-T (ThT) and Congo red (CR) assays showed that CAP hindered the aggregation of HL amyloid fibrils by reducing the β-sheet structure of HL amyloid, with an IC50 value of 34.75 ± 1.23 μM. Meanwhile, the particle size of HL amyloid decreased sharply in a concentration-dependent approach after CAP treatment. According to the visualization of atomic force microscopy (AFM) and transmission electron microscopy (TEM), we verified that in the presence of CAP, the needle-like fibers of HL amyloid were significantly reduced. In addition, CAP incubation dramatically improved the cell survival rate exposed to HL fibers. Our studies also revealed that CAP could form hydrogen bonds with amino acid residues of Glu 35 and Ala 108 in the binding pocket of HL, which help in maintaining the α-helical structure of HL and then prevent the formation of amyloid fibrillation. It can be concluded that CAP has antiamyloidogenic activity and a protective effect on HL amyloid cytotoxicity.

Glyconanoparticle carriers have been synthesized and efficiently delivered into mycobacteria. Mesoporous silica nanoparticles were functionalized with α,α-trehalose through azide-mediated surface photoligation, and loaded with the antitubercular drug isoniazid. The glyconanoparticles showed high isoniazid loading capacity and higher antimicrobial activity than the free drug.

Microorganisms, including bacteria, viruses and fungi, are ubiquitous in nature. Some are extremely beneficial to life on Earth, whereas some cause diseases and disrupt normal human physiology. Pathogenic microorganisms can also undergo mutations and develop resistance to antimicrobial agents, which complicates diagnostic and therapeutic regimens. This calls for continuing efforts to develop new strategies and tools that can provide fast, sensitive and accurate diagnosis, as well as effective treatment of ever-evolving infectious diseases. Aggregation-induced emission luminogens (AIEgens) have shown promise in imaging, identification and inhibition of various microbial species. Compared to conventional organic fluorophores, AIEgens can offer improved photostability, and have found utilities in imaging microorganisms. AIEgens have been shown to detect microbial viability and differentiate among different microbial strains. Theranostic AIEgens that integrate imaging and killing of microbes have also been developed. This review highlights examples in the literature where AIEgens have been employed as molecular probes in the imaging, discrimination and killing of bacteria, viruses and fungi.

We report on a potential method to separate sugars by using the specific interaction between fullerenes and saccharides in liquid chromatography (LC). Aromatic rings with high electron density are believed to interact strongly with saccharides due to CH–π and/or OH–π interactions. In this study, the fullerene-bonded columns were used to separate saccharides by LC under aqueous conditions. As a result, 2-aminobenzamide-labeled glucose homopolymer (Glcs) was effectively separated by both C60 and C70 columns in the range of Glc-1 to Glc-20 and high blood glucose level being retained in greater quantity. Furthermore, similar separations were identified by LC–mass spectrometry with non-labeled glucose homopolymers. Theoretical study based on molecular dynamics and DFT calculation demonstrated that a supramolecular complex of saccharide–fullerene was formed through CH–π and/or OH–π interactions, and that the interactions between saccharide and fullerene increase with the increase units of the saccharide. Additionally, the C60 column retained disaccharides containing maltose, trehalose, and sucrose. In this case, it was assumed that the retention rates were determined by the difference of the dipole moment in each saccharide. These results suggest that the dipole-induced dipole interaction was dominant, and that maltose—with the higher dipole moment—was more strongly retained compared to other disaccharides having lower dipole moment., フラーレンを用いた糖鎖の分離手法を開発 --抗体等の糖タンパク質分離への応用に期待--. 京都大学プレスリリース. 2020-08-26.

Organic azides are involved in a variety of useful transformations, including nitrene chemistry, reactions with nucleophiles and electrophiles, and cycloadditions. The 1,3-dipolar cycloadditions of azides constitute a major class of highly reliable and versatile reactions, as shown by the development and rapid adoption of click chemistry and bioorthogonal chemistry. Metal-catalyzed azide-alkyne cycloaddition (Cu/RuAAC), the prototypical click reaction, has found wide utility in pharmaceutical, biomedical, and materials sciences. The strain-promoted, or distortion-accelerated, azide-alkyne cycloaddition eliminates the need for a metal catalyst.In the azide-mediated 1,3-dipolar cycloaddition reactions, azides are ambiphilic, i.e., HOMO-LUMO-controlled dipoles where both the HOMO and LUMO interact strongly with the dipolarophile. Azide-alkyne cycloaddition proceeds primarily through the HOMOazide-LUMOdipolarophile interaction, and electron-deficient dipolarophiles react more readily. The inverse-electron-demand reaction, involving the LUMOazide-HOMOdipolarophile interaction, is less common because of the low stability of electron-deficient azides such as acyl, sulfonyl, and phosphoryl azides. Nevertheless, there have been reports since the 1960s showing enhanced reaction kinetics between electron-poor azides and electron-rich dipolarophiles. Our laboratory has developed the use of perfluoroaryl azides (PFAAs), a class of stable electron-deficient azides, as nitrene precursors and for reactions with nucleophiles and electron-rich dipolarophiles. Perfluorination on the aryl ring also facilitates the synthesis of PFAAs and quantitative analysis of the products by 19F NMR spectroscopy.In this Account, we summarize key reactions involving electrophilic azides and applications of these reactions in materials synthesis and chemical biology. These electron-deficient azides exhibit unique reactivity toward nucleophiles and electron-rich or strained dipolarophiles, in some cases leading to new transformations that do not require any catalysts or products that are impossible to obtain from the nonelectrophilic azides. We highlight work from our laboratories on reactions of PFAAs with enamines, enolates, thioacids, and phosphines. In the reactions of PFAAs with enamines or enolates, the triazole or triazoline cycloaddition products undergo further rearrangement to give amidines or amides as the final products at rates of up to 105 times faster than their non-fluorinated anlogues. Computational investigations by the distortion/interaction activation strain model reveal that perfluorination lowers the LUMO of the aryl azide as well as the overall activation energy of the reaction by decreasing the distortion energies of the reactants to reach the transition states. The PFAA-enamine reaction can be carried out in a one-pot fashion using readily available starting materials of aldehyde and amine, making the reaction especially attractive, for example, in the functionalization of nanomaterials and derivatization of antibiotics for the preparation of theranostic nanodrugs. Similar fast kinetics was also observed for the PPAA-mediated Staudinger reaction, which proceeds at 104 times higher rate than the classic Staudinger ligation, giving stable phosphoimines in high yields. The reaction is biorthogonal, allowing cell-surface labeling with minimal background noise.

We report hydrogen/deuterium (H/D) isotope effects based on weak intermolecular interactions with polar functional groups and aromatic rings in liquid chromatography (LC). Various LC experiments with different aromatic analytes, separation media, and nonpolar mobile phases were conducted under normal phase LC conditions, where the hydrophobic interaction was completely suppressed. The separation media that had polar functional groups, such as silanol groups, allowed for higher separation efficiencies for the pairs of aromatic H/D isotopologues. In comparing the 13C NMR spectra of protiated and deuterated aromatic analytes, the electron density of the deuterated analyte was found to be slightly higher than that of the protiated analytes. In the case of silanol functional groups, aromatic rings of the analyte acted as donors through the OH-π interaction to hydrogen atoms in the silanol groups. Thus, the deuterated analytes were able to be greatly retained by the stronger OH-π interactions. Furthermore, a C70-fullerene bonded monolithic column (C70 column), which effectively provides CH-π interactions, allowed the opposite isotope effect. Briefly, an electrostatic attraction based on the dipole-(induced) dipole interaction dominated in the CH-π interactions, according to a van't Hoff analysis. Hence, the bonding lengths of the C-H or D bonds were sensitively affected, such that we were able to conclude that the CH-π interaction depended on the geometric effect. Applying these opposing H/D isotope effects, we were able to finally demonstrate effective H/D isotopologue separations by utilizing the complementary action of the OH-π and CH-π interactions.

We report the synthesis of polyphosphazenes by a fast Staudinger reaction between a bis-PFAA (perfluoroaryl azide) and a bis-phospine. Polymerization was completed within 30 min after mixing the two monomers (20 mM) in CH3CN under ambient conditions to give polyphosphazene with molecular weight of up to over 59 000 and a narrow dispersity (Đ) of 1.1–1.2. This is a significant improvement over the polyphosphazenes obtained from the classic Staudinger reaction which had lower molecular weight (Mn = 10 000–25 000) and higher Đ (1.7). This reaction applies to bis-PFAAs and bis-phosphines with either an aromatic or an aliphatic linker. Polarity of the solvent influenced the degree of polymerization, and more polar solvents such as acetonitrile gave higher molecular weight polymer in comparison to less polar solvents such as dichloromethane. The synthesized polyphosphazenes showed high thermal stability, with the aromatic polyphosphazenes giving decomposition temperature and char yield of up to of 441 °C and 5...

We study the isotope effect by liquid chromatography (LC) with a variety of separation media under reversed and normal phase conditions using the protiated and/or deuterated compounds as the solutes. Results of reversed phase LC (RPLC) suggested that the protiated compounds were more hydrophobic than that of deuterated compounds due to the isotope effect based on the hydrogen bonding between hydrogen atoms of isotopologues and hydroxy groups in the mobile phase. The importance of the hydrogen bonding was also supported by the separation of isotopologues with a silica stationary phase on normal phase LC (NPLC), where the deuterated compounds showed stronger hydrogen bonding to hydroxy groups on silanol. Additionally, we investigated the difference of the strength between CH−π and CD−π interactions. Comparison of free energies of isotopologues by RPLC suggested that the CH−π interaction was slightly stronger than CD−π interaction. Finally, we demonstrated the separation of a few isotopologues on NPLC using ...

Bacteria of the genus Burkholderia include pathogenic Burkholderia mallei, Burkholderia pseudomallei and the Burkholderia cepacia complex (Bcc). These Gram-negative pathogens have intrinsic drug resistance, which makes treatment of infections difficult. Bcc affects individuals with cystic fibrosis (CF) and the species B. cenocepacia is associated with one of the worst clinical outcomes. Following the repurposing of auranofin as an antibacterial against Gram-positive bacteria, we previously synthetized auranofin analogs with activity against Gram-negatives. In this work, we show that two auranofin analogs, MS-40S and MS-40, have antibiotic activity against Burkholderia clinical isolates. The compounds are bactericidal against B. cenocepacia and kill stationary-phase cells and persisters without selecting for multistep resistance. Caenorhabditis elegans and Galleria mellonella tolerated high concentrations of MS-40S and MS-40, demonstrating that these compounds have low toxicity in these model organisms. In summary, we show that MS-40 and MS-40S have the potential to be effective therapeutic options to treat Burkholderia infections.

The role of sulfur in glycosidic bonds has been evaluated using quartz crystal microbalance methodology. Synthetic routes towards α1-2- and α1-6-linked dimannosides with S- or O-glycosidic bonds have been developed, and the recognition properties assessed in competition binding assays with the cognate lectin concanavalin A. Mannose-presenting QCM sensors were produced using photoinitiated, nitrene-mediated immobilization methods, and the subsequent binding study was performed in an automated flow-through instrumentation, and correlated with data from isothermal titration calorimetry. The recorded Kd-values corresponded well with reported binding affinities for the O-linked dimannosides with affinities for the α1-2-linked dimannosides in the lower micromolar range. The S-linked analogs showed slightly disparate effects, where the α1-6-linked analog showed weaker affinity than the O-linked dimannoside, as well as positive apparent cooperativity, whereas the α1-2-analog displayed very similar binding compared to the O-linked structure.

We report a fast Staudinger reaction between perfluoroaryl azides (PFAAs) and aryl phosphines, which occurs readily under ambient conditions. A rate constant as high as 18 m−1 s−1 was obtained between methyl 4-azido-2,3,5,6-tetrafluorobenzoate and methyl 2-(diphenylphosphanyl)benzoate in CD3CN/D2O. Furthermore, the iminophosphorane product was stable toward hydrolysis and aza-phosphonium ylide reactions. This PFAA Staudinger reaction proved to be an excellent bioothorgonal reaction. PFAA-derivatized mannosamine and galactosamine were successfully transformed into cell-surface glycans and efficiently labeled with phosphine-derivatized fluorophore-conjugated bovine serum albumin.

The dynamic exchange of enamines from secondary amines and enolizable aldehydes has been demonstrated in organic solvents. The enamine exchange with amines was efficiently catalyzed by Bi(OTf)3 and Sc(OTf)3 (2 mol %) and the equilibria (60 mm) could be attained within hours at room temperature. The formed dynamic covalent systems displayed high stabilities in basic environment with

We report the preparation of stable micelles from random copolymers of 2-hydroxyethyl methacrylate (HEMA) and perfluorophenyl azide (PFPA)-derivatized HEMA (HEMA-PFPA). The copolymers were synthesized by RAFT polymerization at room temperature under mild conditions without affecting the azide functionality. Upon addition of water to the copolymer solution in DMSO, the random copolymers self-assembled into micelles even at the percentage of HEMA-PFPA as low as 4.5%. The size of the micelles can be controlled by the molecular weight and the concentration of the copolymer, and the percentage of HEMA-PFPA in the copolymer. In addition, iron oxide nanoparticles and quantum dots were successfully encapsulated into the micelles with high encapsulation efficiency (∼80%). These nanoparticles, which were hydrophobic and formed agglomerates in water, became fully dispersed after encapsulating into the micelles. The micelles were stable and the size remained unchanged for at least 6months.

We report the modular formulation of ciprofloxacin-based pure theranostic nanodrugs that display enhanced antibacterial activities, as well as aggregation-induced emission (AIE) enhancement that was successfully used to image bacteria. The drug derivatives, consisting of ciprofloxacin, a perfluoroaryl ring, and a phenyl ring linked by an amidine bond, were efficiently synthesized by a straightforward protocol from a perfluoroaryl azide, ciprofloxacin, and an aldehyde in acetone at room temperature. These compounds are propeller-shaped, and upon precipitation into water, readily assembled into stable nanoaggregates that transformed ciprofloxacin derivatives into AIE-active luminogens. The nanoaggregates displayed increased luminescence and were successfully used to image bacteria. In addition, these nanodrugs showed enhanced antibacterial activities, lowering the minimum inhibitory concentration (MIC) by more than one order of magnitude against both sensitive and resistant Escherichia coli. The study represents a strategy in the design and development of pure theranostic nanodrugs for combating drug-resistant bacterial infections.

We report the existence of bimodal interactions, the π–π and halogen–π interactions, between the halogenated benzenes and aromatic materials., The halogen–π (X–π) interaction is an intermolecular interaction between the electron-poor region of bonded halogen atoms and aromatic rings. We report an experimental evaluation of the halogen–π (X–π) interaction using liquid chromatography with carbon-material coated columns providing strong π interactions in the normal phase mode. A C70-fullerene (C70)-coated column showed higher retentions for halogenated benzenes as the number of halogen substitutions increased as a result of X–π interactions. In addition, the strength of the X–π interaction increased in the order of F < Cl < Br < I. Changes to the UV absorption of C70 and the brominated benzenes suggested that the intermolecular interaction changed from the π–π interaction to X–π interaction as the number of bromo substitutions increased. Computer simulations also showed that the difference in dipole moments among structural isomers affected the strength of the π–π interaction. Furthermore, we concluded from small peak shifts in 1H NMR and from computer simulations that the orbital interaction contributes to the X–π interactions. Finally, we succeeded in the one-pot separation of all isomers of brominated benzenes using the C70-coated column by optimizing the mobile phase conditions.

Helicobacter pylori infection poses a worldwide public health crisis, as chronic infection is rampant and can lead to gastric ulcers, gastritis, and gastric cancer. Unfortunately, frontline therapies cause harmful side effects and are often ineffective due to antibiotic resistance. The FDA-approved drug auranofin is a gold complex with a Au(I) core coordinated with triethylphosphine and peracetylated thioglucose as the ligands. Auranofin is used for the treatment of rheumatoid arthritis and also displays potent activity against H. pylori. One of auranofin’s modes of action involves cell death by disrupting cellular thiol-redox balance maintained by thioredoxin reductase (TrxR), but this disruption leads to unwanted side effects due to mammalian cell toxicity. Here we developed and tested sugar-modified analogs of auranofin as potential antibiotics against H. pylori, with the rationale that modulating the sugar moiety would bias uptake by targeting bacterial cells and mitigating mammalian cell toxicity. Sugar-modified auranofin analogs displayed micromolar minimum inhibitory concentrations against H. pylori, maintained nanomolar inhibitory activity against the target enzyme TrxR, and caused reduced toxicity to mammalian cells. Taken together, our results suggest that structurally modifying the sugar component of auranofin has the potential to yield superior antibiotics for the treatment of H. pylori infection. Broadly, glyco-tailoring is an attractive approach for repurposing approved drugs.

Formulas derived from theoretical physics provide important insights about the nematocyst discharge process of Cnidaria (Hydra, jellyfishes, box-jellyfishes and sea-anemones). Our model description of the fastest process in living nature raises and answers questions related to the material properties of the cell- and tubule-walls of nematocysts including their polysialic acid (polySia) dependent target function. Since a number of tumor-cells, especially brain-tumor cells such as neuroblastoma tissues carry the polysaccharide chain polySia in similar concentration as fish eggs or fish skin, it makes sense to use these findings for new diagnostic and therapeutic approaches in the field of nanomedicine. Therefore, the nematocyst discharge process can be considered as a bionic blue-print for future nanomedical devices in cancer diagnostics and therapies. This approach is promising because the physical background of this process can be described in a sufficient way with formulas presented here. Additionally, we discuss biophysical and biochemical experiments which will allow us to define proper boundary conditions in order to support our theoretical model approach. PolySia glycans occur in a similar density on malignant tumor cells than on the cell surfaces of Cnidarian predators and preys. The knowledge of the polySia-dependent initiation of the nematocyst discharge process in an intact nematocyte is an essential prerequisite regarding the further development of target-directed nanomedical devices for diagnostic and therapeutic purposes. The theoretical description as well as the computationally and experimentally derived results about the biophysical and biochemical parameters can contribute to a proper design of anti-tumor drug ejecting vessels which use a stylet-tubule system. Especially, the role of nematogalectins is of interest because these bridging proteins contribute as well as special collagen fibers to the elastic band properties. The basic concepts of the nematocyst discharge process inside the tubule cell walls of nematocysts were studied in jellyfishes and in Hydra which are ideal model organisms. Hydra has already been chosen by Alan Turing in order to figure out how the chemical basis of morphogenesis can be described in a fundamental way. This encouraged us to discuss the action of nematocysts in relation to morphological aspects and material requirements. Using these insights, it is now possible to discuss natural and artificial nematocyst-like vessels with optimized properties for a diagnostic and therapeutic use, e.g., in neurooncology. We show here that crucial physical parameters such as pressure thresholds and elasticity properties during the nematocyst discharge process can be described in a consistent and satisfactory way with an impact on the construction of new nanomedical devices.