Sustainable and Safe -alkylation of -heterocycles by Propylene Carbonate under Neat Reaction Conditions.

A new, eco-friendly process utilising the green solvent propylene carbonate (PC) has been developed to perform -alkylation of -, - and/or -containing heterocyclic compounds. PC in these reactions served as both the reagent and solvent. Importantly, no genotoxic alkyl halides were required.

Effect of the Lipid Landscape on the Efficacy of Cell-Penetrating Peptides.

Every cell biological textbook teaches us that the main role of the plasma membrane is to separate cells from their neighborhood to allow for a controlled composition of the intracellular space. The mostly hydrophobic nature of the cell membrane presents an impenetrable barrier for most hydrophilic molecules larger than 1 kDa. On the other hand, cell-penetrating peptides (CPPs) are capable of traversing this barrier without compromising membrane integrity, and they can do so on their own or coupled to cargos.

Electrospray ionization-tandem mass spectrometric study of fused nitrogen-containing ring systems.

Four fused nitrogen-containing ring systems were investigated by electrospray ionization-tandem mass spectrometry: Pyridazino-indoles, pyridazino-quinolines, a pyrimido-quinoline derivative and pyrimido-cinnolines. Fragmentation patterns of these compounds are discussed and compared. Several characteristic cross-ring fragments were formed mainly on the pyridazine and pyrimidine rings of the ring systems.

An ω-3, but Not an ω-6 Polyunsaturated Fatty Acid Decreases Membrane Dipole Potential and Stimulates Endo-Lysosomal Escape of Penetratin.

Although the largely positive intramembrane dipole potential (DP) may substantially influence the function of transmembrane proteins, its investigation is deeply hampered by the lack of measurement techniques suitable for high-throughput examination of living cells. Here, we describe a novel emission ratiometric flow cytometry method based on F66, a 3-hydroxiflavon derivative, and demonstrate that 6-ketocholestanol, cholesterol and 7-dehydrocholesterol, saturated stearic acid (SA) and ω-6 γ-linolenic acid (GLA) increase, while ω-3 α-linolenic acid (ALA) decreases the DP. These changes do not correlate with alterations in cell viability or membrane fluidity.

Statin-boosted cellular uptake and endosomal escape of penetratin due to reduced membrane dipole potential.

Background And Purpose: Cell penetrating peptides are promising tools for delivery of cargo into cells, but factors limiting or facilitating their cellular uptake are largely unknown. We set out to study the effect of the biophysical properties of the cell membrane on the uptake of penetratin, a cell penetrating peptide.

Experimental Approach: Using labelling with pH-insensitive and pH-sensitive dyes, the kinetics of cellular uptake and endo-lysosomal escape of penetratin were studied by flow cytometry.

Continuous-Flow Synthesis of Thioureas, Enabled by Aqueous Polysulfide Solution.

We have developed the continuous-flow synthesis of thioureas in a multicomponent reaction starting from isocyanides, amidines, or amines and sulfur. The aqueous polysulfide solution enabled the application of sulfur under homogeneous and mild conditions. The crystallized products were isolated by simple filtration after the removal of the co-solvent, and the sulfur retained in the mother liquid.

Polymerization-Driven Photoluminescence in Alkanolamine-Based C-Dots.

Carbonized polymer dots (CPDs), a peculiar type of carbon dots, show extremely high quantum yields, making them very attractive nanostructures for application in optics and biophotonics. The origin of the strong photoluminescence of CPDs resides in a complicated interplay of several radiative mechanisms. To understand the correlation between CPD processing and properties, the early stage formation of carbonized polymer dots has been studied.

ConjuPepDB: a database of peptide-drug conjugates.

Peptide-drug conjugates are organic molecules composed of (i) a small drug molecule, (ii) a peptide and (iii) a linker. The drug molecule is mandatory for the biological action, however, its efficacy can be enhanced by targeted delivery, which often also reduces unwanted side effects. For site-specificity the peptide part is mainly responsible.

-Acetylation of Amines in Continuous-Flow with Acetonitrile-No Need for Hazardous and Toxic Carboxylic Acid Derivatives.

A continuous-flow acetylation reaction was developed, applying cheap and safe reagent, acetonitrile as acetylation agent and alumina as catalyst. The method developed utilizes milder reagent than those used conventionally. The reaction was tested on various aromatic and aliphatic amines with good conversion.

Scope and limitation of propylene carbonate as a sustainable solvent in the Suzuki-Miyaura reaction.

The Suzuki-Miyaura reaction is one of the most used transformations in drug research. Thus making this reaction more sustainable is of considerable current interest. Here we show that propylene carbonate (PC) can be used as a solvent for the Suzuki-Miyaura reaction.

Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches.

The complement system is associated with various diseases such as inflammation or auto-immune diseases. Complement-targeted drugs could provide novel therapeutic intervention against the above diseases. C1s, a serine protease, plays an important role in the CS and could be an attractive target since it blocks the system at an early stage of the complement cascade.

Physicochemical Profiling of Baicalin Along with the Development and Characterization of Cyclodextrin Inclusion Complexes.

Baicalin is a flavone glycoside extracted from Scutellaria baicalensis, a traditional Chinese herbal medicine. Numerous pharmacological effects of baicalin were reported (e.g.

Carbon Dots from Citric Acid and its Intermediates Formed by Thermal Decomposition.

Thermal decomposition of citric acid is one of the most common synthesis methods for fluorescent carbon dots; the reaction pathway is, however, quite complex and the details are still far from being understood. For instance, several intermediates form during the process and they also give rise to fluorescent species. In the present work, the formation of fluorescent C-dots from citric acid has been studied as a function of reaction time by coupling infrared analysis, X-ray photoelectron spectroscopy, liquid chromatography/mass spectroscopy (LC/MS) with the change of the optical properties, absorption and emission.

Flow-chemistry enabled efficient synthesis of β-peptides: backbone topology vs. helix formation.

Enantiodiscriminative helix formation was observed for β-peptide H14 helices. This observation is caused by the synperiplanar orientation of H-O atoms which is more unfavorable than those for H-H interaction. The 1,2 H-O interaction leads to the destruction of the helical structure.

Continuous-flow retro-Diels-Alder reaction: an efficient method for the preparation of pyrimidinone derivatives.

The syntheses of various pyrimidinones as potentially bioactive products by means of the highly controlled continuous-flow retro-Diels-Alder reaction of condensed pyrimidinone derivatives are presented. Noteworthy, the use of this approach allowed us to rapidly screen a selection of conditions and quickly confirm the viability of preparing the desired pyrimidinones in short reaction times. Yields typically higher than those published earlier using conventional batch or microwave processes were achieved.

Homochirality of β-Peptides: A Significant Biomimetic Property of Unnatural Systems.

Homochirality, an interesting phenomenon of life, is mainly an unresolved problem and was thought to be a property of living matter. Herein, we show that artificial β-peptides have the tendency toward homochiral diastereoselective chain elongation. Chain-length-dependent stereochemical discrimination was investigated in the synthesis of foldamers with various side chains and secondary structures.

Highly functionalized cyclic β-amino acid moieties as promising scaffolds in peptide research and drug design.

Peptide-based drug research has received high attention in the field of medicinal chemistry over the past decade. For drug design, to improve proteolytic stability, it is desirable to include unnatural building blocks, such as conformationally restricted β-amino acid moieties, into the peptide sequence. Accordingly, the synthesis and incorporation of such conformationally rigid systems into novel type of peptides has gained large interest.

Kynurenic acid and its analogue can alter the opioid receptor G-protein signaling after acute treatment via NMDA receptor in rat cortex and striatum.

Previously, we have shown that the N-methyl d-aspartate (NMDA)-receptor antagonist kynurenic acid (KYNA) and its analogue KYNA1 do not bind directly to mu, kappa and delta opioid receptors in vitro. On the other hand, chronic administration of KYNA and KYNA1 resulted in region (cortex vs striatum) and opioid receptor-type specific alterations in G-protein activation of mouse brain homogenates. Here we describe for the first time the acute effect of KYNA and KYNA1 on opioid receptor function with the possible involvement of the NMDA receptor.

Deciphering metal ion preference and primary coordination sphere robustness of a designed zinc finger with high-resolution mass spectrometry.

Small zinc finger (ZnF) motifs are promising molecular scaffolds for protein design owing to their structural robustness and versatility. Moreover, their characterization provides important insights into protein folding in general. ZnF motifs usually possess an exceptional specificity and high affinity towards Zn(II) ion to drive folding.

Harnessing the Versatility of Continuous-Flow Processes: Selective and Efficient Reactions.

There is a great need for effective transformations and a broad range of novel chemical entities. Continuous-flow (CF) approaches are of considerable current interest: highly efficient and selective reactions can be performed in CF reactors. The reaction setup of CF reactors offers a wide variety of possible points where versatility can be introduced.

Foldameric probes for membrane interactions by induced β-sheet folding.

Design strategies were devised for α/β-peptide foldameric analogues of the antiangiogenic anginex with the goal of mimicking the diverse structural features from the unordered conformation to a folded β-sheet in response to membrane interactions. Structure-activity relationships were investigated in the light of different β-sheet folding levels.

An overview of peptide and peptoid foldamers in medicinal chemistry.

Introduction: Foldamers are artificial self-organizing systems with various critical properties: i) a stable and designable secondary structure; ii) a larger molecular surface as compared with ordinary organic drug molecules; iii) appropriate control of the orientation of the side-chain functional groups; iv) resistance against proteolytic degradation, which leads to potentially increased oral bioavailability and a longer serum half-life relative to ordinary α-peptides; and v) the lower conformational freedom may result in increased receptor binding in comparison with the natural analogs.

Areas Covered: This article covers the general properties and types of foldamers. This includes highlighted examples of medicinal chemical applications, including antibacterial and cargo molecules, anti-Alzheimer compounds and protein-protein interaction modifiers.

Strategic Application of Residence-Time Control in Continuous-Flow Reactors.

As a sustainable alternative for conventional batch-based synthetic techniques, the concept of continuous-flow processing has emerged in the synthesis of fine chemicals. Systematic tuning of the residence time, a key parameter of continuous-reaction technology, can govern the outcome of a chemical reaction by determining the reaction rate and the conversion and by influencing the product selectivity. This review furnishes a brief insight into flow reactions in which high chemo- and/or stereoselectivity can be attained by strategic residence-time control and illustrates the importance of the residence time as a crucial parameter in sustainable method development.

Highly Selective Continuous-Flow Synthesis of Potentially Bioactive Deuterated Chalcone Derivatives.

The selective synthesis of various dideuterochalcones as potentially bioactive deuterium-labeled products is presented, by means of the highly controlled partial deuteration of antidiabetic chalcone derivatives. The benefits of continuous-flow processing in combination with on-demand electrolytic D gas generation has been exploited to avoid over-reaction to undesired side products and to achieve selective deuterium addition to the carbon-carbon double bond of the starting enones without the need for unconventional catalysts or expensive special reagents. The roles of pressure, temperature, and residence time proved crucial for the fine-tuning of the sensitive balance between the product selectivity and the reaction rate.

Continuous-flow solid-phase peptide synthesis: a revolutionary reduction of the amino acid excess.

A highly efficient continuous-flow technique for the synthesis of peptides was developed. The method allows the application of only 1.5 equivalents of amino acids during coupling, while yielding virtually quantitative conversions.