Vol 9, No 4 (2021)

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.

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

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.