Synthetic Heparanase Inhibitors Can Prevent Herpes Simplex Viral Spread

Herpes simplex virus (HSV-1) employs heparan sulfate (HS) as receptor for cell attachment and entry. During late-stage infection, the virus induces the upregulation of human heparanase (Hpse) to remove cell surface HS allowing viral spread. We hypothesized that inhibition of Hpse will prevent viral release thereby representing a new therapeutic strategy for HSV-1. A range of HS-oligosaccharides was prepared to examine the importance of chain length and 2-O-sulfation of iduronic moieties for Hpse inhibition. It was found that hexa- and octasaccharides potently inhibited the enzyme and that 2-O-sulfation of iduronic acid is tolerated. Computational studies provided a rationale for the observed structure–activity relationship. Treatment of human corneal epithelial cells (HCEs) infected with HSV-1 with the hexa- and octasaccharide blocked viral induced shedding of HS which significantly reduced spread of virions. The compounds also inhibited migration and proliferation of immortalized HCEs thereby providing additional therapeutic properties.     

Solubility and Stability of Some Pharmaceuticals in Natural Deep Eutectic Solvents-Based Formulations

Some medicines are poorly soluble in water. For tube feeding and parenteral administration, liquid formulations are required. The discovery of natural deep eutectic solvents (NADES) opened the way to potential applications for liquid drug formulations. NADES consists of a mixture of two or more simple natural products such as sugars, amino acids, organic acids, choline/betaine, and poly-alcohols in certain molar ratios. A series of NADES with a water content of 0–30% (w/w) was screened for the ability to solubilize (in a stable way) some poorly water-soluble pharmaceuticals at a concentration of 5 mg/mL. The results showed that NADES selectively dissolved the tested drugs. Some mixtures of choline-based NADES, acid-neutral or sugars-based NADES could dissolve chloral hydrate (dissociated in water), ranitidine·HCl (polymorphism), and methylphenidate (water insoluble), at a concentration of up to 250 mg/mL, the highest concentration tested. Whereas a mixture of lactic-acid–propyleneglycol could dissolve spironolacton and trimethoprim at a concentration up to 50 and 100 mg/mL, respectively. The results showed that NADES are promising solvents for formulation of poorly water-soluble medicines for the development of parenteral and tube feeding administration of non-water-soluble medicines. The chemical stability and bioavailability of these drug in NADES needs further studies.     

A Novel Mechanism for the Extraction of Metals from Water to Ionic Liquids

We present a novel mechanism for the extraction of metals from aqueous phases to room-temperature ionic liquids (ILs) by use of a high-temperature salt as an extraction agent. The mechanism capitalizes on the fact that charged metal complexes are soluble in ILs; this allows for extraction of charged complexes rather than the neutral species, which are formed by conventional approaches. The use of a well-chosen extraction agent also suppresses the competing ion-exchange mechanism, thus preventing degradation of the ionic liquid. The approach permits the use of excess extractant to drive the recovery of metals in high yield. This work presents both a thermodynamic framework for understanding the approach and experimental verification of the process in a range of different ILs. The method has great potential value in the recovery of metals, water purification and nuclear materials processing.     

描述甲烷在Pt(110)-(21)表面的化学吸附解离的密度泛函评估

本文探讨了几种梯度近似(GGA)密度泛函及元梯度近似(meta-GGA)密度泛函在描述甲烷在重构的Pt(110)-(2×1)上的解离化学吸附作用的适用性. 金属的体相和表面结构、甲烷的吸附能量和解离能垒等被用来评估泛函的可靠性. 另外,在从头算分子动力学计算中,采用范德瓦尔斯矫正的GGA函数(optPBE-vdW)和范德瓦尔斯矫正的meta-GGA函数(MS-PBEl-rVV10）计算粘附概率. 计算结果表明,使用这两种泛函能更好地与现有的实验结果吻合,从而为发展甲烷在Pt(110)-(2×1)表面解离的可靠机器学习势能面打下重要基础.     

Natural deep eutectic solvents as new potential media for green technology

Developing new green solvents is one of the key subjects in Green Chemistry. Ionic liquids (ILs) and deep eutectic solvents, thus, have been paid great attention to replace current harsh organic solvents and have been applied to many chemical processing such as extraction and synthesis. However, current ionic liquids and deep eutectic solvents have still limitations to be applied to a real chemical industry due to toxicity against human and environment and high cost of ILs and solid state of most deep eutectic solvents at room temperature. Recently we discovered that many plant abundant primary metabolites changed their state from solid to liquid when they were mixed in proper ratio. This finding made us hypothesize that natural deep eutectic solvents (NADES) play a role as alternative media to water in living organisms and tested a wide range of natural products, which resulted in discovery of over 100 NADES from nature. In order to prove deep eutectic feature the interaction between the molecules was investigated by nuclear magnetic resonance spectroscopy. All the tested NADES show clear hydrogen bonding between components. As next step physical properties of NADES such as water activity, density, viscosity, polarity and thermal properties were measured as well as the effect of water on the physical properties. In the last stage the novel NADES were applied to the solubilization of wide range of biomolecules such as non-water soluble bioactive natural products, gluten, starch, and DNA. In most cases the solubility of the biomolecules evaluated in this study was greatly higher than water. Based on the results the novel NADES may be expected as potential green solvents at room temperature in diverse fields of chemistry.     

Mono- and Di-Fucosylated Glycans of the Parasitic Worm S. mansoni are Recognized Differently by the Innate Immune Receptor DC-SIGN

The parasitic worm, Schistosoma mansoni, expresses unusual fucosylated glycans in a stage-dependent manner that can be recognized by the human innate immune receptor DC-SIGN, thereby shaping host immune responses. We have developed a synthetic approach for mono- and bis-fucosylated LacdiNAc (LDN-F and LDN-DF, respectively), which are epitopes expressed on glycolipids and glycoproteins of S. mansoni. It is based on the use of monosaccharide building blocks having carefully selected amino-protecting groups, facilitating high yielding and stereoselective glycosylations. The molecular interaction between the synthetic glycans and DC-SIGN was studied by NMR and molecular modeling, which demonstrated that the α1,3-fucoside of LDN-F can coordinate with the Ca²⁺-ion of the canonical binding site of DC-SIGN allowing for additional interactions with the underlying LDN backbone. The 1,2-fucoside of LDN-DF can be complexed in a similar manner, however, in this binding mode GlcNAc and GalNAc of the LDN backbone are placed away from the protein surface resulting in a substantially lower binding affinity. Glycan microarray binding studies showed that the avidity and selectivity of binding is greatly enhanced when the glycans are presented multivalently, and in this format Le^x and LDN-F gave strong responsiveness, whereas no binding was detected for LDN-DF. The data indicates that S. mansoni has developed a strategy to avoid detection by DC-SIGN in a stage-dependent manner by the addition of a fucoside to a number of its ligands.     

High-Field Asymmetric-Waveform Ion Mobility Spectrometry and Electron Detachment Dissociation of Isobaric Mixtures of Glycosaminoglycans

High-field asymmetric waveform ion mobility spectrometry (FAIMS) is shown to be capable of resolving isomeric and isobaric glycosaminoglycan negative ions and to have great utility for the analysis of this class of molecules when combined with Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) and tandem mass spectrometry. Electron detachment dissociation (EDD) and other ion activation methods for tandem mass spectrometry can be used to determine the sites of labile sulfate modifications and for assigning the stereochemistry of hexuronic acid residues of glycosaminoglycans (GAGs). However, mixtures with overlapping mass-to-charge values present a challenge, as their precursor species cannot be resolved by a mass analyzer prior to ion activation. FAIMS is shown to resolve two types of mass-to-charge overlaps. A mixture of chondroitin sulfate A (CSA) oligomers with 4–10 saccharides units produces ions of a single mass-to-charge by electrospray ionization, as the charge state increases in direct proportion to the degree of polymerization for these sulfated carbohydrates. FAIMS is shown to resolve the overlapping charge. A more challenging type of mass-to-charge overlap occurs for mixtures of diastereomers. FAIMS is shown to separate two sets of epimeric GAG tetramers. For the epimer pairs, the complexity of the separation is reduced when the reducing end is alkylated, suggesting that anomers are also resolved by FAIMS. The resolved components were activated by EDD and the fragment ions were analyzed by FTICR-MS. The resulting tandem mass spectra were able to distinguish the two epimers from each other.

A Traveling Wave Ion Mobility Spectrometry (TWIMS) Study of the Robo1-Heparan Sulfate Interaction

Roundabout 1 (Robo1) interacts with its receptor Slit to regulate axon guidance, axon branching, and dendritic development in the nervous system and to regulate morphogenesis and many cell functions in the nonneuronal tissues. This interaction is known to be critically regulated by heparan sulfate (HS). Previous studies suggest that HS is required to promote the binding of Robo1 to Slit to form the minimal signaling complex, but the molecular details and the structural requirements of HS for this interaction are still unclear. Here, we describe the application of traveling wave ion mobility spectrometry (TWIMS) to study the conformational details of the Robo1-HS interaction. The results suggest that Robo1 exists in two conformations that differ by their compactness and capability to interact with HS. The results also suggest that the highly flexible interdomain hinge region connecting the Ig1 and Ig2 domains of Robo1 plays an important functional role in promoting the Robo1-Slit interaction. Moreover, variations in the sulfation pattern and size of HS were found to affect its binding affinity and selectivity to interact with different conformations of Robo1. Both MS measurements and CIU experiments show that the Robo1-HS interaction requires the presence of a specific size and pattern of modification of HS. Furthermore, the effect of N-glycosylation on the conformation of Robo1 and its binding modes with HS is reported.

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A multifaceted approach to hydrogen storage

The widespread adoption of hydrogen as an energy carrier could bring significant benefits, but only if a number of currently intractable problems can be overcome. Not the least of these is the problem of storage, particularly when aimed at use onboard light-vehicles. The aim of this overview is to look in depth at a number of areas linked by the recently concluded HYDROGEN research network, representing an intentionally multi-faceted selection with the goal of advancing the field on a number of fronts simultaneously. For the general reader we provide a concise outline of the main approaches to storing hydrogen before moving on to detailed reviews of recent research in the solid chemical storage of hydrogen, and so provide an entry point for the interested reader on these diverse topics. The subjects covered include: the mechanisms of Ti catalysis in alanates; the kinetics of the borohydrides and the resulting limitations; novel transition metal catalysts for use with complex hydrides; less common borohydrides; protic-hydridic stores; metal ammines and novel approaches to nano-confined metal hydrides.     

Stereoselective assembly of complex oligosaccharides using anomeric sulfonium ions as glycosyl donors

The development of selectively protected monosaccharide building blocks that can reliably be glycosylated with a wide variety of acceptors is expected to make oligosaccharide synthesis a more routine operation. In particular, there is an urgent need for the development of modular building blocks that can readily be converted into glycosyl donors for glycosylations that give reliably high 1,2-cis-anomeric selectivity. We report here that 1,2-oxathiane ethers are stable under acidic, basic, and reductive conditions making it possible to conduct a wide range of protecting group manipulations and install selectively removable protecting groups such as levulinoyl (Lev) ester, fluorenylmethyloxy (Fmoc)- and allyloxy (Alloc)-carbonates, and 2-methyl naphthyl ethers (Nap). The 1,2-oxathiane ethers could easily be converted into bicyclic anomeric sulfonium ions by oxidization to sulfoxides and arylated with 1,3,5-trimethoxybenzene. The resulting sulfonium ions gave high 1,2-cis-anomeric selectivity when glycosylated with a wide variety of glycosyl acceptors including properly protected amino acids, primary and secondary sugar alcohols and partially protected thioglycosides. The selective protected 1,2-oxathianes were successfully employed in the preparation of a branched glucoside derived from a glycogen-like polysaccharide isolated form the fungus Pseudallescheria boydii , which is involved in fungal phagocytosis and activation of innate immune responses. The compound was assembled by a latent-active glycosylation strategy in which an oxathiane was employed as an acceptor in a glycosylation with a sulfoxide donor. The product of such a glycosylation was oxidized to a sulfoxide for a subsequent glycosylation. The use of Nap and Fmoc as temporary protecting groups made it possible to install branching points.