Enantioselective analysis of venlafaxine and its active metabolites: A review on the separation methodologies

Venlafaxine (VFX) is a serotonin and norepinephrine reuptake inhibitor chiral drug used in therapy as an antidepressant in the form of a racemate consisting of R‐ and S‐VFX. The two enantiomers of VFX exhibit different pharmacological activities: R‐VFX inhibits both norepinephrine and serotonin synaptic reuptake, whereas S‐VFX inhibits only the serotonin one. R‐ and S‐VFX are metabolized in the liver to the respective R‐ and S‐O‐desmethylvenlafaxine (ODVFX), R‐ and S‐N‐desmethylvenlafaxine (NDVFX), and R‐ and S‐N,O‐didesmethylvenlafaxine (NODVFX). The pharmacological profile of ODVFX is close to that of VFX, whereas the other two chiral metabolites (NDVFX and NODVFX) have lower affinity for the receptor sites. The pharmacokinetics of the VFX enantiomers appear stereoselective, including the metabolism process. In the past 20 years, several studies describing the enantioselective analysis of R‐ and S‐VFX in pharmaceutical formulations and its chiral metabolites in biological matrices were published. These methods encompass liquid chromatography coupled with UV detection, mass spectrometry, or tandem mass spectrometry, and capillary electrophoresis. This paper reviews the published methods used for the determination of the individual enantiomers of VFX and its chiral metabolites in different matrices.     

Mechanism and kinetics of thermal degradation of insulating materials developed from cellulose fiber and fire retardants

The mechanism and kinetics of thermal degradation of materials developed from cellulose fiber and synergetic fire retardant or expandable graphite have been investigated using thermogravimetric analysis. The model-free methods such as Kissinger–Akahira–Sunose (KAS), Friedman, and Flynn–Wall–Ozawa (FWO) were applied to measure apparent activation energy (E_α). The increased E_α indicated a greater thermal stability because of the formation of a thermally stable char, and the decreased E_α after the increasing region related to the catalytic reaction of the fire retardants, which revealed that the pyrolysis of fire retardant-containing cellulosic materials through more complex and multi-step kinetics. The Friedman method can be considered as the best method to evaluate the E_α of fire-retarded cellulose thermal insulation compared with the KAS and FWO methods. A master-plots method such as the Criado method was used to determine the possible degradation mechanisms. The degradation of cellulose thermal insulation without a fire retardant is governed by a D3 diffusion process when the conversion value is below 0.6, but the materials containing synergetic fire retardant and expandable graphite fire retardant may have a complicated reaction mechanism that fits several proposed theoretical models in different conversion ranges. Gases released during the thermal degradation were identified by pyrolysis–gas chromatography/mass spectrometry. Fire retardants could catalyze the dehydration of cellulosic thermal insulating materials at a lower temperature and facilitate the generation of furfural and levoglucosenone, thus promoting the formation of char. These results provide useful information to understand the pyrolysis and fire retardancy mechanism of fire-retarded cellulose thermal insulation.

     

Synthese monodisperser linearer und cyclischer Oligomere der (R)-3-Hydroxybuttersäure mit bis zu 128 Einheiten

Monodisperse Linear and Cyclic Oligo[(R)-3-hydroxybutanoates] Containing up to 128 Monomeric Units Using benzyl ester/(tert-butyl)diphenylsilyl ether protection, (COCl)₂/pyridine esterification conditions, and a fragment-coupling strategy (with H₂/Pd-C debenzylation and HF · pyridine desilylation), linear oligomers of (R)-3-hydroxybutanoic acid (3-HB) containing up to 128 3-HB building blocks (mol. weight > 11 000 Da) are assembled (Schemes 1,2,5, and 6). In contrast to the previously employed protecting-group combination, and due to the low-temperature esterifying conditions, this procedure leads to monodisperse oligomers: all steps occur without loss of single 3-HB units. The product oligomers with two, one, and no terminal protecting groups (mostly prepared in multi-gram amounts) are characterized by all standard spectroscopic methods, especially by mass spectroscopy (Figs. 2 and 3), by their optical activity, and by elemental analyses. Cyclization of the oligo[(R)-3-hydroxybutanoic acids] with up to 32 3-HB units, using thiopyridine activation and CuBr₂ for the ring closure, produces oligolides consisting of up to 128 ring atoms (Scheme 7). Mixed oligolides containing 3-HB and (R)-3-hydroxypentanoic units are prepared from the corresponding linear trimers, using Yamaguchi's method for the ring closure (Scheme 8 and Fig.4 (X-ray crystal structures of two folded conformers)). Comparisons of melting points (Table 1), of [α] values (Tables 2 and 3), of ¹H-NMR coupling constants (Table 3), and of molecular volume/hydroxyalkanoate unit (Table 4) of linear and cyclic oligomer derivatives and of the high-molecular-weigh polymer show that the monodisperse oligomers appear to be surprisingly good models for the polymer. Besides this insight, our synthesis is supplying the samples to further test the role of P(3-HB) (ca. 140 units) as a component of complexes forming channels through cell-wall phospholipid bilayers.     

Effects of ethylene polymerization conditions on the activity of SiO2-supported zirconocene and on polymer properties

The effects of polymerization conditions were evaluated on the production of polyethylene by silica-supported (n-BuCp)₂ZrCl₂ grafted under optimized conditions and cocatalyzed by methylaluminoxane (MAO). The Al : Zr molar ratio, reaction temperature, monomer pressure, and the age and concentration of the catalyst were systematically varied. Most reactions were performed in toluene. Hexane, with the addition of triisobutilaluminum (TIBA) to MAO, was also tested as a polymerization solvent for both homogeneous and heterogeneous catalyst systems. Polymerization reactions in hexane showed their highest activities with MAO : TIBA ratios of 3 : 1 and 1 : 1 for the homogeneous and supported systems, respectively. Catalyst activity increased continuously as Al : Zr molar ratios increased from 0 to 2000, and remained constant up to 5000. The highest activity was observed at 333 K. High monomer pressures (≈ 4 atm) appeared to stabilize active species during polymerization, producing polyethylenes with high molecular weight (≈ 3 × 10⁵ g mol⁻¹). Catalyst concentration had no significant effect on polymerization activity or polymer properties. Catalyst aging under inert atmosphere was evaluated over 6 months; a pronounced reduction in catalyst activity [from 20 to 13 × 10⁵ g PE (mol Zr h)⁻¹] was observed only after the first two days following preparation. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 1987–1996, 1999     

Perfluoroaryl Bicyclic Cell‐Penetrating Peptides for Delivery of Antisense Oligonucleotides

Exon‐skipping antisense oligonucleotides are effective treatments for genetic diseases, yet exon‐skipping activity requires that these macromolecules reach the nucleus. While cell‐penetrating peptides can improve delivery, proteolytic instability often limits efficacy. It is hypothesized that the bicyclization of arginine‐rich peptides would improve their stability and their ability to deliver oligonucleotides into the nucleus. Two methods were introduced for the synthesis of arginine‐rich bicyclic peptides using cysteine perfluoroarylation chemistry. Then, the bicyclic peptides were covalently linked to a phosphorodiamidate morpholino oligonucleotide (PMO) and assayed for exon skipping activity. The perfluoroaryl cyclic and bicyclic peptides improved PMO activity roughly 14‐fold over the unconjugated PMO. The bicyclic peptides exhibited increased proteolytic stability relative to the monocycle, demonstrating that perfluoroaryl bicyclic peptides are potent and stable delivery agents.     

Combined Short-Term Glucose Starvation and Chemotherapy in 3D Colorectal Cancer Cell Culture Decreases 14-3-3 Family Protein Expression and Phenotypic Response to Therapy

Short-term glucose starvation prior to chemotherapy has the potential to preferentially weaken cancer cells, making them more likely to succumb to treatment, while protecting normal cells. In this study, we used 3D cell cultures of colorectal cancer and assessed the effects of short-term glucose starvation and chemotherapy compared to treatment of either individually. We evaluated both phenotypic changes and protein expression levels. Our findings indicate that the combined treatment results in more significant phenotypic responses, including decreased cell viability and clonogenicity. These phenotypic responses can be explained by the decreased expression of LDHA and 14-3-3 family proteins, which were found only in the combined treatment groups. This study indicates that short-term glucose starvation has the potential to increase the efficacy of current cancer treatment regimes.

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An eco-friendly tandem tosylation/Ferrier N-glycosylation of amines catalyzed by Er(OTf)3 in 2-MeTHF

Er(OTf)₃ in 2-MeTHF provides a new and eco-friendly process for Ferrier glycosylation of sulfonamides and amino acids with various N-nucleophiles.The stereoselective synthesis of 2,3-unsaturated-N-pseudoglycals was carried out with 3,4,6-tri-O-acetyl-d-glucal and different nucleophiles affording good results in a short time.     

Point approximation of a space-homogeneous transport equation

Summary We present an approximation method of a space-homogeneous transport equation which we prove is convergent. The method is very promising for numerical computation. Comparison of a numerical computation with an exact solution is given for the Master equation.