Synthesis of Non-glucosamino Glucan Oligosaccharides Related to Heparin and Heparan Sulphate

Abstract

A series of three oligosaccharides, α-d-Glc-(1→4)-β-d-GlcA-1ωe, β-d-GlcA-(1→4)-α-d-Glc-(1→4)-β-d-GlcA-lωe and α-d-Glc-(1→4)-β-d-GlcA-(1→4)-α-d-Glc-(1→4)-β-d-GlcA-1ωe was prepared by a short synthetic route, using maltose and glucuronic acid derivatives as starting materials. The oligosaccharides contain glucose residues instead of glucosamines, and have a less complicated structure than the corresponding unsulphated structures found in native heparin and heparan sulphate. This simplification in structure has diminished the number of synthetic steps and raised the total yield compared to the preparation of the corresponding heparin/heparan sulphate structures which have been found to bind acidic and basic FGF.     

Synthesis of (Z)-N-alkenyl-β-arylselanyl imidazoles via additive-free nucleophilic addition of imidazole to arylselanylalkynes

We present herein our results on the nucleophilic addition of imidazole to a range of arylselanylalkynes by simple heating in DMF without any additives to give (Z)-1-(1-organyl-(2-arylselanyl)vinyl)-1H-imidazoles. The reactions were performed under mild conditions with a range of arylselanylalkynes in good yields and with high regio- and stereoselectivity to give the respective (Z)-arylselanyl alkene as the only isomer.     

Identification of groundwater discharge in Cuddalore coast,Tamil Nadu using radium isotopes

For the optimal exploitation and management of coastal aquifers of Tamil Nadu, it is essential to evaluate the groundwater outflow into the sea also called as submarine groundwater discharge. In this study, radium isotopes (^223,224Ra) were employed to understand the groundwater discharge in coastal areas of Cuddalore district, Tamil Nadu. Sea water samples (100 L) were collected from various locations of Cuddalore coast in October 2011 and passed through Mn-impregnated acrylic fiber columns. These acrylic columns were analyzed for ^223,224Ra activities using radium delayed coincidence counter. The observed higher activities of ^223,224Ra excess (0.02 ± 0.001–3.28 ± 0.16 and 64 ± 3–380 ± 19 mBq/100 L respectively) indicate that groundwater discharge occurs in this coastal region.     

Characterization and kinetic performance of 2.1 × 100 mm production columns packed with new 1.6 μm superficially porous particles

The overall kinetic performance of three production columns (2.1 mm × 100 mm format) packed with 1.6 μm superficially porous CORTECS‐C₁₈+ particles was assessed on a low‐dispersive I‐class ACQUITY instrument. The values of their minimum intrinsic reduced plate heights (h_min = 1.42, 1.57, and 1.75) were measured at room temperature (295 K) for a small molecule (naphthalene) with an acetonitrile/water eluent mixture (75:25, v/v). These narrow‐bore columns provide an average intrinsic efficiency of 395 000 plates per meter. The gradient separation of 14 small molecules shows that these columns have a peak capacity about 25% larger than similar ones packed with fully porous BEH‐C₁₈ particles (1.7 μm) or shorter (50 mm) columns packed with smaller core–shell particles (1.3 μm) operated under very high pressure (>1000 bar) for steep gradient elution (analysis time 80 s). In contrast, because their permeabilities are lower than those of columns packed with larger core–shell particles, their peak capacities are 25% smaller than those of narrow‐bore columns packed with standard 2.7 μm core–shell particles.     

Development and characterization of a small electromembrane extraction probe coupled with mass spectrometry for real-time and online monitoring of in vitro drug metabolism

A small and very simple electromembrane extraction probe (EME-probe) was developed and coupled directly to electrospray ionization mass spectrometry (ESI-MS), and this system was used to monitor in real time in vitro metabolism by rat liver microsomes of drug substances from a small reaction (incubation) chamber (37 °C). The drug-related substances were continuously extracted from the 1.0 mL metabolic reaction mixture and into the EME-probe by an electrical potential of 2.5 V. The extraction probe consisted of a 1-mm long and 350-μm ID thin supported liquid membrane (SLM) of 2-nitrophenyl octyl ether. The drugs and formed metabolites where extracted through the SLM and directly into a 3 μL min^?1 flow of 60 mM HCOOH inside the probe serving as the acceptor solution. The acceptor solution was directed into the ESI-MS-system, and the MS continuously monitored the drug-related substances extracted by the EME-probe. The extraction efficiency of the EME-probe was dependant on the applied electrical potential and the length of the SLM, and these parameters as well as the volume of the reaction chamber were set to the values mentioned above to avoid serious depletion from the reaction chamber (soft extraction). Soft extraction was mandatory in order not to affect the reaction kinetics by sample composition changes induced by the EME-probe. The EME-probe/MS-system was used to establish kinetic profiles for the in vitro metabolism of promethazine, amitriptyline and imipramine as model substances.     

Efficient Copper-Catalyzed Highly Stereoselective Synthesis of Unprotected C-Acyl Manno-, Rhamno- and Lyxopyranosides

Due to their high stability towards enzymatic hydrolysis C-acyl glycosidic compounds are useful synthetic intermediates for potential candidates in drug discovery. Syntheses for C-acyl mannosides have remained scarce and usually employ donors obtained from lengthy syntheses. Furthermore, syntheses of unprotected C-acyl mannosides have not been reported so far, due to the incapability of the C-acyl mannoside motif with deprotection conditions for protective groups commonly used in carbohydrate chemistry. Herein, we report an efficient and highly α-selective four-step one-pot method for the synthesis of C-acyl α-d -manno-, l -rhamno- and d -lyxopyranosides from easily accessible persilylated monosaccharides and dithianes requiring only trace amounts of a copper source as catalyst and explain the crucial role of the catalyst by mechanistic studies. Furthermore, the C-acyl α-glycosides were easily isomerized to give rapid access to their β-anomers.     

Cannabis-Derived Compounds Cannabichromene and Δ9-Tetrahydrocannabinol Interact and Exhibit Cytotoxic Activity against Urothelial Cell Carcinoma Correlated with Inhibition of Cell Migration and Cytoskeleton Organization

Cannabis sativa contains more than 500 constituents, yet the anticancer properties of the vast majority of cannabis compounds remains unknown. We aimed to identify cannabis compounds and their combinations presenting cytotoxicity against bladder urothelial carcinoma (UC), the most common urinary system cancer. An XTT assay was used to determine cytotoxic activity of C. sativa extracts on T24 and HBT-9 cell lines. Extract chemical content was identified by high-performance liquid chromatography (HPLC). Fluorescence-activated cell sorting (FACS) was used to determine apoptosis and cell cycle, using stained F-actin and nuclei. Scratch and transwell assays were used to determine cell migration and invasion, respectively. Gene expression was determined by quantitative Polymerase chain reaction (PCR). The most active decarboxylated extract fraction (F7) of high-cannabidiol (CBD) C. sativa was found to contain cannabichromene (CBC) and Δ9-tetrahydrocannabinol (THC). Synergistic interaction was demonstrated between CBC + THC whereas cannabinoid receptor (CB) type 1 and type 2 inverse agonists reduced cytotoxic activity. Treatments with CBC + THC or CBD led to cell cycle arrest and cell apoptosis. CBC + THC or CBD treatments inhibited cell migration and affected F-actin integrity. Identification of active plant ingredients (API) from cannabis that induce apoptosis and affect cell migration in UC cell lines forms a basis for pre-clinical trials for UC treatment.     

In Vitro Antiplasmodial and Cytotoxic Activities of Compounds from the Roots of Eriosema montanum Baker f. (Fabaceae)

Malaria remains one of the leading causes of death in sub-Saharan Africa, ranked in the top three infectious diseases in the world. Plants of the Eriosema genus have been reported to be used for the treatment of this disease, but scientific evidence is still missing for some of them. In the present study, the in vitro antiplasmodial activity of the crude extract and compounds from Eriosema montanum Baker f. roots were tested against the 3D7 strain of Plasmodium falciparum and revealed using the SYBR Green, a DNA intercalating compound. The cytotoxicity effect of the compounds on a human cancer cell line (THP-1) was assessed to determine their selectivity index. It was found that the crude extract of the plant displayed a significant antiplasmodial activity with an IC₅₀ (µg/mL) = 17.68 ± 4.030 and a cytotoxic activity with a CC₅₀ (µg/mL) = 101.5 ± 12.6, corresponding to a selective antiplasmodial activity of 5.7. Bioactivity-guided isolation of the major compounds of the roots’ crude extract afforded seven compounds, including genistein, genistin and eucomic acid. Under our experimental conditions, using Artemisinin as a positive control, eucomic acid showed the best inhibitory activity against the P. falciparum 3D7, a well-known chloroquine-sensitive strain. The present results provide a referential basis to support the traditional use of Eriosema species in the treatment of malaria.     

pH‐controlled reaction divergence of decarboxylation versus fragmentation in reactions of dihydroxyfumarate with glyoxylate and formaldehyde: parallels to biological pathways

The reactions of dihydroxyfumarate with glyoxylate and formaldehyde exhibit a unique pH‐controlled mechanistic divergence leading to different product suites by two distinct pathways. The divergent reactions proceed via a central intermediate (2,3‐dihydroxy‐oxalosuccinate, 3 , in the reaction with glyoxylate and 2‐hydroxy‐2‐hydroxymethyl‐3‐oxosuccinate, 14 , in the reaction with formaldehyde). At pH 7–8, products ( 7 , 8 , and 15 ) exclusively from a decarboxylation of the intermediate are observed, while at pH 13–14, products ( 9 , 10 , and 16 ) solely derived from a hydroxide‐promoted fragmentation of the intermediate are formed. The decarboxylative and fragmentation pathways are mutually exclusive and do not appear to coexist under the range of pH (7–14) conditions investigated. Herein, we employ a combination of quantitative ¹³C NMR measurements and density functional theory calculations to provide a rationale for this pH‐driven reaction divergence. These rationalizations also hold true for the reactions of dihydroxyfumarate produced in situ by the catalytic cyanide‐mediated dimerization of glyoxylate. In addition, the non‐enzymatic decarboxylation and fragmentation transformations of these central intermediates ( 3 and 14 ) appear to have intriguing parallels to the enzymatic reactions of oxalosuccinate and formation of glyceric acid derivatives in extant metabolism – the high and low pH mimicking the precise control exerted by the enzymes over reaction pathways. Copyright © 2016 John Wiley & Sons, Ltd.     

Mean-field versus microconvection effects in nanofluid thermal conduction

Transient hot-wire data on thermal conductivity of suspensions of silica and perfluorinated particles show agreement with the mean-field theory of Maxwell but not with the recently postulated microconvection mechanism. The influence of interfacial thermal resistance, convective effects at microscales, and the possibility of thermal conductivity enhancements beyond the Maxwell limit are discussed.