Band 91, Heft 7

Fucosylated chondroitin sulfates (FCS) are unique glycosaminoglycans isolated from body walls of sea cucumbers (holothuria). These biopolymers are composed of a chondroitin core [→4)-β-D-GlcA-(1→3)-β-D-GalNAc-(1→] n bearing fucosyl branches and sulfate groups. Structural variations of FCS are species specific and depend on type, amount and position of branches, as well as on degree and pattern of sulfation of a backbone and branches. A wide spectrum of biological properties was determined for these polysaccharides including anticoagulant, antithrombotic, antitumor, anti-inflammatory activities. Structural features of FCS influence significantly on their biological effect. In this review recent data about structural variations within holothurian FCS are summarized. The NMR data of the key building blocks are presented, which may be used for the analysis of new FCS.

Fluorescent difluoroboron dipyrromethenes (BODIPYs), have been accessed in a one-pot synthetic operation from phthalides and pyrroles, a process that involves O -ethylation of phthalides with Meerwein’s reagent (Et 3 OBF 4 ) and reaction of the ensuing tetrafluoroborate salts with pyrrole, followed by treatment with BF 3  · OEt 2 . These derivatives are endowed with a ortho -hydroxymethyl 8- C -aryl group for further derivatization and/or conjugation to, among others, carbohydrates. The new conjugate derivatives benefit from the optimal characteristics of BODIPYs as fluorescent dyes, including in some instances water-solubility (in the case of conjugation to unprotected carbohydrates). The different kinds of BODIPY-carbohydrate derivatives are compounds of potential interest for biological studies.

The synthesis and anticancer evaluation of new series of nucleosides constructed on 5/6-azidoglycosyl or glucuronamide moieties and containing an O - or an N -dodecyl chain, respectively, are disclosed. Based on our previous results, their structures were planned to preclude them to act via a similar metabolic pathway than that of clinically used nucleoside antimetabolites, against which cancer cells frequently acquire resistance. Xylo and gluco -configured 5/6-azido-1,2-di- O -acetyl furanosyl and pyranosyl donors containing a 3- O -dodecyl group were synthesized from diacetone- d -glucose and were subsequently coupled with silylated uracil or 2-acetamido-6-chloropurine. N -Dodecyl glucuronamide-based nucleosides were accessed from acetonide-protected glucofuranurono-6,3-lactone, which was converted in few steps into O -benzylated 1,2-di- O -acetyl furanuronamide or pyranuronamide derivatives to undergo further N -glycosylation. Both types of nucleosides demonstrated notorious antiproliferative effects in chronic myeloid leukemia (K562) and in breast cancer (MCF-7) cells. The most potent molecules were a 6ʹ-azidoglucopyranosyl N 7 -linked purine nucleoside and glucofuranuronamide derivatives comprising N 1 -linked uracil and N 7 -linked purine units with activities in the single-digit micromolar order of concentration against both cell lines. Their GI 50 values in MCF-7 cells were similar or ca. 3-fold lower than that of the standard drug 5-fluorouracil. Cell cycle studies and immunoblotting analysis of apoptosis-associated proteins in treated K562 cells indicated that the antiproliferative effect of the most effective nucleosides is based on apoptosis induction.

With no currently available disease-modifying drugs, Alzheimer’s disease is the most common type of dementia affecting over 47 million people worldwide. In light of the most recent discoveries placing the cellular prion protein (PrP C ) as a key player in amyloid β oligomer (Aβo)-induced neurodegeneration, we investigated whether the neuroprotective potential of nature-inspired flavonoids against Aβ-promoted toxicity would translate into the ability to disrupt PrP C -Aβo interactions. Hence, we synthesized a small library of flavones and studied their binding affinity towards Aβo by STD-NMR. C -glucosyl flavones exhibited improved binding affinity with morpholine, thiomorpholine or N -methylpiperazine rings attached to the flavone skeleton in ring B para position. Moreover, a N -methylpiperazinyl flavone displayed suitable physicochemical properties and optimal water solubility even without the sugar moiety, and a high interaction with Aβo involving the whole flavone core. Its C -glucosyl derivative, was, however, the best compound to inhibit PrP C -Aβo interactions in a dose-dependent manner, with 41 % of inhibition capacity at 10 μM. The potential of C- glucosyl flavones and their aglycones as protein-protein interaction inhibitors able to tackle PrP C -Aβo interactions is here presented for the first time, and supports this class of compounds as new prototypes for further development in the treatment of Alzheimer’s disease.

A number of bicyclic imino- and carba-sugars (examples are presented in the Scheme) can be obtained from simple monosaccharides (hexoses or pentoses) by various methods.

The possibility to apply solventless conditions for the Baylis-Hillman reaction of 5-hydroxymethyl furfural (HMF) and its glucosylated analog, glucosyloxymethyl furfural (GMF) has been investigated. This study shows that highly functionalized adducts can be obtained in fair to good yields, under the conditions combining the renewability of the substrates, the straightforwardness of the strategy, and the lowered cost and toxicity of the solvent conditions. The issue of the polarity of the furanic substrate is addressed by comparing HMF with furfural and GMF.

Glycomimetics are compounds that resemble carbohydrate molecules in their chemical structure and/or biological effect. A large variety of compounds can be designed and synthesized to get glycomimetics, however, C -glycosyl derivatives represent one of the most frequently studied subgroup. In the present survey syntheses of a range of five- and six membered C -glycopyranosyl heterocycles, anhydro-aldimine type compounds, exo -glycals, C -glycosyl styrenes, carbon-sulfur bonded oligosaccharide mimics are described. Some of the C -glycopyranosyl azoles, namely 1,2,4-triazoles and imidazoles belong to the most efficient glucose analog inhibitors of glycogen phosphorylase known to date. Biological studies revealed the therapeutical potential of such inhibitors. Other synthetic derivatives offer versatile possibilities to get further glycomimetics.

Almond husk liquefaction can be envisaged as an alternative to fossil sources which are becoming exhausted. Lately, the polyols obtain from the lignocellulosic biomass have been under investigation for the production of sustainable chemicals, fuel, materials or other commodities. Within this context, acid-catalyzed liquefaction of such lignocellulosic biomass has been successfully used to access highly functionalized compounds that can be used to replace those produced from petroleum. Almond shells waste can be considered to be part of the lignocellulosic biomass. Its main constituents of are cellulose, hemicellulose, and lignin. In this assay, the biochemical composition of almond husk was estimated based on atomic mass balances, and at the same time, the pyrolysis outcome was also estimated using a kinetic model using some reference compounds. In order to evaluate the use of almond waste as a substrate for acid-catalyzed liquefaction, the most favorable conditions of the liquefaction process were investigated. To better understand the liquefaction process, response surface methodology, in particular, central composite face-centered factorial design was used to set an array of 17 experiments including three replications at the center point leading to the development of a reaction model for further prediction and optimization of the liquefaction outcome. The effect of temperature (120–150 °C), time (20–200 min) and catalyst amount (0.5–5 wt. %) was investigated and a predictive model established.

The multivalent effect of carbohydrates (glycoclusters) has been explored to study important biological targets and processes involving Trypanosoma cruzi ( T. cruzi ) infection. Likewise, CuAAC cycloaddition reactions (click chemistry) have been applied as useful strategy in the discovery of bioactive molecules. Hence, we describe the synthesis of 1,2,3-triazole-based tetravalent homoglycoclusters ( 1–3 ) and heteroglycoclusters ( 4 and 5 ) of d -galactopyranose (C-1 and C-6 positions) and sialic acid (C-2 position) to assess their potential to inhibit T. cruzi cell invasion and also its cell surface trans- sialidase (TcTS). The target compounds were synthesised in good yields (52–75 %) via click chemistry by coupling azidosugars galactopyranose and sialic acid with alkynylated pentaerythritol or tris(hydroxymethyl)-aminomethane (TRIS) scaffolds. T. cruzi cell invasion inhibition assays showed expressive low parasite infection index values (5.3–6.8) for most compounds. However, most glycoclusters proved to be weak TcTS inhibitors at 1 mM (<17 %), except the tetravalent sialic acid 3 (99 % at 1 mM, IC 50 450 μM). Therefore, we assume that T. cruzi cell invasion blockage is not due to TcTS inhibition by itself, but rather by other mechanisms involved in this process. In addition, all glycoclusters were not cytotoxic and had significant trypanocidal activity upon parasite survival of amastigote forms.

The neuroprotective role of natural polyphenols is well established but phenolics poor water solubility affects their bioavailability and bioactivity. Aiming to overcome this issue, we were encouraged to investigate the 2-deoxyglycosylation of natural or nature inspired neuroprotective molecules, using glycals as easily accessed glycosyl donors. This robust methodology allowed the generation of a set of new resveratrol and caffeic acid ester glycosides, envisioning more effective and bioavailable compounds. Resveratrol 2-deoxyglycosides were more effective at protecting the neuronal cells from peroxide-induced cytotoxicity than resveratrol itself, while the caffeic acid ester glycoside also showed extraordinary neuroprotection activity. Coefficient partition measurements demonstrated the moderate lipophilicity of resveratrol glycosides, which Log D values are typical of a central nervous system (CNS) drug and ideal for blood-brain barrier (BBB) penetration. Passive permeation assessed by the parallel artificial membrane permeability assay (PAMPA) revealed that 2,6-dideoxy- l - arabino -hexopyranosides were more effective than 2-deoxy- d - arabino -hexopyranosides. The lack of toxicity of the neuroprotective glycosides and their promising physicochemical properties revealed the usefulness of sugar coupling towards the modulation of natural product properties and bioactivity.

Polysulfated carbohydrates play an important role in many biological processes because of their ability to bind to various protein receptors such as different growth factors, blood coagulation factors, adhesion lectins etc. Precise information about spatial organization of sulfated derivatives is of high demand for molecular modelling of such interactions as well as for understanding of the mechanism of pyranoside- into -furanoside rearrangement. In this review we summarize the changes recently revealed for the conformations of common pyranosides and furanosides upon total O-sulfation which were studied by means of NMR spectroscopy as well as molecular modelling. It was found that pentoses, being more flexible, undergo complete conformational chair inversion. Meanwhile, for hexoses the situation strongly depends on the monosaccharide configuration. Conformational changes are most pronounced in gluco -compounds though quantum chemical calculations helped to establish that no complete chair inversion occurred. In furanosides distortions of two types were observed: either the ring conformation or the conformation of the side chain changed. The presented data may be used for the analysis of chemical, physical and biological properties of sulfated carbohydrates.

Non-enzymatic transglycosylation reactions are known to occur under high sugar concentrations, high temperatures, low moisture environments and acidic conditions. Although honey is not a thermally processed food, its high sugars concentration under an acidic and low moisture environment for prolonged periods of time may also promote these reactions. To test this hypothesis six model solutions containing combinations of sucrose and glucose or fructose, prepared with water and diluted citric acid at pH 4.0 and 2.0, were incubated at 35 °C during up to 5 months, similar to the honey under hive conditions. Electrospray ionization mass spectrometry (ESI-MS) allowed to observe polymerization products soon after their incubation. After 5 months, a degree of polymerization of 6 was detected, similarly to the honey samples used for comparison. Maltose, isomaltose, inulobiose, sophorose, gentiobiose, 1-kestose and panose were detected in both model solutions and honey samples, showing that non-enzymatic transglycosylation reactions also contribute to oligosaccharides origin and diversity in honey.

Carbohydrate structures are often complex. Unfortunately, synthesis of the range of sugar combinations precludes the use of a single coupling protocol or set of reagents. Adapting known, reliable bench-chemistry reactions to work via automation will help forward the goal of synthesizing a broad range of glycans. Herein, the preparation of di- and tri-saccharides of alpha 1→2 rhamnan fragments is demonstrated using thioglycoside donors with the development for a solution-phase-based automation platform of commonly used activation conditions using N -iodosuccinimide (NIS) with trimethylsilyl triflate. Byproducts of the glycosylation reaction are shown to be compatible with hydrazine-based deprotection conditions, lending broader functionality to this method as only one fluorous-solid-phase extraction step per coupling/deprotection cycle is required.

Simplexides are natural glycolipids isolated from the marine sponge Plakortis simplex , and contain alkyl 4- O -(α-D-glucopyranosyl)-β-D-galactopyranoside. Simplexides can release of cytokines (IL-6) and chemokines (CXCL-8) from human monocytes and cause the expansion of natural killer T-cells (iNKTs) in vitro , with iNKTs contributing to the sustenance of immune homeostasis. Herein, the stereoselective syntheses of S -glycosidic analogues, i.e. S -simplexides, are described. The routes included Lewis acid promoted anomerisation of glycosyl thiols and thioglycolipids, as well as anomeric S -alkylation. Synthesis of O -glycosidic analogues are included. Heptadecanyl O - and S -glycosides as well as the 17-tritriacontyl 4- O -(α-D-glucopyranosyl)-β-D-galactopyranoside, a component of the natural simplexide isolate, all induced IL-6 and CXCL-8 production at both 10 and 30 μg/mL concentrations from PBMCs whereas the two S -simplexides were inactive. It is speculated that the lack of activity for the S -disaccharide analogue could be due to inhibition of cellular α-glucosidase, preventing degradation of the simplex disaccharide to a simpler galactopyranoside, whereas lack of activity for the S -galactolipid analogue could be due to increased conformational flexibility of S -glycosides. On the other hand, simpler unbranched O - and S -glycolipid analogues were active. Natural simplexide, and a synthetic simplexide, the 18-pentatriacontanyl 4- O -(α-D-glucopyranosyl)-β-D-galactopyranoside, were more potent than the new compounds tested.