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Analogues of cell surface-associated carbohydrates or inhibitors of carbohydrateprocessing enzymes are of great pharmaceutical interest. Therefore, many synthetic efforts have been devoted to mimetics of this class of molecules, such as C-glycosyl compounds, which mimic glycosides by replacement of their exocyclic acetalic oxygen with a methylene group. The C-C linkage provides hydrolytic stability without greatly affecting the carbohydrate structure. The C-glycosyl scaffolds should be suitably functionalized in order to mimic their natural counterpart. Toward this aim, regioselective deprotection can be useful for the introduction of the required functional groups. Here, we present an easy procedure for the regioselective deprotection of 3-C-(2, 3, 4, 6-tetra-O-benzyl-α-d-glucopyranosyl)prop-1-ene (1)1 at glycon position 2 and of 3-C-(1, 3, 4, 6-tetra-O-benzyl-α-d-fructofuranosyl)prop-1-ene (4)2 at glycon position 1, respectively. Reaction of the fully benzylated C-glycosylpropene with molecular iodine affords a cyclic iodoether (2 or 5), which upon reductive elimination restores the double bond and a free hydroxyl group. The overall process results in regioselective debenzylation, giving products 3 and 6, respectively. The iodocyclization reaction first involves formation of the iodonium ion, on which the oxygen of the neighboring benzyl ether can act as a nucleophile in a 5-exotype cyclization, with subsequent loss of the benzyl group as benzyl iodide, in an intramolecular process (Scheme 17.1). This regioselective deprotection has been successfully used for the synthesis of a variety of biologically relevant carbohydrate mimetics, such as C-glycosyl derivatives of glucosamine and mannosamine, 3 mimics of α-and β-N-acetyllactosamine, 4 N-acetylgalactosamine, 5 C-glycosyl nojirimycins, 6-8 sugar azido acids, 9 fructose-derived scaffolds, 10 and rigid benzodiazepine chimeric scaffolds.11.

D-Glucose derivatives bearing an anomeric thiophenyl group and orthogonally protections on secondary hydroxyl groups were linked to solid supports (PS/DV polymer, tentagel resin) through an ester bond on C-6. It was investigated the possibility to remove orthogonally protecting groups and functionalize selectively the free hydroxyls groups and the anomeric carbon of sugars in solid phase

The development of 3D printable hydrogels based on the crosslinking between chitosan and gelatin is proposed. Chitosan and gelatin were both functionalized with methyl furan groups. Chemical modification was performed by reductive amination with methyl furfural involving the lysine residues of gelatin and the amino groups of chitosan to generate hydrogels with tailored properties. The methyl furan residues present in both polymers were exploited for efficient crosslinking via Diels-Alder ligation with PEG-Star-maleimide under cell-compatible conditions. The obtained chitosan-gelatin hybrid was employed to formulate hydrogels and 3D printable biopolymers and its processability and biocompatibility were preliminarily investigated.

International audience; Synthetic 3D extracellular matrices (ECMs) find application in cell studies, regenerative medicine, and drug discovery. While cells cultured in a monolayer may exhibit unnatural behavior and develop very different phenotypes and genotypes than in vivo, great efforts in materials chemistry have been devoted to reproducing in vitro behavior in in vivo cell microenvironments. This requires fine-tuning the biochemical and structural actors in synthetic ECMs. This review will present the fundamentals of the ECM, cover the chemical and structural features of the scaffolds used to generate ECM mimics, discuss the nature of the signaling biomolecules required and exploited to generate bioresponsive cell microenvironments able to induce a specific cell fate, and highlight the synthetic strategies involved in creating functional 3D ECM mimics.

Glycans have been selected by nature for both structural and ‘recognition’ purposes. Taking inspiration from nature, nanomedicine exploits glycans not only as structural constituents of nanoparticles and nanostructured biomaterials but also as selective interactors of such glyco-nanotools. Surface glycosylation of nanoparticles finds application in targeting specific cells, whereas recent findings give evidence that the glycan content of cell microenvironment is able to induce the cell fate. This review will highlight the role of glycans in nanomedicine, schematizing the different uses and roles in drug-delivery systems and in biomaterials for regenerative medicine.

The synthesis of new dendrons of the generations 0, 1 and 2 with a double bond at the focal point and a carbonyl group at the termini has been carried out. The carbonyl group has been exploited for the multivalent conjugation to a sample saccharide by reductive amination and alkoxyamine conjugation. © 2014 Bini et al; licensee Beilstein-Institut.

Collagen matrices have been neoglycosylated with lactose by reductive amination at lysine side chains. AFM analysis highlights that the chemical neoglycosylation does not affect molecular assembly into fibrils. Moreover, ELLA biochemical assays show that the glycan moiety is efficiently exposed on the matrix surface for receptor recognition.

Introduction Curcumin is a neuroprotective compound that inhibits the formation of amyloid oligomers and fibrils and binds to β-amyloid plaques in Alzheimer’s disease (AD). We aimed to synthesize an 18F-labeled curcumin derivate ([18F]4) and to characterize its positron emission tomography (PET) tracer-binding properties to β-amyloid plaques in a transgenic APP23 mouse model of AD. Methods We utilized facile one-pot synthesis of [18F]4 using nucleophilic 18F-fluorination and click chemistry. Binding of [18F]4 to β-amyloid plaques in the transgenic APP23 mouse brain cryosections was studied in vitro using heterologous competitive binding against PIB. [18F]4 uptake was studied ex vivo in rodents and in vivo using PET/computed tomography of transgenic APP23 and wild-type control mice. Results The radiochemical yield of [18F]4 was 21 ± 11%, the specific activity exceeded 1 TBq/μmol, and the radiochemical purity exceeded 99.3% at the end of synthesis. In vitro studies of [18F]4 with the transgenic APP23 mouse revealed high β-amyloid plaque binding. In vivo and ex vivo studies demonstrated that [18F]4 has fast clearance from the blood, moderate metabolism but low blood–brain barrier (BBB) penetration. Conclusions [18F]4 was synthesized in high yield and excellent quality. In vitro studies, metabolite profile, and fast clearance from the blood indicated a promising tracer for Aβ imaging. However, [18F]4 has low in vivo BBB penetration and thus further studies are needed to reveal the reason for this and to possibly overcome this issue.

A set of new metabolically stable arabinose 5-phosphate analogues possessing phosphate mimetic groups at position 5 was synthesised. Their ability to interact with arabinose 5-phosphate isomerase from Pseudomonas aeruginosa was evaluated by STD-NMR studies. The synthesised compounds were also characterised for their activity in vivo on P. aeruginosa and Escherichia coli strains. Unfortunately, none of the synthesised compounds was able neither to bind API nor to inhibit bacterial growth.

Despite the relevance of carbohydrates as cues in eliciting specific biological responses, glycans have been rarely exploited in the study of neuronal physiology. We report thereby the study of the effect of neoglucosylated collagen matrices on neuroblastoma F11 cell line behavior. Morphological and functional analysis clearly showed that neoglucosylated collagen matrices were able to drive cells to differentiate. These data show for the first time that F11 cells can be driven from proliferation to differentiation without the use of chemical differentiating agents. Our work may offer to cell biologists new opportunities to study neuronal cell differentiation mechanisms in a cell environment closer to physiological conditions.

Hybrid materials with interpenetrating networks of silica and degradable polymers have the potential to outperform current biomaterials as their mechanical properties and degradation rates can be tightly controlled. GPTMS is one of the most widely used precursors for sol–gel hybrid fabrication. It can be used as the silica precursor or as a coupling agent to create hybrids with covalent bonds between the silica and organic components. Understanding its reactivity with nucleophilic groups on organic molecules in aqueous conditions is of key importance to hybrid synthesis. NMR spectrometry assisted by mass spectrometry was successfully used for the investigation of the reaction system of (3-glycidoxypropyl)trimethoxysilane (GPTMS) in the presence of different simple nucleophiles. Inorganic condensation and silica network formation is accelerated in the presence of propylamine; propanoic acid gives nucleophilic attack on the epoxy ring; propanol and propanthiol do not seem to participate in the reaction.

Aβ-peptide ligands based on a cis-glycofused benzopyran structure have been fluorescently labeled using coumarine derivatives. Among the synthesized compounds, two conserved their binding ability to β-amyloid peptides, as shown by NMR experiments. Moreover, exploiting its fluorescent property, it was demonstrated that one of such compounds was able to cross an in vitro model of blood–brain barrier (BBB) and to stain Aβ‑deposits.

Biomaterials are needed for tissue regeneration applications that provide control of mechanical properties and enhanced toughness compared to conventional bioceramics. New sol–gel hybrids were developed with interpenetrating networks of silica and bis(3-aminopropyl) polyethylene glycol. Covalent coupling between the organic and the inorganic components was used to control mechanical properties of the hybrids. The objective was to synthesise and characterise a bis(3-aminopropyl) polyethylene glycol silica hybrid material with 35 wt% organic and 65 wt% inorganic and covalent coupling between the components. A coupling agent, 3-glycidopropyltrimethoxysilane (GPTMS) was used to form the covalent links. The hypothesis was that the epoxy ring of the GPTMS would react with the polymer, leaving a polymer functionalised with siloxane groups. In a sol of hydrolysed tetraethyl orthosilicate (TEOS) the siloxanes from the GPTMS form –Si–O–Si– bonds between the functionalised polymer and the silica network. Bis(3-aminopropyl) polyethylene glycol contains two terminal amino groups available for the covalent functionalisation with the epoxy group of GPTMS. Hybrids with 35 wt% organic and 65 wt% inorganic with a ratio of GPTMS:PEG of 1:4 were proven to have an excellent balance between strain to failure (10%) and compressive strength (20 MPa). However, the functionalisation of the polymer was followed by liquid NMR as a function of the aging time and temperature and the expected reaction of nucleophilic attack of the epoxy ring by the amino group of the polymer did not happen until the water was removed from the system during drying. Increasing the amount of GPTMS decreased rate of weight loss during immersion in TRIS buffer solution.

Amyloid peptides, Aβ1-40 and Aβ1-42, represent major molecular targets to develop potential drugs and diagnostic tools for Alzheimer's Disease (AD). In fact, oligomeric and fibrillar aggregates generated by these peptides are amongst the principal components of amyloid plaques found post mortem in patients suffering from AD. Rosmarinic acid has been demonstrated to be effective in preventing the aggregation of amyloid peptides in vitro and to delay the progression of the disease in animal models. Nevertheless, no information is available about its molecular mechanism of action. Herein, we report the NMR characterization of the interaction of Salvia sclareoides extract and that of its major component, rosmarinic acid, with Aβ1-42 peptide, whose oligomers have been described as the most toxic Aβ species in vivo. Our data shed light on the structural determinants of rosmarinic acid-Aβ1-42 oligomers interaction, thus allowing the elucidation of its mechanism of action. They also provide important information for the rational design of new compounds with higher affinity for Aβ peptides to generate new anti-amyloidogenic molecules and/or molecular tools for the specific targeting of amyloid aggregates in vivo. In addition, we identified methyl caffeate, another natural compound present in different plants and human diet, as a good ligand of Aβ1-42 oligomers, which also shows anti-amyloidogenic activity. Finally, we demonstrated the possibility to exploit STD-NMR and trNOESY experiments to screen extracts from natural sources for the presence of Aβ peptide ligands.

Great interest is presently given to the analysis of metabolic changes that take place specifically in cancer cells. In this review we summarize the alterations in glycolysis, glutamine utilization, fatty acid synthesis and mitochondrial function that have been reported to occur in cancer cells and in human tumors. We then propose considering cancer as a system-level disease and argue how two hallmarks of cancer, enhanced cell proliferation and evasion from apoptosis, may be evaluated as system-level properties, and how this perspective is going to modify drug discovery. Given the relevance of the analysis of metabolism both for studies on the molecular basis of cancer cell phenotype and for clinical applications, the more relevant technologies for this purpose, from metabolome and metabolic flux analysis in cells by Nuclear Magnetic Resonance and Mass Spectrometry technologies to positron emission tomography on patients, are analyzed. The perspectives offered by specific changes in metabolism for a new drug discovery strategy for cancer are discussed and a survey of the industrial activity already going on in the field is reported.

Synthesis of a library of pyrrolo[2,1-c][1,4]-benzodiazepines derived from spiro bicyclic d- or l-proline analogues containing a d- or l-fructose moiety was developed. The l-fructose moiety was obtained by using a new synthetic pathway starting from l-arabinose through a six steps synthesis in 18% overall yield. Molecular modeling calculations and DNMR studies showed that d- and l-fructose-based pyrrolobenzodiazepines exhibit a rigid (P)- and (M)-helical conformation, respectively, in which the C-11a substituent was always pseudoequatorial. Additionally, pyrrolobenzodiazepines functionalized with a chloride, bromide, nitro, or amino group in the benzene ring, with or without N-methylation and with or without protection of sugar alcohol groups, allowed a relationship between the molecular structure and biological activity to be established. The conformation of the diazepam ring was not the sole key player influencing binding affinities, and the sugar moiety can in some cases increase the binding activity, possibly by participating in the binding event. Finally, these compounds have increased the understanding of the differential recognition of (M)-/(P)-helical benzodiazepines on GABAA receptor. © 2011 American Chemical Society.

The antibiotic tetracycline was reported to possess an anti-amyloidogenic activity on a variety of amyloidogenic proteins both in in vitro and in vivo models. To unveil the mechanism of action of tetracycline on Aβ1-40 and Aβ1-42 at both molecular and supramolecular levels, we carried out a series of experiments using NMR spectroscopy, FTIR spectroscopy, dynamic laser light-scattering (DLS) and atomic force microscopy (AFM). Firstly we showed that the co-incubation of Aβ1-42 oligomers with tetracycline hinders the toxicity towards N2a cell lines in a dose-dependent manner. Therefore, the nature of the interaction between the drug and Aβ oligomers was investigated. To carry out NMR and FTIR studies we have prepared Aβ peptide solutions containing assemblies ranging from monomers to large oligomers. Saturation transfer difference (STD) NMR experiments have shown that tetracycline did not interact with monomers at variance with oligomers. Noteworthy, in this latter case we observed that this interaction was very peculiar since the transfer of magnetization from Aβ oligomers to tetracycline involved all drug protons. In addition, intermolecular cross-peaks between tetracycline and Aβ were not observed in NOESY spectra, indicating the absence of a specific binding site and suggesting the occurrence of a supramolecular interaction. DLS and AFM studies supported this hypothesis since the co-dissolution of Aβ peptides and tetracycline triggered the immediate formation of new aggregates that improved the solubility of Aβ peptides, preventing in this way the progression of the amyloid cascade. Moreover, competitive NMR binding experiments showed for the first time that tetracycline competes with thioflavin T (ThT) in the binding to Aβ peptides. Our data shed light on a novel mechanism of anti-amyloidogenic activity displayed by tetracycline, governed by hydrophobic and charge multiparticle interactions. © 2011 The Royal Society of Chemistry.

A promising strategy to enhance blood-brain barrier penetration by drugs is the functionalization of nanocarriers with uptake-facilitating ligands. We studied the cellular uptake, by cultured RBE4 brain capillary endothelial cells, of nanoliposomes (NLs) covalently coupled with monomer or tandem dimer of apolipoprotein E (ApoE)-derived peptides (residues 141-150), at various densities. NLs without functionalization did not show either relevant membrane accumulation or cellular uptake, as monitored by confocal microscopy and quantified by fluorescence-activated cell sorting. Functionalization with peptides mediated an efficient NLs uptake that increased with peptide density; NLs carrying monomeric peptide performed the best. Moreover, we studied the ability of ApoE-NLs to enhance the transport of a drug payload through a RBE4 cell monolayer. The permeability of a tritiated curcumin derivative was enhanced after its entrapment into ApoE-NLs, in particular those functionalized with the dimer (+83% with respect to free drug, P < 0.01). Thus, these NLs appear particularly suitable for implementing further strategies for drug brain targeting. From the Clinical Editor: Re and her collaborators present a method for delivering nanoliposomes via the blood brain barrier by utilizing peptide fragments including monomers or tandem dimers ApoE. This method may enable enhanced nanoliposome associated drug delivery via the blood-brain barrier, which would have enormous significance in neurodegenerative and other CNS disorders

Small molecules altering protein functions as inhibitors, agonists or antagonists, find application in systems biology enabling an analysis of the in vivo consequences of these alterations. In this context carbohydrates are ideal tools, not only because they are involved in a variety of recognition phenomena of biological relevance, but also because they are ideal scaffolds to generate libraries of bioactive compounds. Examples of design, synthesis and biological assays of different carbohydrate based inhibitors or protein ligands are reported. Exploiting NMR methods, the binding between a small molecules (inhibitor or ligand) and a protein can be detected, the affinity measured, and the interaction topology defined. This set of information is useful not only to clarify the mechanism of protein-ligand interaction, but also to improve the design of new inhibitors/ligands. The multifunctionality and the conformational rigidity of carbohydrates make this class of compounds the ideal scaffolds to generate libraries exploiting the combinatorial approach. An example of solid phase combinatorial synthesis of a library of 37 compounds is reported.

Lipopolysaccharides (LPSs) constitute the lipid portion of the outer leaflet of Gram-negative bacteria; they are essential for growth, and are also responsible for the variety of biological effects associated with Gram-negative sepsis. Recent advances have elucidated the exact chemical structure of this highly complex macromolecule and part of the enzymology involved in its biosynthesis. Enzymes involved in LPS biogenesis are optimal targets for the development of novel therapeutics since they are sufficiently conserved among diverse, clinically-relevant bacteria and no analogue counterpart is present in humans. During the last thirty years a number of inhibitors to LPS biosynthesis have been developed: some of these compounds have antibacterial properties, while others show excellent in vitro activity and are undergoing further investigation. This review will focus on the biology of LPS in bacteria summarizing the knowledge about structure and enzymatic catalysis, as well as chemical efforts towards the synthesis of inhibitors of the key enzymes involved in the biosynthesis of the minimal conserved structure Kdo2-LipA, also referred to as Re LPS. Only a short overview will be given on lipid A biosynthesis and inhibitors, while main focus will be Kdo biosynthesis towards Re LPS. Future directions and perspectives will also be outlined. © 2008 Bentham Science Publishers Ltd.

C-Glucoside derivatives covalently linked to the arsenic atom in different oxidation states have been synthesized by avoiding protection-deprotection steps. While compound 1, bearing an AsV atom, did not show any significant biological activity, compound 2, in which the glucose moiety is linked to the arsenic atom as dithioarsenical (AsIII), showed promising antiproliferative activity on a cell line of neuroblastoma (SK-N-BE). C-Glucoside derivatives covalently linked to the arsenic atom in different oxidation states have been synthesized. The C-glucoside conjugated to the phenyldithioarsolan group, showed promising antiproliferative activity on human neuroblastoma cells (SK-N-BE).

The grafting of galactose units onto poly(epsilon-caprolactone) (PCL) substrates by a wet chemistry two-step procedure is proposed. Even though a reduction of hardness from 0.58-0.31 GPa to 0.12-0.05 GPa is achieved, the chemical functionalization does not negatively affect the tensile modulus (332.2 +/- 31.3 MPa and 328.5 +/- 34.7 MPa for unmodified and surface-modified PCL, respectively) and strength (15.1 +/- 1.3 MPa and 14.8 +/- 1.5 MPa as assessed before and after the surface modification, respectively), as well as the mechanical behaviour evaluated through small punch test. XPS and enzyme-linked lectin assay (ELLA) demonstrate the presence, and also the correct exposition of the saccharidic epitope on PCL substrates. The introduction of carbohydrate moieties on the PCL surfaces clearly enhances the hydrophilicity of the substrate, as the water contact angle decreases from 82.1 +/- 5.8 degrees to 62.1 +/- 4.2 degrees. Furthermore, preliminary biological analysis shows human mesenchymal stem cell viability over time and an improvement of cell adhesion and spreading. (C) 2014

Novel inhibitors of Ras protein activation have been found, containing a bicyclic core derived from D-arabinose and benzyl and phenylhydroxylamine moieties. NMR studies (trNOE, saturation-transfer difference, STD) of the binding between these molecules and human p21 h-Ras are reported. A pharmacophore mapping indicates that both the benzyl and the phenylhydroxylamine moieties are essential for protein binding. Molecules lacking one of these groups were synthesized and tested to confirm this hypothesis, and no interaction with Ras in vitro, nor biological activity in mammalian cells was observed. Our studies led to the development of molecules that selectively inhibit Ras-dependent cellular growth in mammalian cells. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

A bicyclic scaffold derived from the natural monosaccharide d-glucose, and possessing several diversity sites, was linked to various resins through the primary (C-6) hydroxyl and decorated on the solid phase: the hydroxyl group at C-4 was functionalized as ester, ether, and carbamate, the amino group in the second cycle (C-3' position) was functionalized as amide, sulfonamide, and ureido- and thioureido-derivatives. The compounds synthesized on the solid phase were tested for their antiproliferative activity on tumor cell lines.

The use of modified carbohydrates, such as sugar amino acids (SAA), iminosugars and policyclic derivatives, as scaffolds for the generation of bioactive compounds, and the use of carbohydrates as building blocks or ligands for the production of polymers for biomedical applications, is reviewed. Copyright © Taylor & Francis Group, LLC.

A mimetic of Lipid A with a beta-N(OMe) glycosidic linkage, four linear C-14 hydrophobic chains and without phosphate groups has been prepared together with its beta-O-linked analogue. Both these molecules were active in inhibiting the inflammatory action of Escherichia coli lipid A on MT2 macrophages in a dose-dependent manner, while they were completely devoid of inflammatory activity.

The synthesis of new dendrons and their immobilization on collagen patches via thiol − ene photoclick reaction, followed by chemoselective alkoxyamino − carbonyl conjugation to carbohydrates is presented. XPS, FTIR, and ELLA assays con fi rmed the e ff ectiveness of the collagen multivalent neoglycosylation

Structural requirements of d -arabinose 5-phosphate isomerase (KdsD, E.C. 5.3.1.13) from Pseudomonas aeruginosa were analysed in detail using advanced NMR techniques. We performed epitope mapping studies of the binding between the enzyme and the most potent KdsD inhibitors found to date, together with studies of a set of newly synthesised arabinose 5-phosphate (A5P) mimetics. We report here the first experimental evidence that KdsD may bind the furanose form of A5P, suggesting that catalysis of ring opening may be an important part of KdsD catalysis.

Nanoliposomes decorated on their surface with ligands for Aβ-peptides, the key morphological features of Alzheimer's disease (AD), have been synthesized and characterized for their ability to target Aβ-peptide aggregates. A tricyclic benzopyrane-glycofused structure has been exploited as Aβ-peptide ligand, which was linked to liposomes via a copper-free, chemoselective, biocompatible click chemistry reaction. The tricyclic-decorated liposomes presented a mean diameter in the nanomolar range (150–200 nm), a negative z-potential and a good stability, at least up to one month. Integrity studies performed in the presence of serum proteins indicated that these decorated nanoliposomes fulfill the requirements for in vivo applications. NMR experiments carried out with Aβ 1-42 oligomers using both surface functionalized and plain (control) liposomes, revealed that the binding ability of the nanoliposomes was mediated by the presence of the tricyclic ligand on their surface. Finally ThT assay carried out with tricyclic-decorated liposomes showed significant decrease in thioflavine T fluorescence after 24 h, suggesting a significant inhibition/delay of Aβ 1-42 aggregation.

Despite the relevance of carbohydrates as cues in eliciting specific biological responses, the covalent surface modification of collagen-based matrices with small carbohydrate epitopes has been scarcely investigated. We report thereby the development of an efficient procedure for the chemoselective neoglycosylation of collagen matrices (patches) via a thiol-ene approach, between alkene-derived mono-saccharides and the thiol-functionalized material surface. Synchrotron radiation-induced X-ray photoelectron spectroscopy (SR-XPS), Fourier transform-infrared (FT-IR), and enzyme-linked lectin assay (ELLA) confirmed the effectiveness of the collagen neoglycosylation. Preliminary biological evaluation in osteoarthritic models is reported. The proposed methodology can be extended to any thiolated surface for the development of smart biomaterials for innovative approaches in regenerative medicine.

We synthesized fused bicyclic polyfunctional compounds containing a highly hydroxylated pyran ring starting from commercially available methyl glucopyranoside and adopting a RCM annulation approach. The versatile α,β-unsaturated ketone group was introduced on the newly formed ring and, as an example of the potential of these polyfunctionalized building blocks, a tetracyclic compound was synthesized through a Diels-Alder cycloaddition reaction

A new approach for tethering of bioactive molecules via arginine is proposed and validated on collagen 2D matrices. The method involves the introduction of a methyl ketone on arginine side-chains, followed by reaction with model alkoxyamino derivatives. This journal is © the Partner Organisations 2014.

New sulfoquinovose analogues of phosphatidylinositol 3-phosphate have been synthesised based on a sulfoquinovose scaffold as potential protein kinase B (PKB) inhibitors. The synthetic strategy involved the introduction into glucose of a thioacetate group at the 6-position and of an azide group at the anomeric position as precursors of the sulfonate and phosphoramidate moieties present in the final compounds. The synthesised compounds were tested in vitro on isolated PKB by means of ELISA assays and for their anti-proliferative activity against the human ovarian carcinoma cell line IGROV-1. Sulfoquinovose derivatives 2b and 2c showed inhibitory activity in the low micromolar range. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

8-β-d-Glucopyranosylgenistein (1), the major component of Genista tenera, was synthesized and showed an extensive therapeutical impact in the treatment of STZ-induced diabetic rats, producing normalization of fasting hyperglycemia and amelioration of excessive postprandial glucose excursions and and increasing β-cell sensitivity, insulin secretion, and circulating insulin within 7 days at a dose of 4 (mg/kg bw)/day. Suppression of islet amyloid polypeptide (IAPP) fibril formation by compound 1 was demonstrated by thioflavin T fluorescence and atomic force microscopy. Molecular recognition studies with IAPP and Aβ1-42 employing saturation transfer difference (STD) confirmed the same binding mode for both amyloid peptides as suggested by their deduced epitope. Insights into the preferred conformation in the bound state and conformers' geometry resulting from interaction with Aβ1-42 were also given by STD, trNOESY, and MM calculations. These studies strongly support 8-β-d-glucopyranosylgenistein as a promising molecular entity for intervention in amyloid events of both diabetes and the frequently associated Alzheimer's disease.

Our work shows how poly(ethylene glycol), differentially functionalized at two ends, can be easily and efficiently synthesized from commercial symmetric dihydroxy PEG 600. First, we linked the polymer onto functionalized silica gel using one of its hydroxy ends. Then, the second hydroxy group was modified, and finally, the desymmetrized PEG was cleaved from the solid support.

Stable C-glycosidic an analogues of 2-O-(beta-D-glucopyranosyl)-sn-glycerol (In), 2-O-(beta-D-galactopyranosyl)-sn glycerol (Ib), 1-O-(beta-D-glucopyranosyl)-sn-glycerol (7) and their dipalmitoyl ester have been synthesised starting from the corresponding 2,3,4,6-tetra-O-benzyl-glyconolactones 9. The 2-O-derivatives 1 were obtained by methylenation of the lactone 9, reaction of the obtained glycoexoenitol 10 with a malonyl radical, reduction of the malonyl derivative 11 and deprotection. The 1-O-derivative 7 was obtained by reaction of the lactone 9 with butenylmagnesium bromide, reduction of the obtained lactol 14, osmylation and deprotection. (C) 1997 Elsevier Science Ltd.

Hybrid organic-inorganic solids represent an important class of engineering materials, usually prepared by sol-gel processes by cross-reaction between organic and inorganic precur- sors. The choice of the two components and control of the reaction conditions (especially pH value) allow the synthe- sis of hybrid materials with novel prop- erties and functionalities. 3-Glycidoxy- propyltrimethoxysilane (GPTMS) is one of the most commonly used organ- ic silanes for hybrid-material fabrica- tion. Herein, the reactivity of GPTMS in water at different pH values (pH 2- 11) was deeply investigated for the first time by solution-state multinuclear NMR spectroscopic and mass spectro- metric analysis. The extent of the dif- ferent and competing reactions that take place as a function of the pH val- ue was elucidated. The NMR spectro- scopic and mass spectrometric data clearly indicate that the pH value de- termines the kinetics of epoxide hy- drolysis versus silicon condensation. Under slighly acidic conditions, the epoxy-ring hydrolysis is kinetically more favourable than the formation of the silica network. In contrast, under basic conditions, silicon condensation is the main reaction that takes place. Full characterisation of the formed inter- mediates was carried out by using NMR spectroscopic and mass spectro- metric analysis. These results indicate that strict control of the pH values allows tuning of the reactivity of the organic and inorganic moities, thus laying the foundations for the design and synthesis of sol-gel hybrid bioma- terials with tuneable properties.

Poly(-caprolactone), PCL, has been functionalized with a biologically relevant monosaccharide, i.e. glucosamine, in a single step process downstream to material fabrication. Glucosamine-functionalised PCL showed enhanced cell density and spreading then the non-functionalised samples

Metabolically stable arabinose 5-phosphate analogues possessing phosphate mimetic groups at the 5-position were synthesized and evaluated by saturation-transfer-difference (STD) NMR studies for their ability to interact with arabinose 5-phosphate isomerase. Isosteric methylphosphonate 1 and (difluoromethyl)phosphonate 3 were recognised and bound by the catalytic pocket of the enzyme. The synthesized compounds were tested in vivo on E. coli and P. aeruginosa strains in order to evaluate their antibacterial activity.

The synthesis of the disaccharides methyl 4-O-(2'/3'-O-sulfo-beta-D-glucopyranosyluronic acid)-2-amino-2-deoxy-alpha-D-glucopyranoside 3 and 4 as disodium salts is described. Allyl 4,6-O-benzylidene-alpha-D-glucopyranoside 6 was converted to trichloroacetimidate 20. Glycosylation of 20 with 5 promoted by BF3 . OEt(2) gave disaccharide 21. Deacetylation of 21 followed by monoacetylation of the resultant diol 22 afforded the two monoacetylated disaccharides 23 and 24. Sulfation and deprotection of each disaccharide gave the desired sulfated compounds 3 and 4.

Smart biomaterials for tissue regeneration need to incorporate molecules able to interact with specific cellular adhesion or morphogenic proteins of the extracellular matrix (ECM).NMR binding studies allow obtaining structural information essential for the comprehension of biological processes and, nowadays, high-resolution magic-angle-spinning (HR-MAS) NMR spectroscopy is a well-established tool for the study of heterogeneous systems. Here the generation of a model-system used to explore the possibility to reveal interactions between two molecular entities, one of which linked to a solid support, to mimic a bioactive species immobilized on a biomaterial surface, is presented. The carbohydrate recognition processes that take place in the ECM have a pivotal role in promoting cell adhesion and differentiation and, thus, tissue regeneration. Hence, a pseudo-receptor, that mimics the lectin binding site was prepared and its interaction with a panel of different monosaccharides was characterized. The results obtained support the theoretical model according to which lectins bind carbohydrates exploiting the CH-π interactions occurring in their active site. Moreover the NMR experimental approach here described can be generally applied when the interacting species do not have the same solubility properties in physiological conditions and, in particular, can be exploited for the analysis and characterization of molecular recognition events occurring at biomaterial surface.

A small set of nojirimycin- and pyrrolidine-based iminosugar derivatives has been synthesized and evaluated as potential inhibitors of porcine and insect trehalases. Compounds 12, 13 and 20 proved to be active against both insect and porcine trehalases with selectivity towards the insect glycosidase, while compounds 10, 14 and 16 behaved as inhibitors only of insect trehalase. Despite the fact that the activity was found in the micromolar range, these findings may help in elucidating the structural features of this class of enzymes of different origin, which are still scarcely characterised.

Several glycoprocessing enzymes and glycoreceptors have been recognized as important targets for therapeutic intervention. This concept has inspired the development of important classes of therapeutics, such as anti-influenza drugs inhibiting influenza virus neuraminidase, anti-inflammatory drugs targeting lectin-sialyl-Lewis X interaction and glycosidase inhibitors against HIV, Gaucher’s disease, hepatitis and cancer. These therapeutics are mainly carbohydrate mimics in which proper modifications permit stronger interactions with the target protein, higher stability, better pharmacokinetic properties and easier synthesis. Furthermore, the conformational rigidity and polyfunctionality of carbohydrates stimulate their use as scaffolds for the generation of libraries by combinatorial decoration with different pharmacophores. This mini-review will present examples of how to exploit carbohydrates mimics and scaffolds in drug research.

An efficient method for the direct and covalent decoration of granules of nanostructured apatite with a sample monosaccharide is presented: the hydroxyapatite material was directly functionalised with a short azido-containing spacer arm, to which alpha-propargyl glucopyranoside has been chemoselectively ligated by Huisgen-type cycloaddition. The 'glycosylated' hydroxypatite was characterised by its ability to interact with glucose recognising lectins. (C) 2011 Elsevier Ltd. All rights reserved.

Amyloid β (Aβ) aggregates are considered as possible targets for therapy and/or diagnosis of Alzheimer disease (AD). It has been previously shown that curcumin targets Aβ plaques and interferes with their formation, suggesting a potential role for prevention or treatment of AD. Herein, a click chemistry method was used to generate nanoliposomes decorated with a curcumin derivative, designed to maintain the planar structure required for interaction with Aβ, as directly confirmed by Surface Plasmon Resonance experiments. Another type of liposomes was formed starting from curcumin-phospholipid conjugate, in which the planar structure of curcumin is disrupted. Both types of generated curcumin-decorated vesicles had mean diameters in the nano range (131-207 nm) and slightly negative ζ-potential values according to their lipid composition, and were stable for periods up to 20 days. They also demonstrated high integrity during incubation in presence of plasma proteins. Surface Plasmon Resonance experiments, measuring the binding of flowing liposomes to immobilized Aβ1-42, indicated that the liposomes exposing the curcumin derivative (maintaining the planarity) have extremely high affinity for Aβ1-42 fibrils (1-5 nM), likely because of the occurrence of multivalent interactions, whereas those exposing non-planar curcumin did not bind to Aβ1-42. In summary, we describe here the preparation and characterization of new nanoparticles with a very high affinity for Aβ1-42 fibrils, to be exploited as vectors for the targeted delivery of new diagnostic and therapeutic molecules for AD. © 2010 Elsevier Ltd.

Preparation of azido-functionalized polymers is gaining increasing attention. We wish to report an innovative, novel strategy for azido functionalization of polymeric materials, coupling plasma technology and solution processed diazo transfer reactions. This novel approach allows the azido group to be introduced downstream of the material preparation, thus preserving its physicochemical and mechanical characteristics, which can be tailored a priori according to the desired application. The whole process involves the surface plasma functionalization of a material with primary amino groups, followed by a diazo transfer reaction, which converts the amino functionalities into azido groups that can be exploited for further chemoselective reactions. The diazo transfer reaction is performed in a heterogeneous phase, where the azido group donor is in solution. Chemical reactivity of the azido functionalities was verified by subsequent copper-catalyzed azide-alkyne cycloaddition. © 2011 Elsevier Ltd.

The misfolding, aggregation and accumulation of proteins in the brain, represents a common feature of diverse neurodegenerative diseases among which Alzheimer’s disease (AD). Important therapeutic strategies for this pathology aim at inhibiting the aggregation of misfolded amyloid β (αβ) peptides into different species, particularly intermediate oligomeric assemblies, which are believed to be the most neurotoxic species. Here we review the structural data present in the literature, with the purpose to supply useful information for the rational design of new potential molecules able to target αβ peptides and fibrils. In particular, structural information concerning the different αβ peptides assemblies, their supramolecular organization, their interaction with cations, biological membranes and known ligands are reported.