Natural Sesquiterpene Lactones as Renewable Chemical Materials for New Medicinal Products

Literature data and own research results on the technology for isolating natural sesquiterpene lactones such as arglabin, alantolactone, artemisinin, grosheimin, isoalantolactone, parthenolide, santonin and potential possibilities of their use as renewable material for obtaining new compounds as well as biologically active derivatives are generalized in this review. Sesquiterpene lactones from plants are promising sources for the development and practical application of new original medical products possessing antitumor, anti-inflammatory, antimalarial, antiulcer, antiviral and immune-stimulating action. The technology for isolating sesquiterpene lactones is based on the extraction of raw plant material by different organic solvents with the subsequent chromatographic purification. The effective and environmentally safe technology for isolation and purification of sesquiterpene lactone arglabin from Artemisia glabella Kar. et Kir. by the СО2-extraction method is developed. Thereat, it was experimentally determined that the method for isolating arglabin from CO2 extract of Artemisia glabella Kar. et Kir. using centrifugal partition chromatography is effective for preparative isolation of the active substance and its manufacturing application. It is practically important to obtain water-soluble derivatives of biologically active sesquiterpene lactones and also to use the nanotechnology achievements for directed transportation of a molecule of the medicine in the human body thereby reducing toxicity of an active component. Promising direction is chemical modification of molecules in sesquiterpene lactones which are renewable material for obtaining new derivatives, thanks to which it becomes possible to solve two problems at the same time. Firstly, these researches help to obtain derivatives with higher biological activity or improved physical and chemical properties. Secondly, these researches enable us to disclose the mechanism of action of different medicines within the framework of “structure-activity” correlation. The article presents the literature data and own results on chemical modification of sesquiterpene lactones of alantolactone, arglabin, artemisinin, grosheimin, isoalantolactone, parthenolide and santonin. Various reactions on functional groups of these molecules were used to obtain a number of new derivatives of sesquiterpene lactones containing haloid-, pyrazole-, triazole-, amino-, dialkylamino-, hydroxy-, dialkyl phosphonate- and cyclopropane groups, which have shown high physiological activity

Heteroatom-Containing Natural Sesquiterpene Lactones and Methods for their Obtaining

This review shows the data about isolated heteroatom-containing sesquiterpene lactones from various genera of Asteraceae family, natural occurence, isolation methods and their biological activity. Chlorinecontaining sesquiterpene lactones were isolated from genera of Artemisia L., Achillea L., Acroptilon Cass, Centaurea L., Chartolepis Cass, Eupatorium L., Jurinea Cass, Rhaponticum Adams, Saussurea DC. The greatest quantity of chlorine-containing sesquiterpene lactones were isolated from Centaurea genus. 25 new sesquiterpene lactones with chlorine atom in molecule were isolated and characterized. The sesquiterpene lactones, which in their structure contained a sulphur atom as a component of various alkoxyl-, thiohydroxygroups and acid residues, were isolated from genera of Eupatorium L., Petasites Mill, Helenium L., Acritopappus R.M. King and H. Rob., Arctium L., Saussurea DC. Nitrogen atom in the structure of natural sesquiterpene lactones is present in the form of amino groups as a part of ester groups as well as amino acids as Michael adducts. Nitrogen-containing sesquiterpene lactones were isolated from Acanthospermum Schrank, Saussurea DC. Isolated heteroatom-containing sesquiterpene lactones possess bactericidal, antifungal, cytotoxic, antiviral, virucidal, antiulcer and others activities. Another method for obtaining heteroatom-containing sesquiterpene lactones is a directed synthesis of chlorine-, fluorine-, bromine-, sulphur- and nitrogen-containing sesquiterpene lactones. On the basis of sesquiterpene lactone artemisinin known as an effective antimalarial preparation, we synthesized over 200 derivatives, among which fluorine-, chlorine-, bromine-, nitrogen-, sulphur- and azide-containing derivatives of artemisinin were obtained

Experimental, Clinical and Morphological Analysis of H-Ras Oncoproteins for Locally Advanced Breast Cancer

BACKGROUND: Activated forms of Ras are enhanced in both breast cancer as well as the cell lines with EGFR and HER2 expression. Therefore, H-Ras could be activated in breast tumours in the absence of direct mutational activation of Ras itself and could contribute to 20-50% of the cases. Expression inhibition, signal transduction interruption from H-Ras to the nucleus could become a promising therapeutic target. AIM: The aim of this study was to investigate the clinical and morphological criteria of locally advanced breast cancer and the expression of H-Ras oncoprotein in patients who have been subjected to different regimens of farnesyltransferase inhibitor. METHODS: H-Ras status was assessed by immunohistochemistry (IHC). RESULTS: An association between the expressions of H-Ras and Her2/neu (p = 0.001) as well as the tumour proliferation index Ki-67 (p = 0.001) in patients with breast cancer was established. Analysis of the relationship between H-Ras expression showed a relatively strong association with progression-free survival both before the treatment (V = 0.47; p = 0.001) and after the treatment (V = 0.45; p = 0.001). These results may indicate the clinical applicability of H-Ras as a prognostic factor or serve as a therapeutic target for breast cancer treatment. CONCLUSION: These results could indicate the potential clinical application of H-Ras as a prognostic factor or a therapeutic target for breast cancer treatment

Numerical and Experimental Investigation of multiphase flows. Fundamental and Applied studies

Multiphase flows can be met both in nature and in industrial processes. The particular case of multiphase flows is particle-laden flows, consisting of fluid phase and particle phase. Study is aimed at the investigation of the dynamics of particles in laminar and turbulent flows. The dynamics of particles depends on their physical properties. The study of the particle’s dynamics in turbulent flow consisted of three parts: simulation of homogeneous isotropic turbulence (HIT), simulation of particle-laden flows and investigation of particles’ pair dispersion. Initially, the turbulent flow was simulated in OpenFOAM via Large Eddy simulation (LES) and Direct Navier Stokes (DNS) methods. Then not decaying homogeneous isotropic turbulence was achieved by addition of forcing term. The effect of different values of forcing constant on turbulent flow was investigated. The mesh convergence study was performed for LES and DNS. Results showed convergence in LES simulations and the reduction of volume-averaged velocity fluctuations (U’) in DNS with an increase of the number of mesh elements. The particle phase simulation was performed in Matlab and CFDEM. The simulation in Matlab revealed several constraints. The simulation of particles with turbulence phase for a short period of time was performed in CFDEM. However, due to the decaying nature of the flow, the investigation of particles’ trajectories could not be performed. The pair dispersion of inertial particles in turbulent flow was investigated for available experimental data. The results were represented on graphs with normalized scales. The correlation between the velocity of flow and the normalized value of the initial separation was determined. The mean square separation does not change significantly until the first decade. The motion of clots in blood flow was numerically simulated using Ansys Fluent package. The mesh convergence study was performed and the velocity of the particles in blood flow was analyzed. The results obtained for blood flow showed distribution close to Gaussian. The preliminary experiment was conducted for small particles of smoke. The smoke cloud was detected via the image intensity analysis

The Level of Reactive Carbonyl Derivatives of Proteins, Malondialdehyde, and Catalase Activity in the Brain of Rats after Therapy Following Chronic Unpredictable Moderate Stress

BACKGROUND: Understanding the mechanisms of the behavioral disorders’ emergence under the influence of chronic stress is the most important aspect of the subsequent development of a strategy for its therapy and prevention. Changes in the oxidative metabolism processes can be decisive in the development of the pathogenetic cascade in the brain. Information about these processes can be obtained by studying protein carbonylation, lipid peroxidation, and catalase activity (CA). The complexity of the therapeutic impact in various behavioral disorders implies the search for new pharmacological substances and the study of the previously known drugs’ effects based on the available scientific data. AIM: The aim of the study was to study the reactive carbonyl derivatives of proteins (RCDP), malondialdehyde (MDA), and CA in the brain of rats after therapy following chronic unpredictable moderate stress (CUMS). METHODS: Forty male outbred rats weighing 450–500 g were used in this study. For 21 days, all animals were exposed to the diverse stress factors for developing the CUMS. The animals were divided into four groups of 10 rats, each using randomized selection. The rats of one group were euthanized by decapitation with subsequent brain harvesting (Group 4). Remaining three groups of rats were treated with placebo (Group 1), harmine hydrochloride (Group 2), and amitriptyline (Group 3) for 21 days. Upon completion of therapy, all rats were also euthanized by decapitation with subsequent brain harvesting. The levels of RCDP, MDA, and CA were studied in their brain, and after that, we compared the multiple studied indicators in four groups. RESULTS: The results of the rat brain examinations in four groups showed that RCDP level in Group 2 was significantly lower than in Group 4 (p = 0.000). Similarly, in Group 1, it was lower than in Group 4 (p = 0.021), plus, it did not differ statistically from the harmine hydrochloride group (p = 1,000). Indicators of Groups 3 and 4 did not have any significant differences in RCDP level, too, (p = 0.799); however, the RCDP level in Group 2 was significantly lower than in Group 3 (p = 0.040). MDA indicators did not show significant differences; however, a tendency for lower values was revealed in Group 1 (p = 0.233) and Group 2 (p = 0.151). CA in Group 4 was lower than that in Group 1 (p = 0.000), Group 2 (p = 0.001), and Group 3 (p = 0.003) contemporaneously, while all treatment groups were comparable (p = 1.000). CONCLUSION: The result of exposure to chronic stress can be reproduced with the best quality in the CUMS model. The neurobiological foundations of the model make it possible to assess biochemical markers of oxidative metabolism and evaluate the possibilities of pharmacological correction of stress-induced behavioral disorders. To assess the mechanisms of autoregulation of oxidative metabolism, this study included a placebo group (Group 1), the level of RCDP in which was significantly higher in comparison with Group 3 and Group 4 and slightly lower than in Group 2. In this study, harmine hydrochloride demonstrated activity exceeding amitriptyline, particularly limiting the process of protein carbonylation, not noted for amitriptyline. According to the results of the RCDP assessment in the CUMS model, the process of protein carbonylation can be considered to be one of the significant factors in the deactivation of neurotransmitters. The CA levels determined in all groups allowed us to consider this marker as the most sensitive to the effects of stress, which possibly has an inhibitory effect on catalase, as its activity in all groups after therapy was more than two-fold higher than in animals right after CUMS. We can assume that CA plays an important role in starting the processes of autoregulation of oxidative metabolism. The study was carried out as a part of the implementation of the scientific and technical program No. BR05236584 “Development of new herbal preparations and their pharmacological and clinical studies” (O.0820). (2018–2020) in the priority area, “Life and Health Sciences.

Comparative morphological and anatomical characteristics of Saussurea amara (L.) DC. and S. salsa pall. Spreng

In this paper, the authors conducted research of the comparative morphological and anatomical characteristics of two species of Saussurea, which grow in the steppes of Central Kazakhstan - S. amara L. (S. bitter) and S. salsa Pall. Spreng. (S. solonchak). Researchers revealed a number of clear distinctive morphological and anatomical signs of the over ground organs of S. amara and S. salsa, which make it possible to distinguish these species both as at the stage of collection of plants and also in the process of laboratory examination of the raw materials. The distinctive features of the anatomical stems of S. amara and S. salsa are the degree of furrows, strongly marked sclerenchyma of the conducting beams, and the size of parenchymatous cells of the primary cortex and the core. S. amara compared with S. salsa is characterized by more furrowed stems, less sclerenchyma in the conducting vascular bundles and smaller parenchymatous cells

Synthetic Derivatives of Natural Alkaloid Harmine

The indole alkaloid harmine was extracted from underground part of Peganum harmala L. With the purpose of obtaining the new biological active derivatives on base of alkaloid harmine the chemical modification was carried out. The p-toluolsulfochlorid, p-toluolsulfoacid, hydrochloric, sulfuric, nitric acids, dioxide selenium and phthalic anhydride have been chosen as modifiers. For the first time quaternary ammonium salts, derivatives of N-oxide and N (2)-oxyharminiumphthalate harmine are synthesized. The structure of the synthesized compounds is determined by methods of the spectral analysis and X-ray analysis. Antimicrobic and phagocytosis stimulating activities of isolated alkaloids and their derivatives are investigated

Composition of essential oil of leaves and fruits of green strawberry (Fragaria viridis Weston) growing wild in Northern Kazakhstan

Fragaria viridis Weston essential oils from leaves and fruits were obtained by hydrodistillation. The composition of the essential oil from leaves and fruits was analyzed by GC-MS. 39 components were identified in leaves oil representing 67.3-80.7% of the oil composition. The main components of the essential oil from leaves of F. viridis Weston were β-linalool (0.8-8.9%), n-nonanal (0.5-8.6%), tetradecanal (2.1-5.9%), nerolidol (2.1-4.8%), an unidentified component (1.9-6.6%), α-bisabolol (0.8-6.7%), phytol (18.4-47.4%), an unidentified component (0.9-8.2%) depending on the growth conditions. The fruit oil was composed of 34 compounds representing 42.0-70.7% of the total composition of the oil. The main components of the essential oil from fruits of F. viridis Weston were m/p-xylene (2.4-14.0%), isoledene (4.7-8.5%), methyleugenol (3.3-8.4%), α-cedrene (2.5-3.9%), an unidentified component (3.4-9.1%), α-muurolene (6.8-11.3%), nerolidol (1.1-4.8%), α-cedrol (1.7-8.0%), α-bisabolol (2.3-5.0%), an unidentified component (0-25.6%) depending on the growth conditions. This is the first report of the chemical composition of the essential oils obtained from the leaves and fruits of green strawberry (Fragaria viridis Weston)

СИНТЕЗ АМИДОПРОИЗВОДНЫХ ПУЛЕГОНА

Ritter’s reaction of pulegone with a number of both aliphatic and aromatic nitriles in the presence of catalytic amount of concentrated sulfuric acid proceeding through formation of a tertiary carbocation with the subsequent addition of nitrile molecule and formation of ketoamides, has been performed.Осуществлена реакция Риттера пулегона с рядом как алифатических, так и ароматических нитрилов в присутствии каталитического количества концентрированной серной кислоты, которая протекает через образование третичного карбокатиона с последующим присоединением к нему молекулы нитрила и образованием кетоамида.