Electron transfer (ET) is an elementary chemical process that has been widely studied due to its involvement in many chemical, biological and physical processes. Currently, special attention is paid to ET due to the use of electron spins as qubits in spintronics and quantum information science. The phenomenon of chiral-induced electron spin selectivity (CISS) in the ET process opens a new way to control the dynamics of electron spins. However, the physical mechanisms of the influence of chiral centers on the process of electron movement through them have not yet been established. Photoinduced ET (PET) in chiral donor-acceptor dyads is recommended as a model for studying this mechanism. At the same time, a difference in the effects of chemically induced dynamic nuclear polarization was discovered in PET in chiral dyads with different optical orientations in solutions. This phenomenon is called nuclear spin selectivity (NSS). This article is a review of our work on NSS, in which we show that the spin selectivity of nuclear hyperpolarization is not fully described by the theory of radical pairs. A hypothesis is also put forward about a possible connection between the spin selectivity of electrons and nuclei.

β-Escin is a well-known saponin derived from the horse chestnut tree. Saponins, including escin, exhibit a wide range of biological activities, among which membrane-modifying activity is particularly notable. The latter is key to understanding the molecular mechanisms underlying escin's biological effects, including its antiviral properties. For example, altering membrane properties can strongly influence the life cycle of enveloped viruses such as SARS-CoV-2 by modulating the activity of its envelope protein (E protein). In the present paper, we studied the localization of both escin and the E protein transmembrane domain (ETM) in model membranes with different lipid compositions. We demonstrated that escin can alter ETM localization in membranes containing the negatively charged lipid DMPS, and that escin is also capable of extracting cholesterol from model lipid membranes.

The low-energy (0-14 eV) resonance electron interaction with gas-phase ellagic acid (EA) molecules is studied using dissociative electron attachment (DEA) spectroscopy. Photoinduced electron transfer reactions with solvated EA are studied using the chemically induced dynamic nuclear polarization (CIDNP) technique. Molecular negative ions EA˙-, the most abundant species generated by thermal electron attachment to EA, autodetach their extra electrons within 200 µs, allowing us to estimate the adiabatic electron affinity of EA as 1.3 eV-a value in excellent agreement with that predicted at B3LYP/6-31+G(d) level. In an intriguing observation, the slow (microsecond timescale) cleavage of a single O-H bond, resulting in [EA - H]- fragments, can tentatively be explained by the H-atom roaming across the molecular framework or by the statistical accumulation of the energy required to overcome the potential barrier along the reaction coordinate. In contrast to a variety of polyphenolic molecules, [EA - 2H]˙- is not formed at thermal electron energies, despite this decay being energetically favorable, likely due to competition with single H-atom abstraction. Fully deprotonated EA (present in solution at pH > 10 as [EA - 4H+]4-) can attach solvated electrons to produce [EA - 4H+]˙5- radicals, consistent with the high electron-accepting ability of isolated EA. However, deprotonated EA can also donate electrons to the model electron acceptor, 2,2'-dipyridyl, generating [EA - 4H+]˙3- radicals, with no further decomposition observed in the present CIDNP experiments, in agreement with the limited fragmentation seen in gas-phase DEA applied to intact EA. The present findings could be important for understanding the biological effects produced by EA, namely, its synergism with radiotherapy and its antibacterial activity, both likely associated with electron-driven processes.

Salicyluric acid (SUA), the main metabolite of aspirin and a natural product, is known for its ability to chelate iron and other metal ions. In particular, the chelation and increased excretion of iron by SUA may contribute to the aspirin-induced iron deficiency anemia observed in long-term aspirin users. The redox activity of iron and copper complexes of drugs and also drug metabolites, such as SUA, is an important parameter of their overall toxicity profile, including the induction of ferroptosis, which has been associated with many diseases. In this context, the effect of SUA on iron- and copper-induced lipid peroxidation and also its localization within a model lipid membrane have been investigated. A combination of physicochemical methods, including Nuclear Magnetic Resonance (1H NMR), molecular dynamics (MD), and Nuclear Overhauser Effect Spectroscopy (1H NOESY), has been used to demonstrate that SUA does not promote the peroxidation of linoleic acid micelles in the presence of Fe(II) or Cu(II) ions. NMR experiments revealed that SUA incorporates into the lipid bilayer, which stabilizes the ligands and inhibits its metal chelation ability in comparison to the control. NOESY experiments and MD simulations further showed that SUA localizes shallowly within the membrane, interacting primarily with the head group and upper acyl chain regions of lipids. These findings provide crucial insights into the membrane redox reactivity and other behavior of SUA, explaining its lack of pro-oxidant activity and also highlighting its complex role in the pharmacological and toxicological effects on iron metabolism in long-term aspirin users.

Background: Depression is a severe disorder associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation and neuroinflammation, and which restrains the efficacy of conventional antidepressants. Vortioxetine is a multimodal antidepressant with potential immunomodulatory properties. Glycyrrhizic acid (GA) is a natural compound derived from licorice root that exhibits anti-inflammatory activity and modulates glucocorticoid signaling. We hypothesized that a supramolecular complex of vortioxetine with GA (Vort:Na2GA) would exert synergistic effects on inflammatory and glucocorticoid pathways. Methods: Vortioxetine compositions with Na2GA were prepared using a mechanochemical method. Cytotoxicity, anti-inflammatory property, and glucocorticoid receptor (GR) signaling pathway modulation of the complex were evaluated in vitro using SIM-A9 microglial cells. Additionally, a 7-day oral administration study in intact female C57BL/6 mice was conducted to evaluate the effects on peripheral blood cells. Results: The Vort:Na2GA complex improves the solubility of the parent drug while increasing its stability and permeability. Furthermore, the resulting complex exhibits reduced cytotoxicity, particularly under glucocorticoid challenge. In SIM-A9 microglial cells, the Vort:Na2GA complex upregulated expression of Nr3c1 and Nr1d1 genes without activating canonical GR target genes (Fkbp5 and Gilz) and partially reversed dexamethasone-induced glucocorticoid resistance. In vivo, the complex reduced the percentage of inflammatory Ly6Chigh monocytes and preserved dexamethasone-induced Gilz expression in peripheral blood cells, indicating protection against stress-induced glucocorticoid resistance. Conclusions: The Vort:Na2GA supramolecular complex enhances the physicochemical and pharmacological profile of vortioxetine, reduces inflammation-associated myeloid cell populations, and preserves glucocorticoid sensitivity. These findings support its further evaluation as a potential therapeutic agent for depressive disorders with inflammatory and HPA axis-related components.

T 1-weighted MRI contrast agents are essential for accurate diagnosis. However, clinical gadolinium-based contrast agents (Gd-CAs) are increasingly questioned because of risks of nephrogenic systemic fibrosis (NSF) and long-term tissue accumulation. Metal-free organic nitroxides like TEMPO emerge as safer alternatives but are limited by rapid in vivo bioreduction and suboptimal r1 relaxivity. Here, we report TEMPO-PROXY@pGen, a dual-radical, bio-based, π-conjugated polymer synthesized through mechanochemical copolymerization of 4-amino-TEMPO with 4-amino-PROXYL (3,3,5,5-tetramethyl-1-pyrroline N-oxide) on genipin-crosslinked scaffolds. TEMPO-PROXY@pGen integrates rigid π-conjugated backbone anchoring with possible intramolecular biradical interactions, causing the apparent rotational correlation time (τR,app) to approach the regime where Solomon-Bloembergen-Morgan (SBM) theory predicts enhanced relaxivity for simple monoradical systems while preserving high effective spin density (>80 radicals per chain). This yields a longitudinal relaxivity (r1) of 4.35 mM-1s-1 at 1.4 T and 3.69 mM-1s-1 at 3.0 T, 33.5-fold higher than TEMPO and comparable per-molecule r1 to clinically approved gadobutrol at the same field strength. The polymeric architecture confers high resistance to bioreduction and lower cell toxicity. Preliminary biosafety evaluation, including histopathology, serum biomarkers, and functional imaging, in both healthy and cisplatin-induced renal impairment models, suggests an improved safety profile relative to Gd-CAs under the tested conditions. This work establishes a rational molecular engineering framework for fully organic, metal-free MRI contrast agents that separates high relaxivity from heavy metal dependence for safe imaging in patients with compromised renal function.

Photosensitivity is among the most frequently reported adverse drug reactions. In this study, the photochemical behavior of the experimental anticancer ligand di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and its chelate complexes with copper(ii) and zinc(ii) ions were investigated using laser flash photolysis (LFP), electron paramagnetic resonance (EPR) with spin traps, chemically induced dynamic nuclear polarization (CIDNP), and high-resolution liquid chromatography-mass spectrometry (LC-MS) techniques. MTT assay demonstrated a reduction in cell viability when cells were irradiated in the presence of Dp44mT and its complexes with Cu(ii). LFP analysis revealed the formation of transient absorption upon excitation of Dp44mT solutions by UVA light (355 nm). This absorption featured an intense band peaking at similar to 400 nm and a broad, structureless absorption in the visible region. The intermediate absorption spectra of the Dp44mT complexes with Cu(ii) and Zn(ii) ions were characterized by the absence of an intense intermediate absorption band near 400 nm. The spectra and lifetime of this intermediate were independent of the presence of oxygen, indicating the absence of the singlet oxygen generation. CIDNP experiments showed that the photoreaction of Dp44mT with model electron acceptors, such as quinones, proceeds via proton-coupled electron transfer, leading to the formation of an S-centered neutral radical. It was found that complex formation of Dp44mT with zinc and copper ions stabilizes the thiosemicarbazone, which leads to inhibition of the formation of free radical species and increase Dp44mT photostability. Dp44mT and its chelate complexes did not exhibit electron acceptor properties in reaction with the amino acid derivative N-acetyl-l-tryptophan. EPR experiments with the TMIO spin trap showed the redox activity of the Dp44mT chelate complex with Cu(ii) ions in the Fenton reaction under UV-A light (366 nm), which are correlated with its photocytotoxicity. Chromatography-mass spectrometry data were used to propose a photoconversion pathway for Dp44mT and identify its primary photodegradation products. The Dp44mT photocytotoxicity is probably explained by the toxicity of secondary products formed during the photodegradation of Dp44mT. These results provide insight into the possible photodegradation pathways of Dp44mT, highlighting the role of photodegradation products in its biological activity.

NMR and molecular dynamics simulations revealed differences in the localization of the novel thiosemicarbazones: 2-benzoyl ((E)-N-(acridin-9-yl)-2-(phenyl(pyridin-2-yl)methylene)hydrazine-1-carbothioamide (AOBP) and 2-dipyridyl ((E)-N-(acridin-9-yl)-2-(di(pyridin-2-yl)methylene)hydrazine-1-carbothioamide (AODP) within the lipid membrane. It turned out that both thiosemicarbazones can penetrate inside the membrane, but AOBP is able to pass into the center of the hydrophobic region of the lipid bilayer, while AODP is distributed closer to the surface and freely leaves the membrane into the aqueous environment. The presence of cholesterol was also found to prevent both thiosemicarbazones from penetrating the membrane. The mechanism of anti-proliferative activity of some TSCs is related to the penetration through the lysosomal membrane and formation of cytotoxic copper complexes, which generate ROS resulting in lysosomal membrane permeabilization and cell death. Hydrophobic drugs, including TSCs, could penetrate through lysosomal membrane via passive diffusion, thus the affinity of drug to the hydrophobic interior of the lipid membrane could be important for their activity. Since the mechanism of thiosemicarbazones anticancer activity is associated with their penetration into lysosomes, the results obtained are important for a better understanding of the mechanisms of activity of these compounds and the development of new drug agents.

Carotenoids represent a ubiquitous and critically important class of natural isoprenoid pigments, synthesized de novo by plants, algae, and photosynthetic bacteria [...].

Factors governing electron transfer (ET) in proteins and peptides are widely studied due to the role of ET in biologically important processes. One of them is the influence of the optical configuration of amino acids on the ability of peptides to aggregate into ensembles: dimers, oligomers, fibrils. Such assemblies, called amyloids, are known to contain D-isomers of asparagine and serine, and their presence in aging living organisms leads to a number of diseases, including Alzheimer’s disease. However, how these amino acids affect the structure and properties of peptides have not yet been established. Using the example of the pentapeptide (PP)-(L)histidine-(L)asparagine-(L)serine-glycine-(L)tyrosine and its analogues with D-asparagine and D-serine, this article studies the comparative reactivity of optical isomers in photoinduced ET using chemically induced dynamic nuclear polarization (CIDNP), fluorescence spectroscopy and quantum chemical calculations. The CIDNP method was chosen because it had previously demonstrated high sensitivity to ET processes in chiral dyads linked by non-covalent interactions. ET involving Tyr and His residues of PP was detected under UV irradiation both in the presence of an electron acceptor, naproxen, and during photolysis of PP itself. It was shown that the efficiency of ET and PP fluorescence quenching differ for optical isomers of asparagine and serine. In addition, the dependence of the CIDNP efficiency on the PP concentration showed that ET between Tyr and peptide bonds can occur in the dimer of the PP. Quantum chemical calculation confirm the possibility of PP self-association.

Nonsteroidal anti-inflammatory drugs (NSAIDs) can be used to treat a variety of conditions due to their antipyretic, anti-inflammatory, and analgesic effects. Their interaction with lipid membranes can cause various side effects known for these drugs. In this study, we employ 1H 500 MHz liquid-state NMR to study the spin-lattice relaxation rate, T 1 -1, in model lipid membranes with embedded spin-labeled diclofenac (diclofenac-SL) as a relaxation enhancer. The membranes were unilamellar liposomes of four types: consisting of unsaturated 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), a POPC/cholesterol mixture (80:20 mol %), fully saturated 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), and a DMPC/cholesterol mixture (80:20 mol %). The obtained data for protons in different positions in the lipid molecule showed that, in the absence of cholesterol, diclofenac-SL in the POPC membrane is distributed approximately uniformly throughout the entire depth of the membrane, while in the DMPC membrane there is some shift for the hydrophobic interior. In the presence of cholesterol, a slight shift of diclofenac-SL toward the membrane surface is observed for POPC/cholesterol liposomes, whereas a tendency toward displacement away from the membrane surface is observed in DMPC/cholesterol liposomes.

The journal’s Editorial Office and Editorial Board are jointly issuing a resolution and removal of the Journal Notice linked to this article [...]

Background/Objectives: Some specific anthraquinone derivatives (AQs) are known to be used widely as effective chemotherapeutic agents in the treatment of cancer. However, their fundamental shortcoming is the high rate of cardiotoxicity observed in treated patients, which is thought to be caused by the increase in production of reactive oxygen species (ROS) catalyzed by iron and copper. The development of improved AQs and other anticancer drugs with enhanced efficacy but reduced toxicity remains a high priority. The aim of this study was to evaluate the cytotoxic and ROS production effects of chelate iron and copper complexes of two novel AQs, namely 4-hydroxynaphto[2,3-h]cinnoline-7,12-dione (Q2) and 3-(hydroxymethyl)naphto[2,3-h]cinnoline-4,7,12(1H)-trione (Q3). Methods: The chelation ability of Q2 and Q3 was studied using NMR and UV–Vis spectroscopy. Cytotoxicity studies were carried out using the MTT assay. The influence of chelation on ROS production was studied using NMR spectroscopy in linoleic acid micelles. Results: It was found that only Q3 forms complexes with Fe(III) and Cu(II) ions, whereas Q2 does not demonstrate chelating properties. A cytotoxicity study revealed that Fe[Q3]3 significantly decreased the viability of lung cancer A549 cells, while Q3 and Cu[Q3]2 did not demonstrate cytotoxic properties in this cell line. Furthermore, the presence of Q3 lowered the rate of iron-induced lipid peroxidation in linoleic acid micelles. By contrast, Q2 did not influence the rate of lipid peroxidation, probably due to the absence of effective metal chelating ability. Conclusions: The high cytotoxic effects observed with the iron complex of Q3 against cancer cells in combination with a reduced rate of iron induced lipid peroxidation in the presence of Q3, make Q3 and its iron complex promising for further evaluation and use as chemotherapeutic agents in cancer.

Using the mechanochemical method, supramolecular compositions of a potential anthelmintic, artesunate (ARS) with sodium glycyrrhizinate (Na(2)GA), were obtained in different mass ratios of the components included in ARS-Na(2)GA complex (1 : 5, 1 : 10, and 1 : 20). The formation of an inclusion complex of ARS with Na(2)GA micelles was confirmed by NMR relaxation and the nuclear Overhauser effect (NOESY). It has been established that the ARS-Na(2)GA complex (1 : 10) has optimal physicochemical properties for further biological studies on the helminths Opisthorchis felineus, which cause opisthorchiasis in humans and animals. Experiments in vitro showed that ARS-Na(2)GA complex (1 : 10) had a more pronounced inhibition of motility both in invasive individuals of O . felineus (metacercariae) and in adult trematodes (maritae), compared with pure ARS, and even at low concentrations (0.1-10 mu g/mL) for maritae. Despite the fact that the dose of ARS in the composition of ARS-Na(2)GA (1:10) was 11 times lower, the efficiency coefficient (IC50) declined 2.4-fold (for metacercariae) and 1.45-fold (for maritae) with respect to pure ARS. The results obtained indicate the availability of using the new complex for further studies on O . felineus-infected animals.

Anthraquinones (AQs) are very effective chemotherapeutic agent, however their fundamental shortcoming is high cardiotoxicity caused by reactive oxygen species (ROS). Therefore, development of improved antitumor drugs with enhanced efficacy but reduced side effects remains a high priority. In the present study we evaluated the cytotoxicity and ROS generation activity of chelate complex of redox-active anthraquinone 2-phenyl-4-(butylamino)naphtho[2,3-h]quinoline-7,12-dione (Q1) with iron and copper ions. Cytotoxicity study was performed using the lung cancer cell line A549 and breast cancer cell line MDA-MB-231. Q1 and Cu-Q1 complex demonstrate high activity in these experiments, but Fe-Q1 complex inactive. The ROS generation activity has been studied by EPR spin trapping technique using A549, MDA-MB-231 cell lines, and T lymphoblast cell line MOLT-4. It was shown that Q1 is able to penetrate into these cells and participate in redox reactions with the formation of a semiquinone radical. Fe(III) chelate complex formation results in much slower kinetics of ROS generation compared with pure Q1, which could be connected with a lower penetration through the cell membrane.

Physicochemical and pharmacological properties of mechanochemically synthesised supramolecular systems/complexes of the guest-host type have been studied at the institutes of the Siberian Branch of the Russian Academy of Sciences in cooperation with Chinese Zhejiang University of Technology. The guest is a molecule of a medicinal substance, and the host is a carrier particle - a macromolecule of polysaccharide, saponine micelle, silicon dioxide particle, etc. The strengthening of the pharmacological effect of such structures is achieved by increasing the water-solubility and trans-membrane permeability of drug molecules. The most effective hosts among the studied carriers are plant metabolites - glycyrrhizic acid and its salts, as well as polysaccharide arabinogalactan from Larix Siberica wood. An original solid-phase mechanochemical technology has been developed to obtain water-soluble supramolecular systems from the solid dispersions of components. In this case, supramolecular systems are formed in the process of solid-phase synthesis, or by dissolving the obtained dispersions in aqueous media. As a result of studies of a large number of widely used drugs of various pharmacological classes, it has been shown that the inclusion of drug molecules in these supramolecular systems can significantly increase the bioavailability, effectiveness and safety of their action and reduce the effective therapeutic dose of drugs significantly (by a factor of 2-150), and decrease (down to complete disappearance in some cases) harmful side effects. In this paper we give a brief overview of the studies carried out mainly over the last 10 years.

Glycyrrhizinic acid (GA) is one of the active substances in licorice root. It exhibits antiviral activity against various enveloped viruses, for example, SARS-CoV-2. GA derivatives are promising biologically active compounds from perspective of developing broad-spectrum antiviral agents. Given that GA nicotinate derivatives (Glycyvir) demonstrate activity against various DNA- and RNA-viruses, a search for a possible mechanism of action of these compounds is required. In the present paper, the interaction of Glycyvir with the transmembrane domain of the SARS-CoV-2 E-protein (ETM) in a model lipid membrane was investigated by NMR spectroscopy and molecular dynamics simulation. The lipid-mediated influence on localization of the SARS-CoV-2 E-protein by Glycyvir was observed. The presence of Glycyvir leads to deeper immersion of the ETM in lipid bilayer. Taking into account that E-protein plays a significant role in virus production and takes part in virion assembly and budding, the data on the effect of potential antiviral agents on ETM localization and structure in the lipid environment may provide a basis for further studies of potential coronavirus E-protein inhibitors.

Electron transfer plays a crucial role in living systems, including the generation of reactive oxygen species (ROS). Oxygen acts as the terminal electron acceptor in the respiratory chains of aerobic organisms as well as in some photoinduced processes followed by the formation of ROS. This is why the participation of exogenous antioxidants in electron transfer processes in living systems is of particular interest. In the present study, using chemically induced dynamic nuclear polarization (CIDNP) and dissociative electron attachment (DEA) techniques, we have elucidated the affinity of solvated and free electrons to glycyrrhetinic acid (GA)-the aglicon of glycyrrhizin (the main active component of Licorice root). CIDNP is a powerful instrument to study the mechanisms of electron transfer reactions in solution, but the DEA technique shows its effectiveness in gas phase processes. For CIDNP experiments, the photoionization of the dianion of 5-sulfosalicylic acid (HSSA2-) was used as a model reaction of solvated electron generation. DEA experiments testify that GA molecules are even better electron acceptors than molecular oxygen, at least under gas-phase conditions. In addition, the effect of the solvent on the energetics of the reactants is discussed.

Crocin is a unique water-soluble carotenoid found in crocus and gardenia flowers. Crocin has been shown to have a variety of pharmacological activities, such as antioxidant, anti-cancer, memory improvement, antidepressant, anti-ischemia, blood pressure lowering and aphrodisiac, gene protection and detoxification activities. Due to their amphiphilicity, crocin molecules form concentration-dependent self-associates (micelles) in a water solution. In the present study, using various NMR techniques (T2 relaxation and selective gradient NOESY), we have demonstrated that crocin forms mixed micelles with water-soluble drug delivery system glycyrrhizin and linoleic acid molecules. Note, that the spin–spin T2 relaxation time and NOESY spectroscopy are very sensitive to intermolecular interactions and molecular diffusion mobility. The second purpose of this work was the elucidation of the interaction of crocin with a model lipid membrane using NMR techniques and a molecular dynamics simulation and its effects on lipid oxidation. It was shown that the crocin molecule is located near the surface of the lipid bilayer and effectively protects lipids from oxidation by peroxyl radicals. The role of glycyrrhizin and vitamin C in metal-induced lipid oxidation was also elucidated. The results of this study may be useful for expanding the field of application of crocin in medicine and in the food industry.