Thymoquinone (TQ), the main bioactive component of Nigella sativa, has shown promising anticarcinogenic activity in extensive preclinical studies. This study aimed to evaluate the antitumor activity of TQ, in a wide range of doses with monotherapy and combined use with known the chemotherapeutic drug doxorubicin (Dox) and linseed oil (LO) in a rat model with Pliss lymphosarcoma (PLS) and a mouse model with Lewis lung adenocarcinoma (LLC). Animals was administered orally of TQ daily for 12 days at doses of 5, 10 and 30 mg/kg of body weight (rats) and 5 mg/kg (mice) from the 7th day after subcutaneous transplantation of tumors, as well as combinations of TQ with Dox (5 mg/kg, once at the start of treatment by i.p.) and LO (3 ml/kg, orally). It was found that TQ in the studied doses significantly suppresses the growth of the PLS and the LLC tumors (p < 0.001) and increases the frequency of complete tumor regression (FCR) (p < 0.001) compared to control. TQ, especially (TQ + LO) were able to effectively potentiates the antitumor effect of Dox when used in combination, reducing the PLS tumor volume at the end of treatment by 1.9–2.7 times (p < 0.009), increasing the FCR tumors 60 days after the start of treatment by 2.7–3.7 times (p < 0.02) (PLS) and by 1.5 times (p ≤ 0.05) (LLC), as well as reducing the LLC frequency of metastasis compared to Dox monotherapy. The results strongly suggest that TQ and its combination with LO have clinical potential as an adjuvant in cancer chemotherapy using Dox.

Quinones are one of the most commonly used drugs for cancer treatment. Combinations of quinoid compounds and other oxidation inducers with flaxseed oil (FO), which is rich in omega-3 alpha-linolenic acid, show promise for improving the efficacy of antitumor drugs. Effects of benzo-, naphtho-, and anthraquinones, as well as metronidazole and a number of nitro-1,2,4-triazoles on the oxidative stability of FO, were studied. To this end, kinetic curves were obtained showing the accumulation of hydroperoxides in FO during storage at 37 degrees C with free access to atmospheric oxygen. The calculated oxidation induction period demonstrates that the majority of the tested quinones intensify the oxidation of FO. Pro-oxidant activity is maximum for 1,4-benzoquinone and significantly decreases (p < 0.05) when various substituents are introduced into its ring. A noticeable increase in the concentration of hydroperoxides and the rate of oxidation at the initial stage of the oxidation process is characteristic for 1,4-benzoquinone and its derivatives. Additives of 1,4-naphthoquinone and 2-hydroxy-1,4-naphthoquinone (lawsone) do not affect the oxidative stability of FO, while 5-hydroxy-1,4-naphthoquinone (juglone) and 4,6-di-tert-butyl-1,2-benzoquinone effectively inhibit the oxidation of FO. The oxidation of FO lipids is accelerated by all investigated nitroazoles; however, 1-methyl-3,5-dinitro-1,2,4-triazole has the highest pro-oxidant activity. Practical Applications: The results of this study may be useful in the development of new methods of antitumor therapy using omega-3 polyunsaturated substrates in combination with quinoid and nitrotriazole cytostatics. The data obtained can also be used in the development of oxidation-stable foods based on flaxseed oil, as well as in the production of resins, drying oils, varnishes, paints, and other materials.

The interaction of reactive oxygen species with cell membrane lipids is usually considered in the context of lipid peroxidation in the nonpolar component of the membrane. In this work, for the first time, data were obtained indicating that damage to human cell membranes can occur in the polar part of lysophospholipids at the interface with the aqueous environment due to free radical fragmentation (FRF) processes. FRF products, namely 1-hexadecanoyloxyacetone (PAc) and 1-octadecanoyloxyacetone (SAc), were identified in human serum, and a GC-MS method was developed to quantify PAc and SAc. The content of FRF products in serum samples of 52 healthy donors was found to be in the range of 1.98-4.75 mu mol/L. A linear regression equation, CPAc&SAc (mu mol/L) = 0.51 + 0.064 x years, was derived to describe the relationship between age and content of FRF products. In 70 patients with acute surgical pathology in comparison with the control group of healthy donors, two distinct clusters with different concentration levels of FRF products were revealed. The first cluster: groups of 43 patients with various localized inflammatory-destructive lesions of hollow organ walls and bacterial translocation (septic inflammation) of abdominal cavity organs. These patients showed a 1.5-1.9-fold (p = 0.012) decrease in the total concentration of PAc and SAc in serum. In the second cluster: groups of 27 patients with ischemia-reperfusion tissue damage (aseptic inflammation), - a statistically significant increase in the concentration of FRF products was observed: in 2.2-4.0 times (p = 0.0001). The obtained data allow us to further understand the role of free-radical processes in the damage of lipid molecules. FRF products can potentially be used as markers of the degree of free-radical damage of hydroxyl containing phospholipids.

The influence of cycloaminomethyl derivatives of 4-tert-butyl-1,2-dihydroxybenzene, 3,5-di-tert-butyl-1,2-dihydroxybenzene, and 4,6-di-tert-butyl-1,3-dihydroxybenzene with different substituent ring sizes on the formation of n-hexane radiolysis products in the presence and absence of oxygen was studied. It was shown that the activity of sterically hindered diphenol derivatives toward alkyl radicals increased with the ring size in the side substituent, while the activity toward peroxyl radicals remained at the same level.

The γ-radiation-induced transformations of α-diols in deaerated aqueous solutions at pH 7 have been studied. The composition and radiation-chemical yields of the main products of their radiolysis were determined. It has been established that dehydration by a chain mechanism is a characteristic process for α‑diols with terminal positions of hydroxyl groups (1,2-propanediol and 1,2-butanediol). In the radiolysis of an α-diol with the central arrangement of hydroxyl groups (2,3-butanediol), chain processes did not occur: dehydration and destruction of the diol via C–C bond scission occurred with approximately equal probabilities. The observed effects were explained, and the importance of the obtained results for studying the mechanisms of free-radical fragmentation reactions of hydroxyl-containing biomolecules induced by ionizing radiation was stated.

Linseed oil (LO) is known for its exceptional nutritional value due to the high content of alpha-linolenic acid (ALA), an essential omega-3 polyunsaturated fatty acid; its anticarcinogenic effect has been established in several experimental and epidemiological studies. As an adjuvant of chemotherapeutic agents, LO and other ALA-rich vegetable oils have been studied in only a handful of studies at the experimental level. However, the efficacy of antitumoral therapy using doxorubicin (Dox) in combination with ALA and ALA-rich substrates has not yet been investigated. In this work, the antitumor activity of LO in a wide dose range was studied with monotherapy and combined with Dox in animal models with Pliss lymphosarcoma (PLS) and Lewis lung adenocarcinoma (LLC). It was founded the daily oral administration of LO (1, 3, and 10 ml per 1 kg) to rats (PLS) and 6 ml/kg to mice (LLC) for 11–12 days from 7 days after subcutaneous transplantation of tumors has a stable statistically significant effect on the dynamics of tumor growth, reducing the intensity of tumor growth and increasing the frequency of complete tumor regressions (CR) compared with the control. LO showed high antimetastatic activity in the LLC model. Furthermore, LO at a dose of 3 ml/kg potentiates the antitumor effect of Dox in the PLS model, reducing the volume of tumors at the end of treatment by 2.0 times ( p = 0.013), the value of the tumor growth index by 1.6 times ( p < 0.03) and increasing the frequency of CR 60 days after the start of therapy by 3.5 times ( p = 0.019) compared with the use of Dox alone. The combination of Dox and LO or fish oil allows growing efficiency therapy of LLC in comparison with Dox alone, increasing the frequency of CR to 73.68% and 94.4%, respectively, and reducing the frequency of metastasis to zero.

2-Hexadecenal (2-HD)-a biologically active long-chain fatty aldehyde formed in organism enzymatically or nonenzymatically in the reaction of free-radical destruction of sphingolipids under the action of hypochlorous acid, producing by myeloperoxidase. This research aimed to study 2-HD effects on polymorphonuclear leukocytes' (PMNLs) functions. It has been shown that at submicromolar concentrations, 2-HD causes an elevation in ROS production by PMNLs. It has been found that such effect is associated with signal transduction pathways modification and expressed in elevation of NADPH oxidase, MPO, and JNK-MAPK contributions to this process. At higher concentrations, 2-HD induces apoptosis, which correlates with a significant increase in free Ca2+ in the cytoplasm, a decrease in ROS production, and a decline in mitochondrial potential. Both of these processes are accompanied by cytoskeleton reorganization.

It has been shown that the development of coronavirus infection (COVID-19), especially in severe cases, is accompanied by hypoxia as a result of several pathological processes: alveolar blood supply disorders, hemolysis, COVID-associated coagulopathy. Under these conditions, the level of reactive oxygen species is increased and it is more likely that free-radical damage to biomolecules is caused by the process of free-radical fragmentation than oxidation. In contrast to the oxidation process, free-radical fragmentation reactions are more effectively inhibited by oxidizing agents than reducing agents. Therefore, the use of substances possessing both reducing and oxidizing properties, such as natural and synthetic quinones, bioflavonoids, curcuminoids, should reduce the probability of biomolecule destruction by oxidation as well as free-radical fragmentation processes.

In this work, using the example of model compounds, we studied the reactions resulting from the interaction of OH radicals with the hydrophilic part of sphingolipids. We compared the stopped-flow EPR spectroscopy and pulse radiolysis with optical detection methods to characterize radical intermediates formed in the reaction of OH radicals with glycerol, serinol and N-boc-serinol. Quantum chemical calculations were also performed to help interpret the observed experimental data. It was shown that H-abstraction from the terminal carbon atom is the main process that is realized for all the studied compounds. The presence of the unsubstituted amino group (-NH2) is seen to completely change the reaction properties of serinol in comparison with those observed in glycerol and N-boc serinol.

Исследована возможность совместного применения модифицированных пространственно- затрудненных 1,2-дигидроксибензолов и промышленного противостарителя аминного типа (6PPD) в рецептурах наполненных эластомерных композиций на основе комбинации непредельных натурального и синтетического полибутадиенового каучуков. Установлено влияние комбинаций противостарителей фенольного и аминного типов на упруго-прочностные свойства резин, стойкость вулканизатов к воздействию повышенных температур, а также на усталостную выносливость образцов при многократном растяжении. Модифицированные стабилизаторы различаются типом, количеством и пространственным расположением заместителей в бензольном кольце. Исследуемые ингредиенты вводились в резиновые смеси в дозировке 2,0 мас. ч. на 100,0 мас. ч. каучука. В качестве образца сравнения использовались эластомерные композиции, содержащие комбинацию промышленных стабилизаторов фенольного 2,6-ди-трет-бутил-4-метилфенол (ионол) и аминного N-(1,3-диметилбутил)-N'-фенил-п-фенилендиамин (6PPD) типов в дозировке по 2,0 мас. ч. Определено, что замена промышленного стабилизатора ионола на модифицированные производные 1,2-дигидроксибензолов позволяет получать резины, не уступающие или превосходящие по физико-механическим характеристикам вулканизаты с комбинацией промышленных стабилизаторов. Выявлено, что применение в резиновых смесях стабилизатора с азепанильным циклом совместно с 6PPD обеспечивает наиболее существенное улучшение упруго-прочностных свойств резин как до, так и после теплового старения, а также позволяет получать вулканизаты с наибольшей усталостной выносливостью.

Исследована эффективность применения новых производных пространственно-затрудненных пирокатехинов в качестве противостарителей в рецептурах наполненных эластомерных композиций на основе комбинации синтетических полиизопренового и полибутадиенового каучуков. Установлено влияние производных пирокатехинов на упруго-прочностные свойства вулканизатов, стойкость резин к термическому старению в среде воздуха, а также их сопротивление разрастанию трещин при многократном изгибе. Исследуемые стабилизаторы различаются типом, количеством и пространственным расположением заместителей в бензольном кольце. Данные ингредиенты вводились в резиновые смеси в дозировках 1,0 и 2,0 мас. ч. на 100,0 мас. ч. каучука. В качестве образца сравнения использовались эластомерные композиции, содержащие промышленный стабилизатор 2,6-ди-трет-бутил-4-метилфенол (ионол, BHT). Определено, что опытные противостарители имеют более низкую летучесть по сравнению с наиболее известным и эффективным промышленным стабилизатором ионолом. Выявлено, что характер изменения упруго-прочностных свойств эластомерных композиций, содержащих синтезированные противостарители, определяется природой и дозировкой стабилизаторов. Показано, что применение в резиновых смесях новых стабилизирующих добавок приводит к получению вулканизатов, обладающих повышенной стойкостью к воздействию повышенных температур и к разрастанию трещин при продольном изгибе.

Fluorescence assay and Raman spectroscopy were used to study the mechanisms of action of 2-isopropyl-5-methyl- 1,4-benzoquinone (thymoquinone) on HEp-2 human larynx carcinoma cells. Thymoquinone was found to have a more pronounced toxic effect than 1,4-benzoquinone and 2,3,5-trimethyl-1,4-benzoquinone. The action of thymoquinone leads to a decrease in the mitochondrial membrane potential and release of cytochrome c from the mitochondria, indicating activation of apoptosis of tumor cells through the mitochondrial-mediated pathway. These results indicate the possibility of using Raman spectroscopy in the study of programmed cell death.

Методами квантовой химии исследованы спектрально-люминесцентные свойства заряженных (анионной и катионной) форм трех замещенных бензальдегидов, проявляющих биологическую активность: o-анисового (2-метоксибензальдегид) и сиреневого (3,5-диметокси-4-гидроксибензальдегид) бензальдегидов и ванилина (3-метокси-4-гидроксибензальдегид). Расчеты показали, что в случае заряженных форм исследуемых молекул состояние S1 в отличие от нейтральных форм является состоянием ππ*-типа и по своей локализации аналогично S2 (ππ*)-состоянию нейтральных молекул (анисового альдегида и ванилина) или S3 (ππ*)-состоянию сиреневого бензальдегида. По результатам расчета показано, что в области спектра 240-420 nm нет новых электронных переходов, формирующих полосы поглощения в спектре, отличающиеся по природе и локализации от электронных переходов нейтральных молекул. Рассчитанные характеристики флуоресценции заряженных форм исследованных молекул показали, что в отличие от нейтральных форм эффективность радиационного распада заряженных форм много выше, что связано с изменением орбитальной природы состояния S1 при переходе от нейтральной к заряженной форме. Согласно анализу расчетных и экспериментальных данных флуоресценции исследуемых замещенных бензальдегидов в спиртовых растворах, флуоресценция на 410 nm принадлежит катионным формам. В ванилине и сиреневом альдегиде также имеется возможность слабой флуоресценции анионных форм этих соединений. Ключевые слова: замещенные бензальдегиды, спектрально-люминесцентные свойства, методы квантовой химии.

ABSTRACT Degree work contains: 57 pages, 15 figures, 12 tables, 60 references. Keywords: positron emission tomography, radiopharmaceuticals, 2-[18F]-fluorodeoxyglucose, radiolysis, 2-fluoroethanol, model compounds.

Steady-state radiolysis has been used to study the radiation-induced transformations of 2-fluoroethanol in dilute aqueous solutions as a model system for examining the autoradiolytic dehalogenation of the radiopharmaceutical drug 2-[18F]fluorodeoxyglucose ([18F]FDG). A derivatization–gas chromatography procedure for determining the fluoride anion in the presence of organofluorine compounds has been developed. It has been established that •OH and H• induced the dehalogenation of 2-fluoroethanol in aqueous solutions. Unlike bromo- and chlorohydrins, 2-fluoroethanol does not interact with $${\text{e}}_{{{\text{aq}}}}^{ - }$$ according to the dissociative attachment mechanism. It has been shown that О2 halved the radiation-chemical yield of fluoride due to the oxidation of hydroxyl-containing carbon-centered radicals of 2-fluoroethanol. The constant of unimolecular dehalogenation of the 2-fluoroethanol radical is 3.9 × 106 s−1, as calculated using the method of competing reactions.

The mechanisms of 2-isopropyl-5-methyl-1,4-benzoquinone (thymoquinone) action on human larynx carcinoma cells of the HEp-2 line were studied using methods of fluorescence assay and Raman spectroscopy. It was found that thymoquinone has a more pronounced toxic effect compared to 1,4-benzoquinone and 2,3,5-trimethyl-1,4-benzoquinone. A decrease of the mitochondrial potential and the release of cytochrome c from the mitochondria are observed under the action of thymoquinone , which indicates the activation of apoptosis of the tumor cells along the mitochondrial-mediated pathway. The obtained results demonstrate the prospects of using Raman spectroscopy in the study of programmed cell death.

The effectiveness of several synthetic and natural antioxidants (AO) in inhibiting the oxidation of linseed oil has been studied. Under the conditions of accelerated oxidation at 100 °С, the values of the induction period of oxidation and stabilization factors of linseed oil in the presence of additives of known phenolic AOs, tocopherols, fat-soluble ascorbic acid esters and compositions based on them were determined. The data obtained indicate that ascorbic acid esters effectively inhibit the oxidation of linseed oil. The stabilizing effect of ascorbyl palmitate (AP) increases with an elevation in the content of α-linolenic acid in the oil and a decrease in the oxidative stability of the oil. One AP provided better stabilization efficiency than some known compositions based on it. Kinetic data on the accumulation of oxidation products in linseed oil with AP additives during the storage at room temperature and with free access of the air were obtained, demonstrating high inhibiting activity of AP under these conditions, which provides a possibility to increase the shelf life of the stabilized oil up to 18 months or more.

Abstract Vicinal diols and its derivatives can be exploited as model compounds for the investigation of radiation-induced free-radical transformations of hydroxyl-containing biomolecules such as carbohydrates, phospholipids, ribonucleotides, amino acids, and peptides. In this paper, for the first time, the prospects of isotope reinforcement approach in inhibiting free-radical transformations of hydroxyl-containing compounds in aqueous solutions are investigated on the example of radiolysis of 1,2-propanediol and 1,2-propanediol-2-d1 aqueous solutions. At an absorbed dose rate of 0.110 ± 0.003 Gy·s−1 a profound kinetic isotope effect (KIE) is observed for the non-branched chain formation of acetone, which is a final dehydration product of predominant carbon-centred radicals CH3·C(OH)CH2OH. In 0.1 and 1 M deaerated solutions at pH 7.00 ± 0.01, the values of KIE are 8.9 ± 1.7 and 15.3 ± 3.1, respectively. A rationale for the fact that a strong KIE takes place only in the case of chain processes, which may occur during free-radical transformations of vicinal diols, is also provided herein based on the results of 2-propanol and 2-propanol-2-d1 indirect radiolysis. Lastly, the lack of KIE is shown in the case of 2-butanone formation from 2,3-butanediol or 2,3-butanediol-2,3-d2. This indicates that the type (primary, secondary) of the β-carbonyl radicals formed as a result of CH3·C(OH)CH(OH)R (R = H, CH3) dehydration determines the manifestation of the effect. Graphical Abstract