Vol 9, No 4 (2021)
- Year: 2021
- Articles: 6
- URL: https://journals.eco-vector.com/2307-9266/issue/view/5652
Articles
Antitumor drugs based on indolocarbazol derivatives
Abstract
The aim of the work is to generalize the literature data on indolocarbazole derivatives with an antitumor activity.
Materials and methods. The objects of the study were the preparations based on indolocarbazole derivatives with the antitumor activity. To search for materials on the problem under study, the following search and information as well as library databases were used: Ebibrary, PubMed, CyberLeninka, ResearchGate, the State Register of Medicines, clinical trials registries clinline.ru and clinicaltrials.gov. The search for the following words / phrases was performed: indolocarbazoles, indolocarbazole derivatives, staurosporine, rebeccamycin, staurosporine derivatives. The search was conducted from January 11 until March 1, 2021. The compounds with a biological activity which were undergoing or had undergone preclinical and clinical trials, were taken into account. All the materials from 1977 to January 1, 2021, were taken into account.
Results. The materials obtained indicate that indolocarbazole derivatives are promising compounds for the creation of anticancer medicinal preparations due to their properties and peculiarities of the action mechanism. These drugs have a selective action due to the targeted interaction with specific molecular targets: kinases (especially protein kinase C and its isozymes), DNA and DNA topoisomerase. To date, many compounds from the class of indolocarbazoles have been synthesized and investigated. They have shown a high antitumor activity in the treatment of systemic and solid tumors. However, despite this, only one MP based on a staurosporine derivative, registered by the TN of Rydapt® (in the USA and EU countries) and Miticaid® (in the Russian Federation), is approved for use in the clinical practice.
Conclusion. Thus, the basic data from scientific publications on promising anticancer medicinal preparations based on compounds from the class of indolocarbazoles, have been summarized. The information is provided, in particular, on their molecular structure, the origin, classification, the main representatives of the class, which are at various stages of the research and are approved for use in the clinic.
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Development and validation of methods for quantitative determination of active pharmaceutical substances in nasal spray
Abstract
Intranasal administration of H1-histamine receptor blockers may be a promising approach to the treatment of allergic rhinitis. Earlier, an original composition of a nasal spray containing fexofenadine hydrochloride and ammonium glycyrrhizinate and demonstrating a high level of therapeutic efficacy, was developed.
The aim of the study was to develop and validate a method of the quantitative determination of active pharmaceutical ingredients fexofenadine hydrochloride and ammonium glycyrrhizinate in a spray for intranasal administration.
Materials and methods. During the development and validation of the method of the fexofenadine hydrochloride and ammonium glycyrrhizinate quantitative determination in a nasal spray, the method of high performance liquid chromatography was used: a Dionex Ultimate 3000 UV chromatograph with a Luna C18 column (2) containing octadecylsilicagel with a 5 μm grain size as a sorbent. The analysis and validation procedures were performed in accordance with the requirements of the State Pharmacopoeia of the Russian Federation, the XIVth edition.
Results. The study showed that for the simultaneous quantitative determination of fexofenadine hydrochloride and ammonium glycyrrhizinate, the optimal elution regime is a gradient mode with a mobile phase containing 50 mmol/L potassium dihydrogen phosphate solution with methanol (45:55), which ensured the separation of the components in the 20 minutes interval. The validation procedures showed that the developed methodology correspond to all the criteria of validity in terms of the following indicators: correctness, precision, specificity and linearity in the analytical area.
Conclusion. The obtained results indicate the possibility of using the method of high-performance liquid chromatography in a gradient elution mode with a mobile phase of the composition of a 50 mmol/L solution of potassium dihydrogen phosphate with methanol (45:55) for the simultaneous quantitative determination of active pharmaceutical ingredients – fexofenadine hydrochloride and ammonium glycyrrhizinate as parts of a promising nasal spray for the allergic rhinitis treatment.
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Effect of cryopreserved placenta extract on some biochemical indices of therapeutic efficiency and toxicity of diclofenac sodium in adjuvant-induced experimental arthritis
Abstract
Relevance. Non-steroidal anti-inflammatory drugs are among the top requested ones in the clinic of internal medicine. However, these drugs are associated with a wide range of adverse reactions involving a number of organs and systems, in particular the gastrointestinal tract, cardiovascular system and kidneys.
The aim of the study is to characterize the effect of the combined use of cryopreserved placenta extract and diclofenac sodium on the prooxidant-oxidative system, the activity of inflammatory, destructive and cytolytic processes, as well as protein and lipid metabolism in rats with experimental rheumatoid arthritis.
Results. The administration of diclofenac sodium and cryopreserved placenta extract to rats with adjuvant arthritis normalized the level of active products of thiobarbituric acid and hence was indicative of the neutralization of an arthritis-induced oxidative stress. A statistically significant (p=0.01) increase of in a superoxide dismutase activity (by 30.6% relative as compared with rats of the control group) has also been established. An increase in the anti-inflammatory properties of diclofenac sodium in the combined use of diclofenac sodium with a cryopreserved placenta extract has been found out. The level of C-reactive protein decreased (p<0.001) by 61.1% as compared with the untreated rats, and the level of seromucoid has been significantly (p<0.01) decreased by 17.1% as compared with the rats of the monotherapy group treated with the studied NSAIDs. It was shown that alanine aminotransferase and aspartate levels were significantly lower (by 38.9%, p<0.01 and by 37.9%, p<0.01, respectively) as compared with those of the animals that had been administrated with diclofenac sodium. Their indices were by 16.7% (p=0.02) and 17.2% (p<0.001) lower than the indices of the control group rats with untreated adjuvant arthritis. The established changes of aminotransferases levels indicate the ability of a cryopreserved placenta extract to level not only an arthritis-induced cytolytic syndrome, but also a diclofenac-induced one. The combined use of cryopreserved placenta extract and diclofenac sodium was accompanied by the normalization of the total lipids level and phospholipids in the blood serum of rats against the background of experimental rheumatoid arthritis. Thus, the content of phospholipids in the lipid pool statistically significantly (p=0.02) increased by 22.6% as compared with the indices of the animals with adjuvant arthritis without treatment.
Conclusion. The study showed that the combined use of diclofenac sodium and cryopreserved placenta extract leads to the restoration of the balance of the prooxidant-antioxidant system that is more pronounced than monotherapy with diclofenac sodium. A decrease in the activity of inflammatory, destructive and cytolytic processes, as well as the restoration of lipid metabolism in the rats with experimental rheumatoid arthritis, has also been observed
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Study of the pharmacological activity of novel EPOR/CD131 heteroreceptor agonists in mice with endothelial-specific expression of mutant Polg gene
Abstract
The aim of the research was to study antiatherosclerotic and endothelial kinds of a protective activity of peptides mimicking an erythropoietin a-helix B tertiary structure with laboratory codes EP-11-1 (UEHLERALNSS), EP-11-2. (UEQLERALNCS), EP-11-3 (UEQLERALNTS).
Materials and methods. The study was conducted on 96 C57Bl/6J male double transgenic Polgmut/mut/Cdh5-CRE mice. Atherosclerosis was induced by a balloon injury accompanied by Western diet. Then, for 27 days, the drugs under study were administered once per 3 days at the dose of 20 μg/kg. On the 28th day, the animals were euthanized and the area of atherosclerotic plaques was collected for an assessment. The expression of genes associated with the processes of inflammation, apoptosis, and angiogenesis was determined in the tissues of the aorta. In addition, the endothelial protective effect of peptides in isolated segments of the thoracic aorta of wild and transgenic ransgenic Polgmut/mut mice was studied.
Results. The assessment of the plaque size in the animals with the Polgmut/mut/Cdh5-CRE genotype against the background of the peptides under study did not reveal statistically significant differences in comparison to control. However, a quantitative PCR showed a statistically significant decreased expression of pro-apoptotic factors p-53 and Bax, and also increase the expression of anti-apoptotic factor Bcl-2 against the background of the peptides EP-11-1 and EP-11-2 administration. The administration of EP-11-1 and the original peptide pHBSP resulted in a statistically significant decrease in the Bax/Bcl-2 ratio. Compounds EP-11-1, EP-11-2, and EP-11-3 were more effective than the original peptide pHBSP, in reducing the increased expression of genes for inflammatory markers iNos, intercellular adhesion molecules Icam-1, Vcam-1 and E-selectin. The use of EP-11-1 led to a more efficient, in comparison with pHBSP, restoration of endothelial-dependent vasodilation of the aortic segments in mice with endothelial-specific overexpression of the mutant Polg gene.
Conclusion. The study carried out on a murine model of the endothelial-specific expression of mutant gamma polymerase has shown that derivatives of the pHBSP peptide with laboratory codes EP-11-1, EP-11-2, EP-11-3, obtained by BLAST-searching for groups of pHBSP related peptides, have atheroprotective and endothelial protective kinds of a protective activity, which is more pronounced in comparison with the original peptide pHBSP.
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Influence of certain d-metals on formation of advanced glycation end products, aggregation and amyloid transformation of albumin in glycation reaction
Abstract
The aim of the research is to investigate the influence of the factor of the glycation behavior of bovine serum albumin (BSA) by glucose, and the factor of d-metal cations (nickel (II), cobalt (II), iron (II), iron (III), copper (II) or zinc (II)) presence, on the process of aggregation and the amyloid transformation of BSA and, therefore, to establish the effect of these cations on the rate of the formation of advanced glycation end products (AGEs), and the intensity of fluorescence of the amino acids tyrosine and tryptophan.
Materials and methods. Reagents in the glycation are: glucose (at the final concentration of 0.36 M), BSA (at the final concentration of 1 mg/ml), deionized water, one of the d-metal cations, i. e. nickel (II), cobalt (II), iron (II), iron (III), copper (II) or zinc (II) (in the form of chloride, sulfate or nitrate salts, at the final concentration of 40 μM). The conditions for the glycation reaction are the incubation for 24 hours at the temperature of 60°C. The influence of two factors (the factor of the glycation reaction and the factor of a d-metal ion presence in the reaction medium) on the concentration of glycation end products (AGEs) formed during the glycation reaction, on the fluorescence intensity of the amino acids tryptophan and tyrosine, on the aggregation of BSA, and on the ability of BSA to the amyloid transformation under the described conditions, have been studied.
Results. It was found out that the studied factors have a statistically significant effect on the considered parameters. The highest activity was found for the copper ion (II), which intensifies the formation of the AGEs in the samples where glycation occurs, reduces the fluorescence intensity of the amino acids’ tryptophan and tyrosine (independently and increasing the effect against the background of glycation). Besides, it independently causes the aggregation of BSA hereby intensifying the effect against the background of glycation, it independently causes the amyloid transformation of BSA enhancing the effect against the background of glycation. The above-listed effects were the least pronounced in the reaction media with the addition of nickel (II) or cobalt (II). These cations reduce the rate of the AGEs formation, do not cause the formation of protein aggregates. In the presence of glucose, nickel (II) weakly suppresses the fluorescence intensity of tryptophan and tyrosine, and slightly enhances the amyloid transformation of BSA. Cobalt (II) slightly inhibits the amyloid transformation of BSA. In terms of the severity and nature of the effects, the iron (II), iron (III) and zinc (II) cations occupy an intermediate position between copper (II), on the one hand, and nickel (II) and cobalt (II), on the other hand, combining the influence on the AGEs formation, the intensity of fluorescence of tryptophan and tyrosine, the aggregation and amyloid transformation of BSA. In the absence of glucose, the ability of zinc (II) to induce the formation of protein aggregates turned out to be the highest, and its ability to stimulate the amyloid transformation of BSA corresponded to that of copper (II).
Conclusion. The presence of d-metal cations affects the rate of the AGEs formation in the glycation reaction, affects the rate of the BSA amyloid transformation and the protein aggregates formation. Among such ions as nickel (II), cobalt (II), iron (II), iron (III), copper (II) and zinc (II), copper (II) ions turned out to be the most active in their ability to accelerate the AGEs formation, suppress the fluorescence of tryptophan and tyrosine, enhance the aggregation and amyloid transformation of BSA in the glycation reaction. The least manifestation of these properties is observed for nickel (II) and cobalt (II) ions.
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Antimicrobial activity study of new quinazolin-4(3h)-ones against Staphylococcus aureus and Streptococcus pneumoniae
Abstract
Received 08 Jan 2021 Accepted 29 Aug 2021
Quinazolin-4(3H)-one derivatives exhibiting a wide spectrum of a pharmacological activity, represent a promising class of substances used to obtain antibacterial agents, which is especially important in the context of the emergence of pathogenic microorganisms’ resistance to drugs used in medicine. It has been proved that compounds having a naphthyl radical in the molecule, as well as an amide group bound to the benzene ring as quinazolinone substituents, are characterized by a pronounced antimicrobial activity against Staphylococcus aureus and Streptococcus pneumoniae.
The aim of the research is a primary microbiological screening of the in vitro antimicrobial activity of new quinazolin-4(3H)-one derivatives against Staphylococcus aureus and Streptococcus pneumoniae, as well as the assessment of the relationship between the pharmacological effect and the structural transformation of the substance molecule, lipophilicity and the possibility of forming resistance to them.
Materials and methods. The experimental studies have been carried out using well-known nosocomial pathogens of infectious and inflammatory diseases Staphylococcus aureus and Streptococcus pneumoniae by a serial dilution method.
Results. A compound containing a naphthyl radical in its structure, which contributes to an increase in the hydrophobicity of the substance and its solubility in the membrane of a bacterial cell, has a bacteriostatic effect against both Staphylococcus aureus and Streptococcus pneumoniae. A similar pharmacological effect is exhibited by a derivative with an amide group as a substituent of the quinazolinone nucleus linked to a phenyl radical, which probably contributes to an increase in the degree of binding to active sites of enzymes involved in the DNA replication, and protein synthesis. Obviously, the increased lipophilicity, which promotes better binding to the efflux protein, cannot serve as objective characteristics of the emergence possibility of the pathogen’s resistance to this substance.
Conclusion. Among the synthesized compounds, the leading substances that exhibit an antimicrobial activity against Staphylococcus aureus and Streptococcus pneumonia, have been identified. The assessment of the chemical structure made it possible to substantiate their pharmacological action and draw conclusions about the possibility of developing resistance to it in microbial cells.
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