Synthesis and stability evaluation of novel peptidomimetic Caspase-1 inhibitors for topical application

During our search for topically-active Caspase-1 inhibitors, we identified a novel class of potent inhibitors based on a 1,3,5-trisubstituted uracil motif equipped with an l-aspartate semi-aldehyde derived warhead. In the literature, the majority of Caspase-1 inhibitors possessing the same warhead have been designed and evaluated for oral administration as the ethyl acetal pro-drug form. For our topical program, the pro-drug acetal form was not fully hydrolysed in the skin and was unstable in many of our standard topical excipients, therefore, we were obliged to focus on the actual hemiacetal drug form of the molecule during our drug discovery program. Our work focuses on both the synthesis and achiral and chiral stability of the final drug molecules in topical excipients.     

Development of an automatic laboratory-scale respirometric system to measure polymer biodegradability

An automatic direct measurement respirometric system was built, calibrated and tested to determine polymer biodegradation under simulated environmental conditions. The amount of carbon dioxide produced during biopolymer biodegradation was converted to percentage of mineralization, and used as an indicator of the polymer biodegradation. Poly(lactide) (PLA) bottles were used as the test material, and the results were compared with those from corn starch powder and poly(ethylene terephthalate) (PET) bottles. The respirometric system ran for more than 63 days without any user intervention, very stable and efficiently. At 63 days of exposure at 58±2 °C and 55±5% relative humidity, PLA, corn starch, and PET achieved 64.2±0.5%, 72.4±0.7%, and 2.7±0.2% mineralization, respectively. Based on ASTM D 6400 and ISO14855, PLA bottles qualify as biodegradable since mineralization was greater than 60%.     

Theoretical study of the intramolecular CH/π interaction effect on rotation energy barriers in 1-pentene, 2,2′-diisopropyl biphenyl and some amino and nitro derivatives

The 2,2′-diisopropyl biphenyl conformers, and their amino and nitro para-disubstituted derivatives present two typical characteristics: In the ground state, CH/π interactions may induce local structures by positioning H atoms above some C atoms of the unsaturated cycles, and next the main skeleton is of biphenyl type. From ab initio theoretical calculations, we analyse first these characteristics separately by considering smaller molecules, i.e. 1-pentene for CH/π interactions and the biphenyl molecule itself. Sophisticated methods can be used for 1-pentene. We point out that the CH/π interaction present in the syn-conformer is not sufficiently stabilizing to compensate steric repulsions and the anti-conformer is found as the ground state. In the case of the biphenyl molecule, like many authors did before, and experiment compared, we were not able to improve significantly the calculated rotation energy barrier between the ground state and the conformation with a coplanar arrangement of the π-cycles. MP2 and B3LYP calculations, with basis sets of double-ζ plus polarization quality, on 2,2′-diisopropyl biphenyl conformers and their amino and nitro para-disubstituted derivatives, emphasize the difficulties found with 1-pentene and biphenyl, but damped down. The electron-donating and electron-withdrawing group effects of the amino and nitro substituents are analysed in term of σ and π contributions. This is mainly a π effect, which imposes its behaviour to the total electronic population only when considering also the atoms bonded to the amino and nitro groups. An increase of the electronic population on the atoms of the CH/π bond, mainly located on the C atom of the π system, is observed and is rather a σ effect. Moreover we show that CH/π interactions in the ground state only arise between H atoms of CH in iPr groups with C_ipso, not with C_ortho, and fit the experimental substituent effect on the basicity of the aryl group.     

Utilisation des plans factoriels fractionnaires pour l'étude de la réaction de bucherer-bergs: Synthèse de la cyclohexane spirohydantoîne

The only sixteen experiments of a fractional factorial design have been necessary to study the influence on the yield of cyclohexanospirohydantoin of the seven following factors: flask volume, cyanide and ammonium carbonate concentrations, quanities of water and ethanol, temperature and reaction time. The experimental strategy and results are compared with a recently published Simplex optimization, showing a better knowledge of the reaction after using a factorial design.     

Sulfur poisoning of Pt/Al2O3 catalysts, I. Determination of sulfur coverage by infrared spectroscopy

In the case of Pt/Al₂O₃ catalysts, a spectroscopic method was proposed to determine the amount of sulfur irreversibly bonded to platinum. Sulfate contamination of Pt/Al₂O₃ samples does not affect the metal properties for reduction temperatures lower than 300°C. Hydrogen treatment at 500°C reduces the sulfate groups into hydrogen sulfide which poisons platinum. This poisoning is strongly dependent on the metal loading. Irreversibly held sulfur sulfur corresponds to a S/Pt_s ratio close to 0.44.

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, , Pt/Al₂O₃, . Pt/Al₂O₃ 300°C. 500°C , . ⤠ . S/Pt_s, 0,44.

     

UV spectroscopic study of oxidized and reduced palladium loaded zeolites

UV and visible reflectance spectra of Pd(II) ion exchanged zeolites have been recorded before and after hydrogen reduction. The reduction was performed either at 25°C (60% reduction) or at 500°C. Reoxidation by oxygen at 400°C restored the initial Pd(II) ions only in the case of the sample reduced at low temperature. With nitric oxide, reoxidation occurred even at 25°C, regardless of the temperature of reduction, The Pd(II) ions were redispersed in the zeolite lattice through the formation of nitrosyl complexes.

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Pd(II) . 25°C ( 60%) 500°C. 400°C Pd(II) , . 25°C ; Pd(II) .

     

Doctoral Study Programmes in Europe

For a long time, obtaining a PhD in Belgium and in a number of other European countries was based on the philosophy of ‘learning-by-doing’ under the exclusive supervision of a promoter. The completion of the PhD dissertation usually led to a research or staff position. Now, many of today’s young scientists need to build their career outside the university where employers are as interested in the applicant’s skills as in their knowledge. Highly-qualified research scientists are needed in many sectors of society but require a background in its political, economical and cultural dimensions, and additional management, social and communication skills, including the ability to speak other European languages. However, although the purpose of the doctorate is the creation of a multidisciplinary scientist with broad academic qualifications, many research projects at present are restricted to subjects within a particular discipline. The acquirement of the ‘social’ skills through the ‘learning-by-doing’ concept proves to be very difficult, especially if one considers the increase of graduate students at present times. Therefore, additional study programmes for doctoral students are required. In this paper the doctoral study programme of the University of Antwerpen is described, as well as a short survey of comparable initiatives in Western Europe. Received: 25 January 1996 / Accepted: 7 June 1996     

Size- and surface-dependence of enthalpy of oxidation of submicronic magnetites

Submicronic magnetites prepared by two different methods were studied between 30 and 280°, using a fluxmetric microcalorimeter to investigate the size- and surface-dependence ofH, the enthalpy of oxidation of magnetite to-Fe₂O₃.For the particles with mean diameters ranging from 95 to 950 Å and specific surfaces of the order of 100.0 to 10.0 m²/g,H varied from –77.3±2.5 to –61.0±2.5 kJ/mol, and is identified as a linear function of the size of the particles, as depicted by the relationshipH=H _intrinsic+H _D, whereH _D represents the particle size-dependent part of the enthalpy of oxidation.

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Zusammenfassung Nach zwei verschiedenen Methoden hergestellte, submikrone Magnetite werden zwischen 30 und 280° mittels eines fluxometrischen Mikrokalorimeters untersucht, um die Abhängigkeit der EnthalpieH der Oxydation von Magnetit zu-Fe₂O₃ von der Partikelgröße und -Oberfläche zu ermitteln. Für Partikel mit mittleren Durchmessern im Bereich von 95 Å bis 950 Å bzw. spezifischen Oberflächen in der Größenordnung von 100-10 m²/g variieren dieH-Werte von –77,3 ±2,5 kJ/mol bis –61,0±2,5 kJ/mol. Die Enthalpie korreliert linear mit der Partikelgröße, was durch die BeziehungH=H _intrinsic+H _D ausgedrückt werden kann, worinH _D den von der Partikelgröß e abhängigen Teil der Oxydationsenthalpie repräsentiert.

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, , 30–280° H , Fe₂O₃. 95 950 Å , , 100,0 10,0 ²/r, H –77,3±2,5 –61,0±2,5 /. H H=H +H , H — , .

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Paper presented at the World Conference on Thermal Analysis, Madeira (Portugal), 1986.     

Synthesis of substituted bis(heteroaryl)maleimides

Substituted bis(fur-2-yl), bis(fur-3-yl) and bis(thien-2-yl) maleimides with potential antidiabetic properties are described. Their synthesis involves, as a key step, a Suzuki cross-coupling between various boron derivatives and the diiodomaleimides. Therefore, a wide range of substituted symmetric and non-symmetric maleimide derivatives can be prepared.