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Sulfated glycosaminoglycans (GAGs) are complex, linear polysaccharides that are covalently linked to proteins to form proteoglycans. They are located in the extracellular matrix and at the cell surface and interact with many proteins. More than 400 interactions have been reported for heparin/heparan sulfate and these interactions are involved in numerous biological processes such as development, angiogenesis, tumor growth, host–pathogen interactions and inflammation, extracellular matrix (ECM) assembly, cell–matrix interactions and signaling. The building of GAG–protein interaction networks is required to determine how these individual interactions influence each other in vivo, are coordinated in biological processes, and are altered in diseases. This chapter reports the roadmap designed to build and analyze these interaction networks. New interactions were identified by surface plasmon resonance imaging (SPRi) using a Biacore Flexchip system and were combined with data manually curated from the literature to build a GAG–protein network. The values of equilibrium dissociation constants and of association and dissociation rates, calculated by SPR and biolayer interferometry (BLI), were integrated into the network. The network was then analyzed in silico to determine the biological processes and pathways associated with GAG partners.

Objectives The purpose of this study was to investigate the potential of hot-melt extrusion (HME) for masking the taste of bitter active pharmaceutical ingredients (APIs) when incorporated into different polymer formulations. Methods Extrudates were produced by HME using two water soluble cationic model drugs (cetirizine HCl and verapamil HCl) processed with various grades of anionic polymers (Eudragit L100 and Eudragit L100-55 (Acryl EZE)). The process was optimised by using a single screw extruder to produce extruadates with the desirable characteristics. Key findings In-vivo results obtained from a panel of six healthy human volunteers demonstrated that the HME extruded formulations improved the taste significantly compared with that of the pure APIs. In addition, an in-vitro evaluation carried out by an Astree e-tongue equipped with seven specific sensors demonstrated significant taste improvement of the extrudates compared with placebo polymers and the pure APIs. Furthermore, the extrudates characterised by SEM, X-ray and differential scanning calorimetry studies showed the existence of molecularly dispersed APIs while in-vitro dissolution showed fast release for all drug substances. Conclusions HME can effectively be used to mask the taste of bitter APIs by enhancing drug–polymer interactions.

A general method for the palladium-catalyzed formation of diaryl ethers is described. Electron-rich, bulky aryldialkylphosphine ligands, in which the two alkyl groups are either tert-butyl or 1-adamantyl, are the key to the success of the transformation. A wide range of electron-deficient, electronically neutral and electron-rich aryl bromides, chlorides, and triflates can be combined with a variety of phenols with the use of sodium hydride or potassium phosphate as base in toluene at 100 °C. The bulky yet basic nature of the phosphine ligand is thought to be responsible for increasing the rate of reductive elimination of the diaryl ether from palladium.

Palladium-catalyzed reaction of 1,3-cyclohexadiene with alcohols and acetic or benzoic acid under mild acidic conditions gives trans -1-acetoxy- or trans -1-benzyloxy-4-alkoxy-2-cyclohexenes, respectively, with high regio- and stereo-selectivity. The unsymmtrical 1,4-acyloxy-alkoxy products are obtained by fine tuning the reaction conditions in a narrow pH range.

Nucleophilic addition to (η3-2-chloropropenyl)palladium complexes 1 with stabilized carbanions such as dialkyl malonates was studied. These complexes are used as probes to determine whether nucleophilic attack occurs at the central or terminal carbon of the π-allyl group. Attack at the central carbon leads to substitution of chloride via a palladacyclobutane intermediate. The regiochemistry of the reaction (central versus terminal attack) is controlled by proper choice of ligands. Thus, σ-donor ligands direct the attack of the nucleophile to the central carbon (C-2) of the allyl group whereas π-acceptor ligands direct the attack to the terminal carbons (C-1 or C-3). It was found that there is a correlation between the relative rate of central versus terminal attack and the 13C NMR shifts of the allyl group. The shift difference between the central and terminal carbons, Cc − Ct, can be used to predict the site of attack. Ab initio calculations were performed on (π-allyl)palladium complexes as well as on th...

Total syntheses of theaspirone (A and B) and vitispirane (A and B) are described. The key step in the syntheses is the palladium(II)-catalyzed intramolecular oxaspirocyclization of diene alcohol 4 to either vitispirane or the allylic alcohol 9. The outcome of the oxaspirocyclization is very much dependent on the solvent employed. In water-acetic acid (4:1) a 1:1 mixture of the diastereomeric alcohols 9A and 9B was exclusively formed. In water with 8 equiv of a strong non-nucleophilic acid, vitispiranes A and B (1:1) were obtained. An alternative procedure to obtain vitispirane with the use of LiCl and K(2)CO(3) is described. In the latter reaction vitispirane B is formed preferentially. This result is explained by an equilibrium between the two possible pi-allyl complexes 5A and 5B, the kinetically favored 5B being transformed into vitispirane 3B before isomerization to 5A occurs.

A new palladium-mediated tandem cyclization-carbonylation of 1,3-dienes is described. The reaction proceeds via an intramolecular nucleophilic addition on the diene to give an intermediate π-allyl palladium complex which is subsequently carbonylated to give either a overall 1,2- or 1,4-addition over the diene. By proper choice of reaction conditions control of the regiochemical outcome of the reaction was obtained.

The purpose of this study was the in vitro and in vivo evaluation of the masking efficiency of hot melt extruded paracetamol (PMOL) formulations. Extruded granules containing high PMOL loadings in Eudragit EPO® (EPO) or Kollidon® VA64 (VA64) were prepared by hot-melt extrusion (HME). The taste masking effect of the processed formulation was evaluated in vivo by a panel of six healthy human volunteers. In addition, in vitro evaluation was carried out by an Astree e-tongue equipped with seven sensors. Taste sensing technology demonstrated taste improvement for both polymers by correlating the data obtained for the placebo polymers and the pure APIs alone. The best masking effect was observed for VA64 at 30% PMOL loading. The e-tongue results were in good agreement with the in vivo evaluation. In vitro dissolution of the extruded granules showed rapid PMOL releases.

NUCLEOPHILIC-ATTACK ON (PI-ALLYL)PALLADIUM COMPLEXES - DIRECTION OF THE ATTACK TO THE CENTRAL OR TERMINAL CARBON-ATOM BY LIGAND CONTROL

Palladium-catalyzed unsymmetrical 1,4-functionalizations of cyclic 1,3-dienes are described. Trifluoroacetate in combination with acetate or alcohols is utilized to obtain 1-acetoxy-4-(trifluoroacetoxy)-2-cycloalkenes and 1-alkoxy-4-(trifluoroacetoxy)-2-cycloalkenes, respectively, with good regio- and stereoselectivities. The chemoselectivity of these reactions relies on the different kinetic stability of the intermediate 4-(trifluoroacetoxy)-, 4-acetoxy-, and 4-methoxy-[eta(3)-(1,2,3)-cycloalkenyl]palladium complexes. Under the acidic reaction conditions employed, the 4-trifluoroacetoxy pi-allyl intermediate is the least stable of the three. Certain mechanistic aspects of the reactions are discussed in the light of DFT calculations.

The role of the base in RuCl2(PPh3)3-catalyzed hydrogen transfer reactions is to generate a highly active RuH2(PPh3)3 catalyst from the dichloride via two consecutive alkoxide displacement–β-elimination sequences.