Potent inhibitors of the human UDP-glucuronosyltransferase 2B7 derived from the sesquiterpenoid alcohol longifolol

The tricyclic sesquiterpenol (+)-longifolol served as a lead structure for the design of inhibitors of the human UDP-glucuronosyltransferase (UGT) 2B7. Twenty-four homochiral and epimeric longifolol derivatives were synthesized and screened for their ability to inhibit the enzyme. The absolute configuration at the stereogenic center C1' was determined by X-ray crystallography and 2D NMR spectroscopy (gHSQC, gNOESY). The phenyl-substituted secondary alcohol 16 b (beta-phenyllongifolol) displayed the highest affinity toward UGT2B7, and its inhibitory dissociation constant was 0.91 nM. The mode of inhibition was rapidly reversible and competitive. The inhibitor was not glucuronidated by UGT2B7 or other hepatic UGTs, presumably as a result of the high steric demand exerted by the phenyl group. Inhibition assays employing 14 other UGT isoforms suggested that inhibitor 16 b was highly selective for UGT2B7.     

Model development and validation: Co-combustion of residual char, gases and volatile fuels in the fast fluidized combustion chamber of a dual fluidized bed biomass gasifier

A one-dimensional steady state model has been developed for the combustion reactor of a dual fluidized bed biomass steam gasification system. The combustion reactor is operated as fast fluidized bed (riser) with staged air introduction (bottom, primary and secondary air). The main fuel i.e., residual biomass char (from the gasifier), is introduced together with the circulating bed material at the bottom of the riser. The riser is divided into two zones: bottom zone (modelled according to modified two phase theory) and upper zone (modelled with core-annulus approach). The model consists of sub-model for bed hydrodynamic, conversion and conservation. Biomass char is assumed to be a homogeneous matrix of C, H and O and is modelled as partially volatile fuel. The exit gas composition and the temperature profile predicted by the model are in good agreement with the measured value.     

New developments in cold spray based on higher gas and particle temperatures

In cold spraying, bonding is associated with shear instabilities caused by high strain rate deformation during the impact. It is well known that bonding occurs when the impact velocity of an impacting particle exceeds a critical value. This critical velocity depends not only on the type of spray material, but also on the powder quality, the particle size, and the particle impact temperature. Up to now, optimization of cold spraying mainly focused on increasing the particle velocity. The new approach presented in this contribution demonstrates capabilities to reduce critical velocities by well-tuned powder sizes and particle impact temperatures. A newly designed temperature control unit was implemented to a conventional cold spray system and various spray experiments with different powder size cuts were performed to verify results from calculations. Microstructures and mechanical strength of coatings demonstrate that the coating quality can be significantly improved by using well-tuned powder sizes and higher process gas temperatures. The presented optimization strategy, using copper as an example, can be transferred to a variety of spray materials and thus, should boost the development of the cold spray technology with respect to the coating quality. This article was originally published inBuilding on 100 Years of Success, Proceedings of the 2006 International Thermal Spray Conference (Seattle, WA), May 15–18, 2006, B.R. Marple, M.M. Hyland, Y.-Ch. Lau, R.S. Lima, and J. Voyer, Ed., ASM International, Materials Park, OH, 2006.     

Glycerolysis of Fatty Acid Methyl Esters: 1. Investigations in a Batch Reactor

The present work focused on the glycerolysis of fatty acid methyl esters. The aim was to develop and test a kinetic model that could be used to reliably simulate different process alternatives for this reaction. A prerequisite was the identification and characterization of the factors that affect the reaction kinetics. Experiments were carried out in a batch reactor with and without forced removal of methanol, which is one of the reaction products. Concentrations of all components in the two-phase system were measured. It was found that the methanol concentration has a strong effect on the reaction rate and equilibrium conversion. Near-complete conversions were obtained by stripping methanol with an inert gas. The glycerol concentration in the ester phase was found to increase as the reaction proceeds, which also accelerates the reaction. Effects of mass transfer on the reaction rate were not found to control the reaction rate under well-agitated conditions. A semi-empirical model was used to simulate the reaction. The results from the semi-empirical model show good agreement with experimental results.     

Dehydrogenation of Light Alkanes Over Rhenium Catalysts on Conventional and Mesoporous MFI Supports

Recently, Re/HZSM-5 (Si/Al = 15) was shown to be an efficient catalyst for ethane dehydrogenation and aromatization at 823 K and atmospheric pressure. In this reaction, the major initial products were benzene, toluene and xylene (BTX), but increasing amounts of ethene were produced with time on stream due to deactivation of the catalyst. We show that by use of rhenium impregnated MFI supports with very few or no acidic sites (Si/Al > 500), highly selective ethane dehydrogenation catalysts are obtained with ethene selectivities of 98%. By use of mesoporous MFI supports (Si/Al >500) the lifetime of the catalyst appears to be slightly improved compared to conventional MFI crystals. The beneficial effect of a mesoporous MFI support is convincingly demonstrated in propane dehydrogenation, where both conversion and selectivities on the mesoporous MFI (Si/Al > 500) impregnated with Re are significantly higher than on Re supported on a comparable conventional MFI support.     

Development of a new experimental method to determine critical pigment–volume–concentrations using impedance spectroscopy

The critical pigment–volume–concentration (CPVC) of a solvent-based epoxy coating with various pigment–volume–concentrations (PVC) was analyzed. It was shown that electrochemical impedance spectroscopy (EIS) is a suitable method to detect the CPVC of coatings. The CPVC can be derived from EIS Bode plots or by fitting the EIS-curves using simple equivalent circuit diagrams. The parameters pore resistance R_P, capacitance C of the constant phase element (CPE), the relative dielectric constant _R derived from C, and the exponent n of the CPE allow the determination of the CPVC.     

Directed evolution of an esterase from Pseudomonas fluorescens yields a mutant with excellent enantioselectivity and activity for the kinetic resolution of a chiral building block

A triple mutant of an esterase from Pseudomonas fluorescens (PFE) that was created by directed evolution exhibited high enantioselectivity (E=89) in a kinetic resolution and yielded the building block (S)-but-3-yn-2-ol. Surprisingly, a mutation close to the active site caused the formation of inclusion bodies, but remote mutations were found to be responsible for the high selectivity. Back mutations gave a variant (double mutant PFE Ile76Val/Val175Ala) that showed excellent selectivity (E=96) and activity (20 min for 50% conversion, which corresponds to 1.25 U per mg of protein).     

An efficient method for the synthesis of peptide aldehyde libraries employed in the discovery of reversible SARS coronavirus main protease (SARS-CoV Mpro) inhibitors

A method for the parallel solid-phase synthesis of peptide aldehydes has been developed. Protected amino acid aldehydes obtained by the racemization-free oxidation of amino alcohols with Dess-Martin periodinane were immobilized on threonyl resins as oxazolidines. Following Boc protection of the ring nitrogen to yield the N-protected oxazolidine linker, peptide synthesis was performed efficiently on this resin. A peptide aldehyde library was designed for targeting the SARS coronavirus main protease, SARS-CoV M(pro)(also known as 3CL(pro)), on the basis of three different reported binding modes and supported by virtual screening. A set of 25 peptide aldehydes was prepared by this method and investigated in inhibition assays against SARS-CoV M(pro). Several potent inhibitors were found with IC(50) values in the low micromolar range. An IC(50) of 7.5 muM was found for AcNSTSQ-H and AcESTLQ-H. Interestingly, the most potent inhibitors seem to bind to SARS-CoV M(pro) in a noncanonical binding mode.