Cathepsin B is an abundant and ubiquitously expressed cysteine peptidase of the papain family. It is involved in many physiological processes, such as remodeling of the extracellular matrix (wound healing), apoptosis, and activation of thyroxine and renin. In addition to its physiological roles, cathepsin B is important in many pathological processes, such as inflammation, parasite infection and cancer, where it is highly up-regulated. In cancer patients, elevated cathepsin B activity correlates to poor therapy outcome. Therefore, it is not surprising that the use of cathepsin B inhibitors reduces both tumor cell motility and invasiveness in vitro. This review summarizes recent developments in cathepsin B inhibition. To date, numerous protein inhibitors of cathepsin B have been described, some of which are of endogenous origin and function as regulators of cathepsin B activity in the cell, such as the cystatins. In addition, some exogenous protein inhibitors of cathepsin B have been isolated from various natural sources, and the use of X-ray crystal structures of cathepsin B complexed with such protein inhibitors has resulted in the design and synthesis of many new small-molecular-weight compounds as inhibitors of cathepsin B. These synthetic compounds generally contain an electrophilic functionality that reacts with cathepsin B. In the present review, these inhibitors are divided according to their mechanisms of action, as reversible and irreversible, and then further subdivided into groups for their full descriptions.
Diaryl ethers form an important class of organic compounds, both in life sciences and in the polymer industry. In general, diaryl ethers can be synthesized by means of copper-catalyzed Ullmann diaryl ether coupling, palladium-catalysed BuchwaldHartwig reaction, nucleophilic aromatic substitution, arylboronic acid diaryl ether coupling, oxidative coupling, and nucleophilic aromatic addition to metal-arene complexes. This review covers the progress in diaryl ether synthesis since 1999, with literature coverage through September 2005. 9Su mmary
A sustainable D-glucosamine ligand is successfully introduced into iron-catalysed C-C cross-coupling reactions for the first time. The Fe(acac) 2 /D-glucosamine·HCl/Et 3 N catalytic system was effective at 5 mol% loading in coupling reactions of Grignard reagents with organic bromides. Moderate to high efficiency was achieved with preserved stereochemistry when allyl (Csp 3 ) or alkenyl (Csp 2 ) bromides were coupled with phenylmagnesium (Csp 2 ) or benzylmagnesium (Csp 3 ) bromides. The catalytic system developed was also successfully applied for the novel and economic preparation of a Michael-acceptor-like starting material used in an alternative synthesis of the drug sitagliptin, a known blockbuster for the treatment of type II diabetes mellitus.
Microencapsulation by the solvent evaporation method is a complex process, which can be influenced by many process parameters, e.g. solvent evaporation rate, 1) temperature, [2][3][4][5] solubility of polymer, drug and excipients in both emulsion phases, 6,7) dispersion stirring rate, 7-9) viscosity, solubility, volume and volume ratio between the inner and outer phases, [10][11][12] the quantity of polymer and drug, 1,6) and the physico-chemical properties and concentration of the stabilizator.11,13) Some authors have previously studied the effects of preparation temperature on microsphere formation and characteristics: mean microsphere diameter and size distribution width, 2,5) particles morphology, 2) porosity, 5) and drug loading. 5)One can find only one report on the effect of temperature on microspheres containing Eudragit. We have previously reported that temperature (40, 50, 60°C) had an insignificant effect on mean diameter or drug encapsulation yield using Eudragit E as a matrix polymer.3) However, these results differ from the findings of the above mentioned authors. 2,5) Thus, the objective of this study was to investigate the effect of preparation temperature on Eudragit RS microsphere properties in a different temperature range. Lower temperatures were examined, where more pronounced influences were expected. Average particle size and microsphere morphology, drug content and release kinetics, and drug crystal state in microspheres were evaluated. ExperimentalMaterials Eudragit RS were kindly provided by Röhm GmbH, Darmstadt, Germany, magnesium stearate and ketoprofen by Lek Pharmaceuticals d.d., Slovenia. All other substances used were of analytical grade.Microsphere Preparation Microspheres were prepared using emulsification and a solvent evaporation technique in an acetone/liquid paraffin solvent system. 1.25 g of Eudragit RS and 0.75 g of ketoprofen were dissolved in 5 ml of acetone. 0.35 g of magnesium stearate was separately dispersed in 3 ml of acetone and added to the mentioned solution. The dispersion of magnesium stearate, Eudragit RS and ketoprofen in acetone was emulsified into 80 ml of liquid paraffin with fixed temperatures (10, 25, 35, 40°C). The system was stirred at 250 rpm at the above-mentioned constant temperatures for 1 h. The microspheres were filtered, washed with n-hexane, and dried overnight at room temperature under reduced pressure. Microspheres were prepared in triplicates at each of the defined temperatures. All the experiments for microsphere characterization were performed with one-day-old samples, except in the cases specified otherwise.Particle Size Analysis Microsphere size was determined with sieve analysis (AS200 Analytical Sieve Shaker, Retsch GmbH & Co. KG, Germany). Sieves with mesh sizes 630, 500, 400, 315, 250, 200, 160, 125, 100, 80, 63, and 50 mm were used. Sifting time was 20 min.Drug Content Determination A known quantity of microspheres (ca. 10 mg) was dispersed in 96% ethanol and stirred for an hour. A small volume of the sample was filtered, diluted w...
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