The Editorial Board and the Editor-in-Chief of Tonkie Khimicheskie Tekhnologii [Fine Chemical Technologies] cordially congratulate Academician Ivan Novakov on his 75th birthday, wishing him good health and new creative successes.
THEORETICAL BASIS OF CHEMICAL TECHNOLOGY
- The effectiveness of the chitosan–colloidal silica composite sorbent in the process of dynamic purification of aqueous media to remove Cu(II), Zn(II), Cd(II), and Cr(III) ions was established.
- After determining the times of ion breakthrough and saturation of the developed sorbent, its dynamic exchange capacity was calculated by processing the kinetic curves of sorption of heavy metal ions under dynamic conditions.
- The results of regeneration of the sorbent were presented in the context of the possibility of its reuse. It is shown that the sorbent can withstand up to five sorption–desorption cycles while maintaining a level copper cation extraction above 90%.
Objectives. The study set out to investigate the sorption, toxicological, and regeneration properties of a composite sorbent based on chitosan hydrogel and unsuspended silicon dioxide (chitosan–colloidal silica), which manifest themselves under dynamic conditions of purification of aqueous solutions, as a means of removing heavy metal ions.
Methods. The total dynamic exchange capacity of a chitosan–colloidal silica composite sorbent was evaluated under dynamic sorption conditions by passing solutions containing Zn(II), Cd(II), Cu(II), and Cr(III) ions having a concentration of 240–251 mg/L through a fixed sorption bed. The method for determining acute toxicity using daphnia (Daphnia magna Straus) is based on the direct calculation of the mortality of daphnia exposed to toxic substances contained in the test aqueous extract in comparison with a reference culture in samples that do not contain toxic substances. The regeneration ability of the sorbent was assessed by counting the number of sorption–desorption cycles using 0.1 M NaOH and 0.1 M NaHCO3 eluents, as well as aqueous solutions of H2O2 (1 and 3%).
Results. The effectiveness of the chitosan–colloidal silica composite sorbent in the process of dynamic purification of aqueous media to remove Cu(II), Zn(II), Cd(II), and Cr(III) ions was established. After determining the times of ion breakthrough and saturation of the developed sorbent, its dynamic exchange capacity was calculated by processing the kinetic curves of sorption of heavy metal ions under dynamic conditions. The results of regeneration of the sorbent were presented in the context of the possibility of its reuse. It is shown that the sorbent can withstand up to five sorption–desorption cycles while maintaining a level copper cation extraction above 90%.
Conclusions. Analysis of the kinetic curves demonstrated that the driving force behind the removal of heavy metals from aqueous media by means of the obtained sorbent is the external diffusion mass transfer of ions from the mobile phase of the solution. Biotesting of samples showed that the developed chitosan-based sorbent does not have acute toxicity.
CHEMISTRY AND TECHNOLOGY OF ORGANIC SUBSTANCES
- The reactions of intramolecular acid–catalytic dehydration of 2-hexanol and isomerizing alkoxycarbonylation of the resulting 2-hexene, catalyzed by the Pd(PPh3)2Cl2–XANTPHOS–methanesulfonic acid system, can be performed as a one-pot
- Methanesulfonic acid simultaneously functions as a catalyst for the dehydration of 2-hexanol and a cocatalyst for the palladium–phosphine system for the alkoxycarbonylation of hexenes.
- In the presence of the Pd(PPh3)2Cl2–XANTPHOS–methanesulfonic acid catalytic system, processes for the synthesis of heptanoic acid esters from 2-hexanol, methanol, and CO can be combined within one reactor.
- An increase in the methanol concentration negatively affects the rate of the dehydration of 2-hexanol and the formation of 2-hexyl esters of C7carboxylic acids.
- A small amount of methanol in the reaction mass leads to an increase in the fraction of heptanoic acid esters among C7 carboxylic acid esters.
Objectives. To study the possibility of one-pot synthesis (combination of two processes in one reactor) for the following pairs of processes: (1) dehydration of 2-hexanol and isomerizing alkoxycarbonylation of the resulting 2-hexene, in order to obtain 2-hexyl heptanoate, and (2) dehydration of 2-hexanol and isomerizing methoxycarbonylation of the resulting 2-hexene, in order to obtain methyl esters of C7 carboxylic acids. To investigate the effect of the concentrations of 2-hexanol and methanol on the rate of the one-pot synthesis.
Methods. One-pot synthesis was studied in a toluene medium in a steel batch reactor designed to operate at elevated pressure and equipped with a glass insert, a magnetic stirrer, a sampler, and gas input and discharge devices. Samples of the reaction mass were taken during the combined process and were analyzed by means of gas–liquid chromatography with a flame ionization detector.
Results. The possibility of one-pot combination was demonstrated for 2-hexanol dehydration catalyzed by methanesulfonic acid, as well as for the isomerizing alkoxycarbonylation of the resulting 2-hexene with 2-hexanol and CO, catalyzed by the Pd(PPh3)2Cl2–XANTPHOS–methanesulfonic acid system. The dependencies of the rates of the dehydration of 2-hexanol and the formation of esters of C7 carboxylic acids on the concentration of 2-hexanol were shown to pass through a maximum. The possibility of the one-pot process was proved for the synthesis of esters from 2-hexanol, methanol, and CO with the predominant formation of heptanoic acid esters in the presence of the above catalytic system. The rates of dehydration of 2-hexanol and the formation of 2-hexyl esters of C7 carboxylic acids were found to decrease with increasing the concentration of methanol in the reaction mass. Under mild conditions (temperature 115°C, CO pressure 3 MPa) with the addition of methanol, the total fraction of 2-hexyl and methyl heptanoic acid esters among C7 carboxylic acid esters was determined to be 85.5%.
Conclusions. The reactions of intramolecular acid–catalytic dehydration of 2-hexanol and isomerizing alkoxycarbonylation of the resulting 2-hexene, catalyzed by the Pd(PPh3)2Cl2–XANTPHOS–methanesulfonic acid system, can be performed as a one-pot process. Methanesulfonic acid simultaneously functions as a catalyst for the dehydration of 2-hexanol and a cocatalyst for the palladium–phosphine system for the alkoxycarbonylation of hexenes. In the presence of the Pd(PPh3) 2Cl2–XANTPHOS–methanesulfonic acid catalytic system, processes for the synthesis of heptanoic acid esters from 2-hexanol, methanol, and CO can be combined within one reactor. An increase in the methanol concentration negatively affects the rate of the dehydration of 2-hexanol and the formation of 2-hexyl esters of C7 carboxylic acids. A small amount of methanol in the reaction mass leads to an increase in the fraction of heptanoic acid esters among C7 carboxylic acid esters.
CHEMISTRY AND TECHNOLOGY OF MEDICINAL COMPOUNDS AND BIOLOGICALLY ACTIVE SUBSTANCES
- Developed schemes for the preparation of bivalent cationic amphiphiles based on L-ornithine derivatives are presented. Differences in the structure of aliphatic amino acids (glycine, β-alanine, γ-aminobutyric acid (GABA)), in the length of alkyl radicals (C8, C12), or in the presence of an indole moiety, were used in the design of target compounds.
- The high antibacterial activity of the synthesized compounds was demonstrated. The most active compounds were lipoamino acids with terminal GABA residues and asymmetrical non-polar block (tryptamyl–dodecylamine).
- The MIC values were 0.39 μg/mL for gram-positive bacteria and 1.56 μg/mL for gram-negative bacteria. A GABA derivative with a symmetrical lipophilic moiety based on dioctylamine demonstrated activity with an MIC of 0.78 μg/mL against B. subtilis and 3.12 μg/mL against E. coli.
Objectives. Cationic amphiphiles and antimicrobial peptidomimetics are widely investigated as antibacterial agents due to their membrane-active mechanism of action. Particular attention is focused on the rational design of compounds in this class to achieve high antimicrobial activity. The aim of the present work is to synthesize bivalent cationic amphiphiles with L-ornithine as a branching element and evaluate the effectiveness of their antibacterial action. The compounds differ in terms of hydrophobicity due to the variation of N-terminal aliphatic amino acids in the polar block and alternation of dialkyl and alkyl-hetaryl radicals in the lipophilic block.
Methods. For the synthesis of nonpolar fragments of amphiphiles, methods for the alkylation of amines with alkyl bromides in the presence of carbonate salts were used. The formation of amide bonds of L-ornithine derivatives with amino acids was carried out using the carbodiimide method. For the reaction products recovery from the reaction mixture, column chromatography on silica gel and aluminum oxide activated Brockmann Grade II was used. The antimicrobial activity of the synthesized compounds against gram-positive B. subtilis 534 and gram-negative E. coli M17 bacterial strains was evaluated. Minimum inhibitory concentration (MIC) values were recorded using a serial microdilution method in a nutrient medium.
Results. Developed schemes for the preparation of bivalent cationic amphiphiles based on L-ornithine derivatives are presented. Differences in the structure of aliphatic amino acids (glycine, β-alanine, γ-aminobutyric acid (GABA)), in the length of alkyl radicals (C8, C12), or in the presence of an indole moiety, were used in the design of target compounds. The high antibacterial activity of the synthesized compounds was demonstrated. The most active compounds were lipoamino acids with terminal GABA residues and asymmetrical non-polar block (tryptamyl–dodecylamine). The MIC values were 0.39 μg/mL for gram-positive bacteria and 1.56 μg/mL for gram-negative bacteria. A GABA derivative with a symmetrical lipophilic moiety based on dioctylamine demonstrated activity with an MIC of 0.78 μg/mL against B. subtilis and 3.12 μg/mL against E. coli.
Conclusions. Nine new lipoamino acid cationic bivalent amphiphiles based on L-ornithine were synthesized. The structure of the obtained compounds was confirmed by nuclear magnetic resonance 1H spectroscopy and mass spectrometry data. Leading compounds in antimicrobial activity against both gram-positive and gram-negative strains of bacteria were determined. The influence of the degree of lipophilicity in the asymmetric nonpolar block on the level of exhibited antimicrobial activity is demonstrated.
- The review outlines the principle of PROTAC® technology: the construction of a chimeric molecule consisting of three fragments. One fragment specifically binds to the biotarget, another recruits the proteolytic system of the host cell, and the third binds them together.
- The main areas of the current development of the technology are described herein, as well as the opportunities and limitations of chimeric molecules in the fight against different types of infectious diseases.
Objectives. To describe the pharmaceutical technology of controlled degradation of protein molecules (PROTAC®, Proteolysis Targeting Chimera), approaches to the design of the PROTAC® molecule, methods of ligand and linker selection and synthesis, as well as the application of this technology in dealing with a variety of diseases and the possible limitations of its use.
Results. The review covers 77 sources, mostly from 2020–2023. The review outlines the principle of PROTAC® technology: the construction of a chimeric molecule consisting of three fragments. One fragment specifically binds to the biotarget, another recruits the proteolytic system of the host cell, and the third binds them together. The main areas of the current development of the technology are described herein, as well as the opportunities and limitations of chimeric molecules in the fight against different types of infectious diseases.
Conclusion. The potential to use PROTAC® technology to combat cancer as well as neurodegenerative, autoimmune, and infectious diseases is shown.
BIOCHEMISTRY AND BIOTECHNOLOGY
- The aim of the work is to study changes in the level of methylation of a number of microRNA genes and compile a potential panel of markers for the diagnosis and prognosis of non-small cell lung cancer.
- The analysis of methylation levels of microRNA genes revealed a significant (p < 0.05) increase in the methylation level of eight microRNA genes: MIR124-1/2/3, MIR125В-1, MIR129-2, MIR137, MIR375, MIR1258, and MIR339 (p < 0.01, FDR ≤ 0.25).
- On the basis of ROC analysis, a panel of markers is proposed for the diagnosis of non-small cell lung cancer according to the nature of methylation of the studied microRNA genes in the tumor and in the normal tissue.
Objectives. Lung cancer, representing a difficult-to-diagnose heterogeneous malignant neoplasm, is characterized by an asymptomatic course up to late stages, a high incidence of adverse outcomes, and a high probability of metastasis. Its most common form is non-small cell lung cancer (NSCLC). Recent studies have demonstrated a significant role of non-coding RNAs—in particular, microRNAs—in the development of NSCLC. MicroRNAs, which function as post-transcriptional regulators of the expression of protein-coding genes, including those associated with oncogenesis, are involved in the processes of cell proliferation, differentiation, and apoptosis. One of the approaches for regulating the expression of microRNAs themselves is to change the methylation of the CpG island adjacent to the microRNA gene or overlapping it. It has been shown that microRNA genes are several times more likely to undergo methylation than protein-coding genes. The aim of the present work is to study changes in the level of methylation of a number of microRNA genes and compile a potential panel of markers for the diagnosis and prognosis of NSCLC.
Methods. Samples of NSCLC tumors were collected and clinically characterized at the Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia. High-molecular-weight DNA was isolated from tissues using a standard method. The level of methylation was analyzed using bisulfite conversion of DNA and quantitative methyl-specific polymerase chain reaction with real-time detection. The significance of differences between the studied groups was assessed by the nonparametric Mann–Whitney U test for independent samples. Differences were considered significant at p < 0.05.
Results. The analysis of methylation levels of microRNA genes revealed a significant (p < 0.05) increase in the methylation level of eight microRNA genes: MIR124-1/2/3, MIR125В-1, MIR129-2, MIR137, MIR375, MIR1258, and MIR339 (p < 0.01, false discovery rate ≤ 0.25). On the basis of receiver operating characteristic analysis, a panel of markers is proposed for the diagnosis of NSCLC according to the nature of methylation of the studied microRNA genes in the tumor and in the normal tissue.
Conclusions. Our results, which contribute to the understanding of molecular mechanisms involved in NSCLC development, can be used in the development of new diagnostic and prognostic approaches in clinical oncology.
- An effective technology for the cultivation of Chinese hamster ovary (CHO) cells stably producing GamP2C5 antibody which is a component I of GamCoviMab for emergency prophylaxis and therapy of infection caused by SARS-CoV-2 virus is developed.
- Using molecular-genetic and biotechnological methods, a stable clone of antibody producer CHO-GamP2C5 clone 78 was obtained. Then a technique was worked out for the cultivation of the obtained clone of the producer on different culture media.
- The most suitable cultivation regimes, culture media and optimal supplements were selected.
- This technology was tested in laboratory conditions in a 10-L reactor, and then successfully scaled up for production.
Objectives. To develop an effective technology for the cultivation of Chinese hamster ovary (CHO) cells stably producing GamP2C5 antibody which is a component I of the GamCoviMab candidate drug for emergency prevention and therapy of infection caused by SARS-CoV-2 virus; to select optimal cultivation parameters and to scale this technology in production.
Methods. The study was performed on CHO GamP2C5 (clone 78) cell culture, producing a single-domain antibody fused to the Fc fragment of human IgG1 GamP2C5. Different culture media and supplements were used. Cells were cultured in Erlenmeyer flasks, Biostat® RM 20 wave-mixed bioreactor, Ambr® 250 mini bioreactors, STR 200 stirred-tank bioreactor.
Results. Using molecular-genetic and biotechnological methods, a stable clone producer of CHO GamP2C5 antibody, clone 78, was obtained. Then a technique was worked out for the cultivation of the obtained clone producer on different culture media. The most suitable cultivation regimes, culture media, and optimal supplements were selected. This technology was tested in laboratory conditions in a 10-L reactor, and then successfully scaled up for production at the MedGamal Branch of the Gamaleya National Research Center for Epidemiology and Microbiology.
Conclusions. This study demonstrates the fundamental feasibility of developing and scaling up a culture technology, in order to produce a drug based on a modified single-domain antibody with virus neutralizing activity against different strains of SARS-CoV-2 virus.
CHEMISTRY AND TECHNOLOGY OF INORGANIC MATERIALS
- The aim of the work is to obtain and study phases in systems Re(IV)S2–Ti(IV)S2, Re(IV)S2–Mo(IV)S2 и Re(IV)S2–W(IV)S2.
- The samples were obtained by high-temperature solid-phase ampoule synthesis in a vacuum.
- The regions of existence of solid solutions, intercalates and two-phase regions in the resulting systems were established.
- Intercalated solid solutions are formed in areas rich in rhenium, while in areas close to titanium and molybdenum disulfides, intercalated phases are attained. In the ReS2–WS2 system there is a region of solid solutions, including 30, 50 and 70 mol % rhenium disulfide. Their structure is a polymorphic modification of the structure of the original components.
Objectives. Chalcogenides of transition elements with low oxidation states, as well as their substituted derivatives, remain a poorly studied class of chemical compounds. Rhenium disulfide has many distinctive features and great application potential as a new twodimensional semiconductor. This is due to its unusual structure and unique anisotropic properties. The presence of weak interlayer bonding and a unique distorted octahedral (1T) structure suggests the possibility of creating new phases on its basis. The aim of this work is to obtain and study phases in systems Re(IV)S2–Ti(IV)S2, Re(IV)S2–Mo(IV)S2, and Re(IV)S2–W(IV)S2.
Methods. The samples were obtained by high-temperature solid-phase ampoule synthesis in a vacuum. The study was carried out using X-ray phase analysis and X-ray photoelectron spectroscopy.
Results. The regions of existence of solid solutions, intercalates and two-phase regions in the resulting systems were established.
Diffraction patterns were obtained for the new phases and the crystal lattice parameters were calculated. Based on data relating to the binding energies of core electrons with the nucleus, the study showed the valence states of the elements after synthesis. The study also confirmed that all phases obtained as a result of synthesis contain transition elements in the oxidation state (IV).
Conclusions. Intercalated solid solutions are formed in areas rich in rhenium, while in areas close to titanium and molybdenum disulfides, intercalated phases are attained. In the ReS2–WS2 system there is a region of solid solutions, including 30, 50, and 70 mol % rhenium disulfide. Their structure is a polymorphic modification of the structure of the original components. The presence of rhenium, molybdenum, and tungsten in these phases in the oxidation state (+IV) was confirmed. The data obtained on phase formation in dichalcogenide systems can be practically used in the creation of materials with unique electronic, magnetic, and optical properties with a wide range of applications.
ISSN 2686-7575 (Online)