Auswahl der wissenschaftlichen Literatur zum Thema „Membranotropic compounds“

This paper demonstrates the membranotropic effect of modified levopimaric acid diene adducts on liver mitochondria and lecithin liposomes. We found that the derivatives dose-dependently reduced the efficiency of oxidative phosphorylation of mitochondria due to inhibition of the activity of complexes III and IV of the respiratory chain and protonophore action. This was accompanied by a decrease in the membrane potential in the case of organelle energization both by glutamate/malate (complex I substrates) and succinate (complex II substrate). Compounds 1 and 2 reduced the generation of H2O2 by mitochondria, while compound 3 exhibited a pronounced antioxidant effect on glutamate/malate-driven respiration and, on the other hand, caused ROS overproduction when organelles are energized with succinate. All tested compounds exhibited surface-active properties, reducing the fluidity of mitochondrial membranes and contributing to nonspecific permeabilization of the lipid bilayer of mitochondrial membranes and swelling of the organelles. Modified levopimaric acid diene adducts also induced nonspecific permeabilization of unilamellar lecithin liposomes, which confirmed their membranotropic properties. We discuss the mechanisms of action of the tested compounds on the mitochondrial OXPHOS system and the state of the lipid bilayer of membranes, as well as the prospects for the use of new modified levopimaric acid diene adducts in medicine.

The Changes of membrane rest potential (RP), action potential (AP), impulse activity (IA) as well as sodium, calcium and potassium ionic currents in neurons of isolated central nervous system of the Planorbarius corneus mollusk (pedal ganglia) under the extracellular action of inhibitory amino acids GABA, glycine and β-alanine and their litium-containing derivatives (LCD) in 0.1, 1 and 5 mM concentrations have been studied using a microelectrode technique. They induced the same dose-dependent and irreversible depolarization of neurons on 2-10 mV accompanied by increase of AP frequency, prolongation of their duration and decrease of summmerized ionic currents (dV/dt). According to degree of depolarization, the drugs were placed in the following range in decreasing activity: compound 3 > compound 2 > compound 1. In identified pedal ganglion neurons (PPed1), compound 3 in contrast to other compounds induced hyperpolarization by 2-10 mV and blocked impulse activity. The amplitude of sodium and calcium channels was decreased by 7-15 %, in the same degree after application of all compounds exposed in concentration of 5 mM. Efflux potassium ionic currents were increased in dose-dependent manner and irreversibly about by 3-7 % assessed on amplitude indexes without changes in kinetic parameters after application of LCD. Therefore, the decrease of ionic current amplitudes was due to both depolarization of neurons and direct action of LCD on ionic channels. Thus, LCD possess membranotropic activity and can modulate functional state of neurons. In the study of chloride channels in cells culture of rat glioma C6 in vitro by patch-clamp method, GABA, glycine, β-alanine and their LCD 10 µM/l activated chloride channels, shifting equiliblium membrane potential of glioma cells from -90… -70 mV to -55... -60 mV. All compounds (transmitters and LCD) were placed in the following range: glycine > GABA > β-alanine and compound 1 > compound 3 > compound 2 according to descending activity. Therefore, the most active compounds activating Cl--channels were glycine and compound 1 (LCD). Glycine was shown to be coagonist GABA receptors and its litium salt possessed significant membranotropic activity.

Currently, targeted drug delivery is of great interest in the field of medicine. The study of compounds capable of permeating cell membranes is a major problem in this area. The synthesis of pharmacologically active compounds includes the formation of structures with various combinations of pharmacophore fragments and properties. Amphiphilic compounds tend to exhibit membranotropic activity. From this point of view, the modification of natural products, especially terpenoids, is of particular interest. Terpenoid structures are used as membrane anchors in the development of modulators for membrane-integrated proteins or structures for creating nanocontainers. In this paper we synthesized a number of water-soluble amphiphilic meroterpenoids containing a charged pyridinium fragment on the basis of acyclic terpene alcohols. Residue of terpene alcohols – geraniol (monoterpenol), farnesol (sesquiterpenol), and phytol (diterpenol) – were used as the hydrophobic part of the amphiphilic structure. Linear acyclic alcohols are commercially available reagents and have a structure similar to that of polyprenols in archaeal lipids, which made it possible to obtain synthetic lipid-like meroterpenoids capable of self-assembly in aqueous solutions. The charged pyridinium fragment, which is included in numerous natural compounds, was of interest as a polar component. This meroterpenoids are synthetic analogs of archaeal lipids. It was shown that the studied meroterpenoids form nanosized aggregates in aqueous solutions by the method of dynamic light scattering and the Doppler microelectrophoresis method. Turbidimetric titration on model dipalmitoylphosphatidylcholine vesicles revealed that the synthesized compounds are embedded into the bilayer membrane without destroying it. Self-assembled aggregates of synthesized compounds in water can find application for drug delivery – in the creation of nanocontainers containing membrane anchors capable of interacting with the outer surface of the cell (lipid membrane).

The ability of artificial ribonucleases to cause in the concentration-dependent manner death of cancer cells has been studied. The cytotoxic activity of artificial ribonucleases is observed at rather low concentration of these compounds (10-5 М). Analysis of the mechanism of artificial ribonucleases citotoxicity revealed that compounds under the study exhibit membranotropic activity in addition to ribonucleases activity found earlier. This activity is responsible for effective penetration of these compounds inside cells. The results obtained show that artificial ribonucleases induce cell death via damage of cells membrane, detachment of plasmalemma and derangement its macromolecular organization. In the case of short-term exposure of cells to the compounds, cells, even with damaged membrane, survive.

Introduction. Currently, low molecular-weight compounds are being developed as potential inhibitors of CoVs replication, targeting various stages of the replication cycle, such as major protease inhibitors and nucleoside analogs. Viroporins can be alternative protein targets. The aim of this study is to identify antiviral properties of histidine derivatives with cage substituents in relation to pandemic strain SARS-CoV-2 in vitro. Materials and methods. Combination of histidine with aminoadamantane and boron cluster anion [B10H10]2 (compounds IIV) was carried out by classical peptide synthesis. Compound were identified by modern physicochemical methods. Antiviral properties were studied in vitro on a monolayer of Vero E6 cells infected with SARS-CoV-2 (alpha strain) with simultaneous administration of compounds and virus. Results. Derivatives of amino acid histidine with carbocycles and boron cluster were synthesized and their antiviral activity against SARS-CoV-2 was studied in vitro. Histidine derivatives with carbocycles and [B10H10]2 have the ability to suppress virus replication. The solubility of substances in aqueous media can be increased due to formation of hydrochloride or sodium salt. Discussion. 2HCl*H-His-Rim (I) showed some effect of suppressing replication of SARS-CoV-2 at a viral load of 100 doses and concentration 31.2 g/ml. This is explained by the weakly basic properties of compound I. Conclusion. The presented synthetic compounds showed moderate antiviral activity against SARS-CoV-2. The obtained compounds can be used as model structures for creating new direct-acting drugs against modern strains of coronaviruses.

Antimicrobial, membranotropic and cytotoxic properties of dicationic imidazolium surfactants of n-s-n (Im) series with variable length of alkyl group (n = 8, 10, 12, 14, 16) and spacer fragment (s = 2, 3, 4) were explored and compared with monocationic analogues. Their activity against a representative range of Gram-positive and Gram-negative bacteria, and also fungi, is characterized. The relationship between the biological activity and the structural features of these compounds is revealed, with the hydrophobicity emphasized as a key factor. Among dicationic surfactants, decyl derivatives showed highest antimicrobial effect, while for monocationic analogues, the maximum activity is observed in the case of tetradecyl tail. The leading compounds are 2–4 times higher in activity compared to reference antibiotics and prove effective against resistant strains. It has been shown that the antimicrobial effect is not associated with the destruction of the cell membrane, but is due to specific interactions of surfactants and cell components. Importantly, they show strong selectivity for microorganism cells while being of low harm to healthy human cells, with a SI ranging from 30 to 100.

New polymer complexes of copper (II) were obtained on the basis of apple pectin modified with the amino acid L-tryptophan. The stoichiometry of the complexes formed was determined by spectrophotometric methods, and the stability constants and standard thermodynamic characteristics of the complexation process (Hº; Gº; Sº) were calculated. It was found that the interaction of pectin modified with an amino acid with Cu (II) cations leads to the formation of enthalpy - entropy stabilized metal complex compounds. The IR spectral method showed that the coordination interaction of copper (II) cations with tryptophan-modified pectin involves not only carboxyl groups, but also the hydroxyl functions of the polymer matrix. The obtained polymer metal complexes in the future can be proposed for the production of new generation drugs, which, in addition to the specific properties of the amino acid introduced into the polysaccharide, also have membranotropic, immunomolulatory properties and prolonged action.

Unique sizes and a high level of bioavailability allow nanoparticles of metals (NPMe) to come into direct contact with biological systems, with infectious agents, toxins, as well as with different chemical compounds and separate cell structures (proteins, lipids, nucleic acids). Other biological effects, including less toxicity than in microscopic substances, require attention to be paid to the study of the potential risk of using nanoparticles of each type in a particular way, therefore scientific support is absolutely necessary in this direction. It is believed that the cytotoxicity of nanomaterials is due to genomic and mutagenic effects, but the mechanical forces of interaction of NPMе with cells, obviously, will change not only cytological but also their metabolic reactions. Therefore, the purpose of this research was to determine the biochemical markers of safety (potential toxicity) of NPMe (Au, Ag, Cu, Fe, Co, GFCo, Zn, MnO2) on the model of isolated membrane and cytosolic fractions of eukaryotic test cells of CHO-K1 and U937 lines. Under conditions of preincubation of experimental samples of NPMe at a final concentration of 1 μg/cm3 by the metal with preparations of subcellular fractions of CHO-K1 and U937 (in the final amount of protein 150–200 μg/cm3) for 3 minutes at 37 ± 1 ºС, there was determined the magnitude of membrane ATP-ase and cytosolic LDH-ase activity compared to intact cells ("control"). According to the results of the research, colloidal dispersions of NPAg average size ~30 nm, NPFe ~100 nm, NPCu ~70 nm, and NPMnO2 ~50 nm are safe and biocompatible by their membranotropic effect on subcellular fractions of eukaryotic test cells, as evidenced by an increase in the level of membrane ATPase and cytosolic LDHase of test-cells CHO-K1, and the experimental samples NPCo, NPGFCo and NPZn average size of ~100 nm are membrane-toxic, that is, dangerous. By the nature of the changes in the enzymatic activity of the test cells U937, the discrete dimensions of the membranotropic action of NPAu have been demonstrated: nanoparticles of size ~10 nm caused the inhibition of the membrane Na+,K+-ATPase, and the size of ~30 nm and ~45 nm – its induction; nanoparticles of size ~10, ~20 and ~30 nm induced cytosolic LDHase and the size of ~45 nm – its inhibition relative to the control level of enzymes, so NPAu ~10 and ~45 nm can be considered membrane toxic, and size ~30 nm – safe and biocompatible for eukaryotic cells. Based on the hypothesis about the involvement of metabolism-dependent mechanisms of contact interaction of colloidal dispersions of experimental samples of NPMe with cells through membranotropic properties, the study of their potential danger or biocompatibility in further research can be carried out by determining the intensity of oxidation of the main structural components of biomembranes of cells – lipids and proteins and indicators of their AO-regulation.

Les rhamnolipides (RLs) et les fengycines (FGs), des composés sécrétés par des bactéries, ont des propriétés antifongiques contre les champignons phytopathogènes Sclerotinia sclerotiorum et Botrytis cinerea. Cependant, les effets biocides induits et les mécanismes impliqués sont peu étudiés chez les champignons. De par leur caractère amphiphile, un mode d’action membranotrope est proposé pour ces composés intéréssants pour le biocontrôle. Les travaux présentés ici démontrent que les deux Sclérotiniacées ont des sensibilités opposées aux RLs et aux FGs. Une étude en microscopie montre que les RLs peuvent induire une mort cellulaire programmée (PCD) ou nécrotique chez les deux champignons selon la concentration alors que les FGs induisent systématiquement une PCD, probablement par un mécanisme d’autophagie. Des analyses lipidomiques (contenus en acides gras, phospholipides et ergostérol) de souches de S. sclerotiorum et B. cinerea plus ou moins sensibles aux RLs et aux FGs permettent de rapprocher les contenus lipidiques des champignons à leurs sensibilités. Ces données ont été utilisées pour étudier les interactions entre les RLs ou les FGs et des modèles de membranes plasmiques biomimétiques des deux champignons. Les études de dynamique moléculaire montrent que les RLs s’insèrent, sous forme de monomères, dans les différents modèles étudiés sans les fluidifier et que les FGs s’agrègent puis s’insèrent dans certains modèles en induisant une fluidification. L’ergostérol et les acides phosphatidiques défavoriseraient cette insertion tandis que les phosphatidylcholines et les phosphatidyléthanolamines les favoriseraient. Ces travaux permettent de mieux appréhender le mode d’action antifongique des RLs et des FGs, et contribueront, à terme, au développement de produits de biocontrôle plus efficaces pour la protection des cultures vis-à-vis de pathogènes spécifiques
Rhamnolipids (RLs) and fengycins (FGs), are compounds produced by bacteria displaying antifungal properties against the phytopathogenic fungi Sclerotinia sclerotiorum and Botrytis cinerea. However, the induced biocidal effects, and the involved mechanisms are poorly understood in fungi. Due to their amphiphilic properties, a membranotropic mode of action is proposed for these interesting compounds for biocontrol. The present work demonstrates that the two Sclerotiniaceae have opposite sensitivities to RLs and FGs. A microscopy study shows that RLs can induce programmed cell death (PCD) or necrotic cell death in both fungi depending on the concentration whereas FGs systematically induce PCD, probably by triggering autophagy. Lipidomic analyses (fatty acid, phospholipid and ergosterol contents) of S. sclerotiorum and B. cinerea strains differently sensitive to RLs and FGs allow to correlate the lipid contents of the fungi to their sensitivities. These data are used to study the interactions of RLs or FGs on biomimetic plasma membrane models of the two fungi. The dynamics show that the RLs monomers insert into the models without fluidizing them and that the FGs auto-aggregate themselves and insert into some models, inducing fluidization. Ergosterol and phosphatidic acids seems to disfavour this insertion while phosphatidylcholine and phosphatidylethanolamine seem to favour it.This work allows to better understand the antifungal mode of action of RLs and FGs, with a view to develop more effective biocontrol products for crop protection targeting specific pathogens