Synthesis and determination of analytical characteristics and differentiation of positional isomers in the series of N-(2-methoxybenzyl)-2-(dimethoxyphenyl)ethanamine using chromatography-mass spectrometry.

N-(2-Methoxybenzyl)-2,5-dimethoxyphenethylamines (NBOMes) are synthetic phenethylamine derivatives emerging on the global drug market and reported to be associated with untoward effects in people who use drugs. Its action involves agonism at serotonin 5-HT2A receptors, affecting cognitive and behavioral processes. However, certain isomers of NBOMes may not show any psychoactive effects. They are not controlled by legislation and can be tested as pharmaceutical drugs. This study deals with the differentiation among positional isomers of 25H-NBOMe differing in the position of the two methoxy groups in the phenylethyl moiety of the molecule, using chromatography-mass spectrometry methods. The gas chromatography analysis showed that the isothermal mode was more efficient than the usually applied temperature-programming mode for the separation of the mentioned isomers. Electron ionization mass spectra of 25H-NBOMe isomers were highly similar, often resulting in a high probability of erroneous identification. However, mass spectra of their trifluoroacetyl or pentafluoropropanoyl derivatives were easily identified as they contained fragments with many significant differences. The proposed analysis using liquid chromatography-tandem mass spectrometry could distinguish the isomers of 25H-NBOMe without the need for any derivatization.

Novel approaches for the rational design of PROTAC linkers.

Proteolysis targeting chimeras (PROTACs) represent a promising class of hetero-bivalent molecules that facilitate ubiquitination of a target protein by simultaneously binding and bringing together both the E3 enzyme and the target. These compounds consist of three structural components: two ligands one of which binds the protein of interest (POI) while the other binds an E3 ubiquitin ligase to promote POI ubiquitination, and a linker connecting both moieties. Recent developments in the field highlight the fact that linker composition and length play a crucial role in achieving optimal PROTAC properties, modulate binding kinetics and substantially impacts the potency and selectivity. In this review, the authors briefly discuss the recent findings in PROTAC design approaches with focus on the linker. For each PROTAC such linker parameters as chemical nature, length, hydrophilicity and rigidity have to be optimized to achieve improved stability, bioavailability cell membrane permeability and suitable spatial orientation between the target POI and the E3 ubiquitin ligase. Thus rational linker design with respect to composition, length and attachment sites is essential for the development of potent PROTAC compounds. Computer-aided design and novel innovative linker strategies, such as PROTAC shortening, photo-switchable PROTACs, in-cell click-formed CLIPTACs, "click chemistry" approaches are also discussed in the review.

Biological Activity and Pharmacological Application of Pectic Polysaccharides: A Review.

Pectin is a polymer with a core of alternating α-1,4-linked d-galacturonic acid and α-1,2-l-rhamnose units, as well as a variety of neutral sugars such as arabinose, galactose, and lesser amounts of other sugars. Currently, native pectins have been compared to modified ones due to the development of natural medicines and health products. In this review, the results of a study of the bioactivity of pectic polysaccharides, including its various pharmacological applications, such as its immunoregulatory, anti-inflammatory, hypoglycemic, antibacterial, antioxidant and antitumor activities, have been summarized. The potential of pectins to contribute to the enhancement of drug delivery systems has been observed.