Synthesis and Evaluation of Water‐Soluble Prodrugs of Ursodeoxycholic Acid (UDCA), an Anti‐apoptotic Bile Acid

Ursodeoxycholic acid (UDCA) is a bile acid with demonstrated anti‐apoptotic activity in both in vitro and in vivo models. However, its utility is hampered by limited aqueous solubility. As such, water‐soluble prodrugs of UDCA could have an advantage over the parent bile acid in indications where intravenous administration might be preferable, such as decreasing damage from stroke or acute kidney injury. Five phosphate prodrugs were synthesized, including one incorporating a novel phosphoryloxymethyl carboxylate (POMC) moiety. These prodrugs were highly water‐soluble, but showed significant differences in chemical stability, with oxymethylphosphate prodrugs being the most unstable. In a series of NMR experiments, the POMC prodrug was bioactivated to UDCA by alkaline phosphatase (AP) faster than a prodrug containing a phosphate directly attached to the alcohol at the 3‐position of UDCA. Both of these prodrugs showed significant anti‐apoptotic activity in a series of in vitro assays, although the POMC prodrug required the addition of AP for activity, while the other compound was active without exogenous AP.     

Process analysis and optimisation of hybrid processes for the dehydration of ethanol

Promising hybrid processes for ethanol dewatering consist of different combinations of distillation with adsorption and/or vapour permeation. This paper presents an analysis and optimisation of these hybrid processes using non-equilibrium models and an evolutionary algorithm. Four different membrane assisted configurations are compared with a benchmark process consisting of distillation and pressure swing adsorption. In total 12 cases were investigated while assuming different feed and product compositions at different production capacities: three ethanol mass fractions in feed 45, 80, 92 wt.%, two product purities 99.6, 99.95 wt.% and two production capacities 25,000, 250,000 m³/year. The influence of decisive operating and structural variables on important target variables such as total membrane area is demonstrated. Finally, the processes are evaluated regarding operating costs and energy consumption depending on product purity and production capacity. The operating costs of the membrane assisted configurations differ only in a small range of −3% to 6% from those of the benchmark. The energy consumption of the membrane assisted configurations without distillation is up to 30% lower compared to the benchmark. Especially the combination of vapour permeation and adsorption is a promising alternative allowing for producing ethanol with high purities at lower operating pressures compared to the vapour permeation as stand alone process.     

Oxygen Vacancy Relaxation and Domain Wall Hysteresis Motion in Cobalt-Doped Barium Titanate Ceramics

Mechanical and dielectric loss measurements were carried out in the BaTiO₃ ceramics doped with Co at frequencies between 0.01 Hz and 1 MHz as a function of temperature from −150° to 150°C. The relaxation peak observed in the ferroelectric phase with an activation energy of 0.27 eV is assumed to be related to the motion of oxygen vacancies. This peak could be because of the reorientation of an electrical dipole made of oxygen vacancies and Co³⁺ ions in the lattice. Furthermore, another loss peak located just below the Curie temperature T _c could be interpreted as hysteretic motion of the domain walls in a regime where the domain wall density is changing.     

Drag reduction by DNA-grafting for single microspheres in a dilute λ-DNA solution

The fluid resistance of single micrometre-sized blank and DNA-grafted polystyrene microspheres under shear flow is compared in purified water and dilute λ-DNA solutions by means of optical tweezers experiments with a high spatial (±4 nm) and temporal (±0.2 ms) resolution. The measurement results show that the drag experienced by a colloid in a dilute λ-DNA solution (molecular weight of 48,502 bp per molecule, radius of gyration of 0.5 μm) is significantly decreased if the microsphere bears a grafted DNA brush. This newly discovered drag reduction effect is studied for different parameters, comprising the molecular weight of the grafted DNA molecules (250 bp, 1000 bp and 4000 bp), the concentration of the λ-DNA solution (11, 17 and 23 μg ml^?1, all being significantly smaller than the critical entanglement concentration c¹), the microsphere core diameter (2 μm, 3 μm and 6 μm) as well as the flow speed of the medium (10–50 μm s^?1). The maximum extent of the drag reduction is found to amount to (60 ± 20)% compared to the λ-DNA-induced contribution on the drag acting on blank colloids. We propose a theoretical explanation of this effect based on the combination of the dynamic density functional theory of Rauscher and co-workers [Rauscher M. J. Phys.: Condens. Matter 2010;22:364109] and the stagnation length theory of polymer brushes, as it was established by Kim, Lobaskin et al. [Kim et al. Macromolecules 2008;42(10):3650–3655]. In particular, the solution of the Stokes equation (i.e., the Navier–Stokes equation for creeping flow) for the studied system yields a numerical prediction that is found to be in full accord with our experimental results within measurement uncertainty.     

The effective hydrodynamic radius of single DNA-grafted colloids as measured by fast Brownian motion analysis

Optical tweezers accomplished with fast position detection enable one to carry out Brownian motion analysis of single DNA-grafted (grafting density: ∼1000 molecules per particle, molecular weight: 4000 bp) colloids in media of varying NaCl concentration. By that the effective hydrodynamic radius of the colloid under study is determined and found to be strongly dependent on the conformation of the grafted DNA chains. Our results compare well both with recent measurements of the pair interaction potential between DNA-grafted colloids (Kegler et al. Phys Rev Lett 2008; 100:118302) and with microfluidic studies (Gutsche et al. Microfluid Nanofluid 2006; 2:381-386). The observed scaling of the brush height with the ion concentration is in full accord with the theoretical predictions by Pincus, Zhulina, Birshtein and Borisov.     

Polymer electrolyte membranes from fluorinated polyisoprene-block-sulfonated polystyrene: Structural evolution with hydration and heating

Small-angle neutron scattering (SANS) and ultra-small-angle X-ray scattering (USAXS) have been used to study the structural changes in fluorinated polyisoprene/sulfonated polystyrene (FISS) diblock copolymers as they evolved from the dry state to the water swollen state. A dilation of the nanometer-scale hydrophilic domains has been observed as hydration increased, with greater dilation occurring in the more highly sulfonated samples or upon hydration at higher temperatures. Furthermore, a decrease in the order in these phase separated structures is observed upon swelling. The glass transition temperatures of the fluorinated blocks have been observed to decrease upon hydration of these materials, and at the highest hydration levels, differential scanning calorimetry (DSC) has shown the presence of tightly bound water. A precipitous drop in the mechanical integrity of the 50% sulfonated materials is also observed upon exceeding the glass transition temperature (T_g), as measured by dynamic mechanical analysis (DMA).     

Industrial experience in the scale-up of reactive distillation with examples from C4-chemistry

The objective of this paper is to illustrate process design from the industrial point of view for a heterogeneous reactive distillation exemplified by the decomposition of MTBE. Based on thermodynamics a plausible column concept is suggested. Open questions concerning scale-up of structured catalytic packings are discussed on the basis of experiments in the lab and pilot plant scale. Lab scale experiments were modelled satisfactorily with an equilibrium stage approach. In order to perform the scale-up from lab to pilot scale with the equilibrium stage approach the reaction rate constant had to be reduced significantly. Incomplete catalyst wetting due to maldistribution effects or mass transfer phenomena might be possible reasons.     

Aromatic Linkers Unleash the Antiproliferative Potential of 3-Chloropiperidines Against Pancreatic Cancer Cells

In this study, we describe the synthesis and biological evaluation of a set of bis-3-chloropiperidines (B−CePs) containing rigid aromatic linker structures. A modification of the synthetic strategy also enabled the synthesis of a pilot tris-3-chloropiperidine (Tri-CeP) bearing three reactive meta-chloropiperidine moieties on the aromatic scaffold. A structure–reactivity relationship analysis of B−CePs suggests that the arrangement of the reactive units affects the DNA alkylating activity, while also revealing correlations between the electron density of the aromatic system and the reactivity with biologically relevant nucleophiles, both on isolated DNA and in cancer cells. Interestingly, all aromatic 3-chloropiperidines exhibited a marked cytotoxicity and tropism for 2D and 3D cultures of pancreatic cancer cells. Therefore, the new aromatic 3-chloropiperidines appear to be promising contenders for further development of mustard-based anticancer agents aimed at pancreatic cancers.