Evaluation of the enantioselectivity of new chiral ligands based on imidazolidin-4-one derivatives.

The new chiral ligands I-III based on derivatives of imidazolidin-4-one were synthesised and characterised. The catalytic activity and enantioselectivity of their corresponding copper(II) complexes were studied in asymmetric Henry reactions. It was found that the enantioselectivity of these catalysts is overall very high and depends on the relative configuration of the ligand used; cis-configuration of ligand affords the nitroaldols with major enantiomer S- (up to 97% ee), whereas the application of ligands with trans-configuration led to nitroaldols with major R-enantiomer (up to 96% ee). The "proline-type" ligand IV was also tested in asymmetric aldol reactions. Under the optimised reaction conditions, aldol products with enantioselectivities of up to 91% ee were obtained.

Immobilization of Trifluoromethyl-Substituted Pyridine-Oxazoline Ligand and Its Application in Asymmetric Continuous Flow Synthesis of Benzosultams.

This study presents an improved synthetic route to ligand (S)-4-(tert-butyl)-2-(5-(trifluoromethyl)pyridin-2-yl)-4,5-dihydrooxazole and its application as a highly active and enantioselective catalyst in the addition of arylboronic acids to cyclic N-sulfonylketimines. Immobilization of such a ligand was achieved using a commercially available starting material and a PS-PEG TentaGel S NH2 support, resulting in a stable heterogeneous catalyst. Although the anchored catalyst exhibited a slight reduction in enantioselectivity and a 4-fold decrease in reaction rate, it displayed remarkable stability, enabling 10 consecutive reaction cycles. Furthermore, the successful transition to a continuous flow system demonstrated even higher turnover numbers compared to batch arrangements. These findings provide valuable insights into the development of efficient flow reactors for continuous synthesis of benzosultams, further advancing the field of asymmetric catalysis.

Direct Cyclopalladation of Fluorinated Benzyl Amines by Pd3(OAc)6: The Coexistence of Multinuclear Pdn Reaction Pathways Highlights the Importance of Pd Speciation in C-H Bond Activation.

Palladacycles are key intermediates in catalytic C-H bond functionalization reactions and important precatalysts for cross-couplings. It is commonly believed that palladacycle formation occurs through the reaction of a substrate bearing a C-H bond ortho to a suitable metal-directing group for interaction with, typically, mononuclear "Pd(OAc)2" species, with cyclopalladation liberating acetic acid as the side product. In this study, we show that N,N-dimethyl-fluoro-benzyl amines, which can be cyclopalladated either ortho or para to fluorine affording two regioisomeric products, can occur by a direct reaction of Pd3(OAc)6, proceeding via higher-order cyclopalladated intermediates. Regioselectivity is altered subtly depending on the ratio of substrate:Pd3(OAc)6 and the solvent used. Our findings are important when considering mechanisms of Pd-mediated reactions involving the intermediacy of palladacycles, of particular relevance in catalytic C-H bond functionalization chemistry.

The asymmetric Henry reaction as synthetic tool for the preparation of the drugs linezolid and rivaroxaban.

The human drugs - the antibiotic linezolid (1) and the anticoagulant rivaroxaban (2) - belong among modern pharmaceutics, which contain an oxazolidine-2-one moiety bearing a stereogenic center. The chirality of these drugs is a fundamental attribute for their biological activity. Herein, one of the efficient asymmetric syntheses of these drugs was studied in detail. Highly enantioselective catalysts were tested in the key step of the synthetic procedure, i.e., the asymmetric Henry reaction, under different reaction conditions, using several starting aldehydes. The corresponding nitroaldols as chiral intermediates in the syntheses of these drugs were obtained in high yields and enantiomeric excesses of up to 91% ee.

Diphyllin Shows a Broad-Spectrum Antiviral Activity against Multiple Medically Important Enveloped RNA and DNA Viruses.

Diphyllin is a natural arylnaphtalide lignan extracted from tropical plants of particular importance in traditional Chinese medicine. This compound has been described as a potent inhibitor of vacuolar (H+)ATPases and hence of the endosomal acidification process that is required by numerous enveloped viruses to trigger their respective viral infection cascades after entering host cells by receptor-mediated endocytosis. Accordingly, we report here a revised, updated, and improved synthesis of diphyllin, and demonstrate its antiviral activities against a panel of enveloped viruses from Flaviviridae, Phenuiviridae, Rhabdoviridae, and Herpesviridae families. Diphyllin is not cytotoxic for Vero and BHK-21 cells up to 100 µM and exerts a sub-micromolar or low-micromolar antiviral activity against tick-borne encephalitis virus, West Nile virus, Zika virus, Rift Valley fever virus, rabies virus, and herpes-simplex virus type 1. Our study shows that diphyllin is a broad-spectrum host cell-targeting antiviral agent that blocks the replication of multiple phylogenetically unrelated enveloped RNA and DNA viruses. In support of this, we also demonstrate that diphyllin is more than just a vacuolar (H+)ATPase inhibitor but may employ other antiviral mechanisms of action to inhibit the replication cycles of those viruses that do not enter host cells by endocytosis followed by low pH-dependent membrane fusion.

Synthesis and Characterization of New Boron Compounds Using Reaction of Diazonium Tetraphenylborate with Enaminoamides.

A family of oxazaborines, diazaborinones, triazaborines, and triazaborinones was prepared by reaction of polarized ethylenes, such as ß-enaminoamides, with 4-methylbenzenediazonium tetraphenylborates. The reaction conditions (stirring in CH2Cl2 at room temperature (Method A) or stirring with CH3COONa in CH2Cl2 at room temperature (Method B) or refluxing in the CH2Cl2/toluene mixture (Method C)) controlled the formation and relative content of these compounds in the reaction mixtures from one to three products. Substituted oxazaborines gradually rearranged into diazaborinones at 250 °C. The prepared compounds were characterized by 1H NMR, 13C NMR, IR, and UV-Vis spectroscopy, HRMS, or microanalysis. The structure of individual compounds was confirmed by 11B NMR, 15N NMR, 1D NOESY, and X-ray analysis. The mechanism of reaction of enaminoamides with 4-methylbenzenediazonium tetraphenylborate was proposed.

Recent advances in palladium-catalysed asymmetric 1,4-additions of arylboronic acids to conjugated enones and chromones.

The transition metal (palladium)-catalysed asymmetric 1,4-addition of arylboronic acids to conjugated enones belong to the most important and emerging strategies for the construction of C-C bonds in an asymmetric fashion. This review covers known catalytic systems used for this transformation. For clarity, we are using the type of ligand as a sorting criterion. Finally, we attempted to create a flowchart facilitating the selection of a suitable ligand for a given combination of enone and arylboronic acid.

Disruption of Cell Adhesion and Cytoskeletal Networks by Thiol-Functionalized Silica-Coated Iron Oxide Nanoparticles.

One of the major obstacles that limits the use of magnetic nanoparticles in biomedical applications is their potential toxicity. In the present study, we evaluated the cytotoxic effects of thiol-functionalized silica-coated iron oxide (Fe3O4@SiO2-SH) nanoparticles using human lung epithelial cells A549. We investigated the effect of Fe3O4@SiO2-SH nanoparticles on the cell viability, proliferation, cell cycle distribution, adhesion, apoptosis, and the orientation of the cytoskeletal networks, as well as on expression of proteins involved in cell death, cell survival, and cell adhesion. We demonstrated that exposure of A549 cells to Fe3O4@SiO2-SH nanoparticles resulted in severe disruption of the actin microfilaments and microtubule cytoskeleton and reduced the size of focal adhesions. Furthermore, cell adhesion was significantly affected as well as the phosphorylation of focal adhesion kinase (FAK), extracellular-signal-regulated kinase (ERK), and p38. Our findings highlight the need for in-depth cytotoxic evaluation of nanoparticles supporting their safer use, especially in biomedical applications.

Silica coated iron oxide nanoparticles-induced cytotoxicity, genotoxicity and its underlying mechanism in human HK-2 renal proximal tubule epithelial cells.

Iron oxide nanoparticles (IONPs) have a great potential with regard to cell labelling, cell tracking, cell separation, magnetic resonance imaging, magnetic hyperthermia, targeted drug and gene delivery. However, a growing body of research has raised concerns about the possible unwanted adverse cytotoxic effects of IONPs. In the present study, the in vitro cellular uptake, antiproliferative activity, cytotoxicity, genotoxicity, prooxidant, microtubule-disrupting and apoptosis-inducing effect of Fe3O4@SiO2 and passivated Fe3O4@SiO2-NH2 nanoparticles on human renal proximal tubule epithelial cells (HK-2) have been studied. Both investigated silica coated IONPs were found to have cell growth-inhibitory activity in a time- and dose-dependent manner. Determination of cell cycle phase distribution by flow cytometry demonstrated a G1 and G2/M phase accumulation of HK-2 cells. A tetrazolium salt cytotoxicity assay at 24 h following treatment demonstrated that cell viability was reduced in a dose-dependent manner. Microscopy observations showed that both Fe3O4@SiO2 and Fe3O4@SiO2-NH2 nanoparticles accumulated in cells and appeared to have microtubule-disrupting activity. Our study also revealed that short term 1 h exposure to 25 and 100 µg/mL of silica coated IONPs causes genotoxicity. Compared with vehicle control cells, a significantly higher amount of γH2AX foci correlating with an increase in DNA double-strand breaks was observed in Fe3O4@SiO2 and Fe3O4@SiO2-NH2-treated and immunestained HK-2 cells. The investigated nanoparticles did not trigger significant ROS generation and apoptosis-mediated cell death. In conclusion, these findings provide new insights into the cytotoxicity of silica coated IONPs that may support their further safer use.

C-H Functionalizations by Palladium Carboxylates: The Acid Effect.

Finding optimal reaction conditions is usually complex, requires many experiments, and is therefore demanding in terms of human, financial, and environmental resources. This work provides a simple workflow for easier design of popular palladium-catalyzed C-H functionalization reactions, where the active palladium catalysts contain carboxylate ligands. The key factor for optimizing reaction conditions is to find a balance between two opposing effects of the carboxylic acid in the reaction mixture: generation of more reactive palladium catalyst versus deactivation of a substrate by its protonation.

Synthesis and characterization of new inhibitors of cholinesterases based on N-phenylcarbamates: In vitro study of inhibitory effect, type of inhibition, lipophilicity and molecular docking.

Based on current treatment of Alzheimer's disease, where the carbamate inhibitor Rivastigmine is used, two series of carbamate derivatives were prepared: (i) N-phenylcarbamates with additional carbamate group (1-12) and (ii) N-phenylcarbamates with monosaccharide moiety (13-24). All compounds were tested for the inhibitory effect on both of the cholinesterases, electric eel acetylcholinesterase (eeAChE) and butyrylcholinesterase from equine serum (eqBChE) and the inhibitory activity (expressed as IC50 values) was compared with that of the established drugs Galanthamine and Rivastigmine. The compounds with two carbamate groups 1-12 revealed higher inhibitory efficiency on both cholinesterases in compared with monosaccharide derived carbamates 13-24 and with Rivastigmine. The significant decrease of inhibitory efficiency on eqBChE (also for eeAChE but in less manner) was observed after deacetalization of monosaccharide. Moreover, the type of inhibitory mechanism of five chosen compounds was studied. It was found, that compounds with two carbamate groups act presumably via a mixed inhibitory mechanism and the compounds with monosaccharide moiety act as non-competitive inhibitors. The lipophilicity of tested compounds was determined using partition coefficient. Specific positions of the inhibitors in the binding sites of cholinesterases were determined using molecular modeling and the results indicate the importance of phenylcarbamate orientation in the catalytic gorges of both enzymes.

Bi and trinuclear complexes in palladium carboxylate-assisted C-H activation reactions.

The role of polynuclear species in C-H activations assisted by palladium carboxylates has not been clear so far. The summary of the key findings covering this issue shows its important role under certain conditions. However, much more effort is necessary for a deeper understanding of the whole issue.

The role of trinuclear species in a palladium acetate/trifluoroacetic acid catalytic system.

Reactions catalyzed by palladium(ii) acetate and trifluoroacetic acid (TFA) have a clear preactivation phase. However, the structure of real catalytic species remains unclear. We show that the key species are cyclic trinuclear complexes of composition [Pd3(OAc)6-x(OTFA)x] (x = 1-6) formed by a sequential ligand exchange from [Pd3(OAc)6]. Furthermore, we prove that the trinuclear palladium backbone of the precatalyst remains preserved during the first phase of the C-H activation reaction of acetanilides. In other words, the reaction pathway including the trinuclear species should be taken into account in discussion about mechanisms of the reactions catalyzed by palladium acetates.

Recent Advances in C-C and C-N Bond Forming Reactions Catalysed by Polystyrene-Supported Copper Complexes.

This present mini-review covers recently published results on Cu(I) and Cu(II) complexes immobilized on polystyrene carriers, which are used as heterogeneous, eco-friendly reusable catalysts applied for carbon-carbon and carbon-nitrogen forming reactions. Recent advances and trends in this area are demonstrated in the examples of oxidative homocoupling of terminal alkynes, the synthesis of propargylamines, nitroaldolization reactions, azide alkyne cycloaddition, N-arylation of nitrogen containing compounds, aza-Michael additions, asymmetric Friedel-Crafts reactions, asymmetric Mukaiyama aldol reactions, and asymmetric 1,3-dipolar cycloaddition of azomethine ylides. The type of polystyrene matrix used for the immobilization of complexes is discussed in this paper, and particularly, the efficiency of the catalysts from the point of view of the overall reaction yield, and possible enantioselectivity and potential reusing, is reviewed.

Synthesis, characterization and in vitro evaluation of substituted N-(2-phenylcyclopropyl)carbamates as acetyl- and butyrylcholinesterase inhibitors.

A serie of O-substituted N-2-phenylcyclopropylcarbamates was prepared and characterized. These carbamates were tested as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). It was found, that these compounds exhibit moderate inhibition activity with values of IC50 in the range of 54.8-94.4 µM (for AChE) and up to 5.8 µM (for BChE). The AChE/BChE selectivity for each carbamate was calculated. These values varied from 0.50 to 9.46, two carbamate derivatives inhibited only AChE selectively. The most promising derivative was prepared in all optically pure forms (four isomers). It was found that individual stereoisomers differed only slightly in the inhibition ability. The cytotoxicity of all carbamates was evaluated using the standard in vitro test with Jurkat cells. With regard to their inhibition activity and cytotoxicity as well as easy preparation, O-substituted N-2-phenylcyclopropylcarbamates can be considered as promising compounds for potential medicinal applications.

Synthesis and characterization of a pH-sensitive conjugate of isoniazid with Fe3O4@SiO2 magnetic nanoparticles.

The Letter describes the preparation and characterization of a conjugate of isoniazid (INH) with magnetic nanoparticles Fe3O4@SiO2 115±60 nm in size. The INH molecules were attached to the surface of nanoparticles by a covalent pH-sensitive amidine bond. The conjugate was characterized by X-ray diffraction, SEM, dynamic light scattering, IR spectroscopy and microanalysis. The conjugate released isoniazid under in vitro conditions (pH=4; 37 °C; t1/2≈115 s). In addition, the cytotoxicity of the Fe3O4@SiO2-INH conjugate was evaluated in SK-BR-3 cells using the xCELLigence system.

Inverse neighboring group participation: explanation of an unusual S→N alkyl migration of isothiuronium salts containing a lactone group.

A detailed experimental and DFT study of the S to N alkyl migration of substituted S-(1(3H)-isobenzofuranon-3-yl)isothiuronium bromide to N,N'-dimethyl-N-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)thiourea provided evidence for the existence of an unusual double displacement mechanism involving two consecutive back-side S(N)2 reactions where a carboxylate anion has a crucial role both as a leaving group as well as an internal nucleophile. The thiazetidine zwitterionic species that is involved in this mechanism as an intermediate was characterized by infrared multiphoton dissociation spectroscopy and was trapped with methyl iodide. It was found that the intermediate has a structure of a free ion pair. The double-displacement mechanism can be considered as a new type of inverse lactone neighboring group participation.

Synthesis and characterization of pH-sensitive conjugate of isoniazid--methoxypoly(ethylene glycol)-b-poly(L-lysine).

The present paper deals with the preparation and characterization of a conjugate of isoniazid (INH) with the block copolymer methoxypoly(ethylene glycol)-b-poly(L-lysine) (mPEG-b-PLL). The structure of the conjugate (mPEG-b-PLL-INH) was verified by means of (1)H NMR, GPC, infrared spectroscopy, elemental analysis and powder X-ray diffraction. The conjugate contains six l-lysine units with five INH molecules, which are attached by means of pH-sensitive amidine bond. Under in vitro conditions, the conjugate is hydrolyzed and isoniazid is released (pH 4; 37 °C; t(1/2) ≈ 10 h).

Recent advances in the design and synthesis of prednisolone and methylprednisolone conjugates.

Glucocorticoid drugs are commonly used in the treatment of many acute and chronic inflammatory diseases. However, application of these steroids is limited because of their physico-chemical properties, such as very low water solubility. Glucocorticoids also exhibit serious adverse side effects. Therefore, new drug delivery systems are being developed, with the aim of improving the physicochemical properties of glucocorticoids while avoiding undesirable side effects associated with systemic administration. Here we discuss the design and synthesis of conjugates of prednisolone (PD), methylprednisolone (MPD) and similar glucocorticoids. In this review, possibilities for targeting inflammatory sites, and reducing dosages and administration frequency through increasing drug circulation time are discussed. This review summarises synthetic approaches for the preparation of covalent conjugates, which are divided into two groups: low molecular weight conjugates and polymeric conjugates. These two groups are further divided into subgroups based on the chemical structure of the conjugates. Published results from in vitro and in vivo testing of prepared conjugates are also discussed.