Development of the telescoped flow Pd-catalyzed aerobic alcohol oxidation/reductive amination sequence in the synthesis of new phosphatidylinositide 3-kinase inhibitor (CPL302415).

Herein, we describe a two-step sequential flow synthesis: Pd-catalyzed aerobic oxidation to an aldehyde 2, which is then converted by reductive amination in H-Cube® PRO into CPL302415 (3). CPL302415 is our new PI3Kδ inhibitor, which is now under evaluation for the treatment of systemic lupus erythematosus. The process was optimized using the DoE approach and generalized to other biologically active derivatives of CPL302415.

Generation of red light with intense photoluminescence assisted by Forster resonance energy transfer from Znq2 and DCM thin films.

In this work, a novel experimental investigation of photoluminescence properties of Znq2 thin films co-doped with different concentrations of DCM were performed. The thin films were successfully deposited on glass substrates with different compositions, under high vacuum, by using the vacuum evaporation technique. For all compositions, the photoluminescence was measured at room temperature and also at low temperature in a wide range from 77 to 300 K with a step of 25 K in a high vacuum. The lifetime of the sample studied in real time was also measured using the decay time technique. The results obtained confirm that the doping influences the intensity of the DCM photoluminescence and also shows a complete energy transfer occurred from Znq2 to DCM which may have shifted the photoluminescence peak from Znq2 to the orange wavelength region which is related to DCM. The lifetime of the sample studied in real time was about 4.47 ns for Znq2 and while all the other samples showed two decay time components. As a result, the doping influences the optical properties of Znq2 and makes it a potential candidate for optoelectronic applications.

Discovery and development of CPL207280 as new GPR40/FFA1 agonist.

Due to a unique mechanism that limits the possibility of hypoglycemia, the free fatty acid receptor (FFA1) is an attractive target for the treatment of type 2 diabetes. So far, however, none of the promising agonists have been able to enter the market. The most advanced clinical candidate, TAK-875, was withdrawn from phase III clinical trials due to liver safety issues. In this article, we describe the key aspects leading to the discovery of CPL207280 (13), the design of which focused on long-term safety. The introduction of small, nature-inspired acyclic structural fragments resulted in compounds with retained high potency and a satisfactory pharmacokinetic profile. Optimized synthesis and upscaling provided a stable, solid form of CPL207280-51 (45) with the properties required for the toxicology studies and ongoing clinical trials.

Novel pegylated liposomal formulation of docetaxel with 3-n-pentadecylphenol derivative for cancer therapy.

The taxanes are commonly used in the treatment of many types of cancer. The disadvantages of using taxanes in therapy are their low solubility in water, the toxicity or relatively poor pharmacokinetics of existing formulations. Using liposomes as carriers would help in overcoming these problems, however, their use is limited by the low incorporation efficiency of taxane molecules within bilayer and by subsequent drug crystallization. Most of published taxanes liposomal formulations use natural soy phosphatidylcholine (PC) as main liposomes lipid. This allows a relatively good drug retention during the liposomes storage, but on the other hand, the use of liposomes with more liquid bilayer facilitates fast drug release after its intravenous administration. In order to decrease the drug release from liposomes in circulation, we used pegylated HSPC (hydrogenated soy PC) liposomes containing a novel synthetic 3-n-pentadecylphenol derivative - KW101, that showed a remarkably stabilizing action for the docetaxel (DTX) dopped HSPC liposomes over 30 days, expressed by the inhibition of DTX crystallization. The resulting liposomes with DTX showed similar cytotoxicity on MCF-7 and MDA-MB-231 breast cancer cell lines and higher toxicity in drug-resistant NCI/ADR-RES cell line in comparison with the free DTX. Moreover, this formulation has good pharmacokinetics in mice, in comparison to control pegylated DTX formulation composed of egg phosphatidylcholine (ePC). This novel liposomal formulation of docetaxel consisting of HSPC with the stabilizing compound KW101, appears to be a promising carrier for DTX cancer therapy.

Investigation of damping effects on low-frequency steady-state acoustical behaviour of coupled spaces.

In the low-frequency range, the acoustical behaviour of enclosed spaces is strongly influenced by excited acoustic modes resulting in a spatial irregularity of a steady-state sound field. In the paper, this problem has been examined theoretically and numerically for a system of coupled spaces with complex-valued conditions on boundary surfaces. Using a modal expansion method, an analytic formula for Green's function was derived allowing to predict the interior sound field for a pure-tone excitation. To quantify the spatial irregularity of steady-state sound field, the parameter referred to as the mean spatial deviation was introduced. A numerical simulation was carried out for the system consisting of two coupled rectangular subspaces. Eigenfunctions and eigenfrequencies for this system were determined using the high-accuracy eigenvalue solver. As was evidenced by computational data, for small sound damping on absorptive walls the mean spatial deviation peaks at frequencies corresponding to eigenfrequencies of strongly localized modes. However, if the sound damping is much higher, the main cause of spatial irregularity of the interior sound field is the appearance of sharp valleys in a spatial distribution of a sound pressure level.

Diversity of extended-spectrum beta-lactamase-producing Escherichia coli rods.

INTRODUCTION: The aim of the study was to evaluate genetic relatedness and antimicrobial susceptibility of extended-spectrum beta-lactamase-producing E. coli strains isolated from patients hospitalized in the University Hospital in Bydgoszcz (Poland). MATERIAL AND METHODS: The study included 33 extended-spectrum beta-lactamase-producing E. coli strains isolated from 31 patients. The chromosomal DNA was extracted from the strains and separated by pulsed-field gel electrophoresis. Antimicrobial susceptibility testing was performed by the agar dilution method and carried out according to the European Committee on Antimicrobial Susceptibility Testing recommendations. RESULTS: According to the pulsed-field gel electrophoresis results, 32 distinct pulsotypes were revealed. Based on Molecular Analyst Fingerprinting software analysis, the studied isolates were divided into four subgroups: 6 (18.2%) isolates showing similarity greater than 90% (group A); 19 (57.6%) showing 80-90% similarity (group B); 7 (21.2%) showing 70-79% similarity (group C); and one isolate with less than 70% similarity (group D). Among E. coli isolates showing similarity greater than 90%, four antimicrobial patterns were noted. Among the isolates showing 80-90% similarity, 18 antimicrobial patterns were observed. E. coli isolates showing 70-79% similarity presented 6 antimicrobial patterns. CONCLUSIONS: Our results show a high degree of genetic diversity of extended-spectrum beta-lactamase-producing E. coli isolates. However, based on a similarity of ≥80%, almost 75% of E. coli isolates were clonally related. Although it is difficult to identify definitive transmission events based on the recovery of indistinguishable pulsed-field gel electrophoresis types alone, we speculate that extended-spectrum beta-lactamase-producing E. coli strains may have disseminated throughout the hospital.

[Relationship of serum alanine aminotransferase (ALT) to body weight, age and sex in blood donors population]. / Aktywnosc aminotransferazy alaninowej (ALT) a masa ciala, wiek i plec w populacji krwiodawców.

The activity of alanine aminotransferase (ALT) is the most popular parameter in hepatology. Increase of ALT usually suggests the damage of hepatocytes. The aim of the study was to assess the range of value of serum alanine aminotransferase in healthy population and to assess the relationship between ALT level and body mass index (BMI), age and gender. We have analyzed a large population of healthy blood donors--all of them were screened for ALT, weight and height. Patients were divided into four groups: I--patients with underweight, II--patients with normal weight, III--patients with overweight, IV--obese patients. In the studied population 862 persons were taken into account (820 men and 42 women), 19-62 years of age. The ALT level varied from 6 to 77 U/L, mean 27.39 U/L. Inadequate BMI was found in 12 persons, normal BMI in 497 persons, overweight in 270 persons and obesity in 83 persons. ALT and BMI are statistically significantly higher in men than in women. In general population and in men group we found correlations between ALT and BMI (p = 0.0000), between ALT and age (p = 0.0000). In women we did not find those dependences. ALT level was statistically significantly higher in groups with higher BMI: ALT level in group II was higher than in group I (p < 0.024), ALT level in group III was higher than in group III (p = 0.0000). We did not find any differences in ALT level between group III and IV. ALT level strongly correlates with body mass, age and gender. We suggest the necessity of taking into consideration those parameters in a clinical interpretation of ALT level.