Quantitation of talinolol and other beta-blockers by capillary electrophoresis for in vitro drug absorption studies

A capillary zone electrophoresis method is described for the enantioseparation of talinolol using heptakis(2,3-diacetyl-6-sulfo)-beta-cyclodextrin (HDAS-beta-CD) as a chiral selector. After liquid-liquid extraction of talinolol from physiological solution, electrokinetic injection was employed to improve the sensitivity. The use of a coated capillary was necessary to achieve stable and reproducible enantioseparations. A baseline separation of the talinolol enantiomers was achieved in less than 10 min using 100 mM phosphate solution as background electrolyte and pH 3.5, at the presence of 3.0 mM HDAS-beta-CD and at 20 degrees C. In addition, this analytical condition proved to be useful for the enantioseparation of a number of other beta-blocking agents such as alprenolol, atenolol, bisoprolol, celiprolol, metipranolol, oxprenolol, and sotalol. For determining talinolol, the method could be validated in terms of precision, accuracy and linearity, and was found to be suitable in determination of talinolol enantiomers in highly diluted samples obtained from in vitro experiments.     

Development of Passive and Active Barrier Coatings on the Basis of Inorganic–Organic Polymers

Summary. With a new kind of barrier coating material, namely inorganic–organic polymers, it is possible to obtain excellent barrier properties against oxygen, water vapor, and flavor permeation. These hybrid polymers can be synthesized by the sol–gel technique. If extremely low permeation values are needed, the combination of hybrid polymer coatings with thin inorganic oxidic layers (SiO_x, AlO_x) is very effective and leads to permeation values for oxygen and water vapor below 10⁻³ cm³/m² · d · bar or g/m² · d. These passive barrier layers can be further improved by the combination with active oxygen barrier layers which have been developed for the food packaging industry. This approach makes these multilayer laminates promising candidates for special applications in the food packaging industry as well as for sophisticated applications in technical areas: the encapsulation of sensitive organic devices like solar cells, organic light emitting diodes, or polymer electronic systems.     

Atomic-Scale Studies of Fe3O4(001) and TiO2(110) Surfaces Following Immersion in CO2-Acidified Water

Difficulties associated with the integration of liquids into a UHV environment make surface-science style studies of mineral dissolution particularly challenging. Recently, we developed a novel experimental setup for the UHV-compatible dosing of ultrapure liquid water and studied its interaction with TiO₂ and Fe₃O₄ surfaces. Herein, we describe a simple approach to vary the pH through the partial pressure of CO₂ ( ) in the surrounding vacuum chamber and use this to study how these surfaces react to an acidic solution. The TiO₂(110) surface is unaffected by the acidic solution, except for a small amount of carbonaceous contamination. The Fe₃O₄(001)-( × )R45° surface begins to dissolve at a pH 4.0–3.9 ( =0.8–1 bar) and, although it is significantly roughened, the atomic-scale structure of the Fe₃O₄(001) surface layer remains visible in scanning tunneling microscopy (STM) images. X-ray photoelectron spectroscopy (XPS) reveals that the surface is chemically reduced and contains a significant accumulation of bicarbonate (HCO₃⁻) species. These observations are consistent with Fe(II) being extracted by bicarbonate ions, leading to dissolved iron bicarbonate complexes (Fe(HCO₃)₂), which precipitate onto the surface when the water evaporates.     

The influence of phosphane coligands on the nuclearity of rhodium(I) 4-thiolatobenzoic acid complexes

[RhCl(PR3)3] (R = Ph, Et) reacts with the potassium salt of 4-mercaptobenzoic acid to give a mixture of the monomeric and dimeric complexes, [Rh(SC6H4COOH)(PR3)3] and [{Rh(-SC6H4COOH)(PR3)2}2], respectively. With the labile PPh3 coligand, the dimer is the major product, while for the electron-richer coligand PEt3, the equilibrium is easily shifted to the monomer by the addition of excess PEt3. Phosphane dissociation and dimerization could be prevented by using the chelating coligand PPh(C2H4PPh2)2. [{Rh(-SC6H4COOH)(PPh3)2}2] (2b), [Rh(SC6H4COOH)(PEt3)3] (3a), and [Rh(SC6H4COOH){PPh(C2H4PPh2)2}] (4) were fully characterized by nuclear magnetic resonance and infrared spectroscopy, mass spectrometry, and elemental analysis. The molecular structures of 2b and 4 were determined by X-ray structure analysis. In solution, the lability of the phosphane ligands leads to the decomposition of 2b. One of the decomposition products, namely, the mixed-valent complex [{RhIRhIII(-SC6H4COO)(-SC6H4COOH)(SC6H4COOH)(PPh3)3}2] (5), was characterized by X-ray structural analysis. The dinuclear rhodium(III) complex [{Rh(-SC6H4COO)(SC6H4COOH)(PEt3)2}2] (6) was shown to be a byproduct in the synthesis of 3a, and this demonstrates the reactivity of the rhodium(I) complexes toward oxidative addition. The structurally characterized complexes 2b, 4, 5, and 6 show hydrogen bonding of the free carboxyl groups.     

Palladium-catalyzed asymmetric [3 + 2] trimethylenemethane cycloaddition reactions

Transition-metal-catalyzed trimethylenemethane (TMM) [3 + 2] cycloadditions provide direct routes to functionalized cyclopentanes. This reaction has been shown to be a highly chemo-, regio-, and diastereoselective process. We report a palladium-catalyzed asymmetric [3 + 2] trimethylenemethane (TMM) cycloaddition between 3-acetoxy-2-trimethylsilylmethyl-1-propene and various di- and trisubstituted olefins. Yields of exo-methylenecyclopentane products range from 59 to 99%, and enantiomeric excesses range from 58 to 92% ee.     

Prey for the Proteasome: Targeted Protein Degradation—A Medicinal Chemist's Perspective

Targeted protein degradation (TPD), the ability to control a proteins fate by triggering its degradation in a highly selective and effective manner, has created tremendous excitement in chemical biology and drug discovery within the past decades. The TPD field is spearheaded by small molecule induced protein degradation with molecular glues and proteolysis targeting chimeras (PROTACs) paving the way to expand the druggable space and to create a new paradigm in drug discovery. However, besides the therapeutic angle of TPD a plethora of novel techniques to modulate and control protein levels have been developed. This enables chemical biologists to better understand protein function and to discover and verify new therapeutic targets. This Review gives a comprehensive overview of chemical biology techniques inducing TPD. It explains the strengths and weaknesses of these methods in the context of drug discovery and discusses their future potential from a medicinal chemist's perspective.     

Peptide‐Templated Acyl Transfer: A Chemical Method for the Labeling of Membrane Proteins on Live Cells

The development of a method is described for the chemical labeling of proteins which occurs with high target specificity, proceeds within seconds to minutes, and offers a free choice of the reporter group. The method relies upon the use of peptide templates, which align a thioester and an N‐terminal cysteinyl residue such that an acyl transfer reaction is facilitated at nanomolar concentrations. The protein of interest is N‐terminally tagged with a 22 aa long Cys‐E3 peptide (acceptor), which is capable of forming a coiled‐coil with a reporter‐armed K3 peptide (donor). This triggers the transfer of the reporter to the acceptor on the target protein. Because ligation of the two interacting peptides is avoided, the mass increase at the protein of interest is minimal. The method is exemplified by the rapid fluorescent labeling and fluorescence microscopic imaging of the human Y₂ receptor on living cells.