Design, Synthesis, and Characterization of HBP-Vectorized Methotrexate Prodrug Molecule 1102-39: Evaluation of In Vitro Cytotoxicity Activity in Cell Culture Models, Preliminary In Vivo Safety and Efficacy Results in Rodents.

A novel bone-targeted prodrug, 1102-39, is discussed with the aim of enhancing the therapeutic effects of methotrexate (MTX) within bone tissues while minimizing systemic toxicity. Within the 1102-39 molecule, the central linker part forms a cleavable ester group, with MTX being also linked by a stable imine bond to the specially designed hydroxybisphosphonic (HBP) vector. Synthesized through a convergent approach starting from MTX, this prodrug advantageously modulates MTX's activity by selective esterification of its α-carboxyl group.

[An overview of investments in the development of the Russian Medtech market and the prospects for the impact of digitalization in medicine on the economic performance of companies until 2030].

Today, the topic of digitalization, the introduction of innovations based on Big Data, the complexity of technologies due to the introduction of artificial intelligence in medicine and healthcare is one of the most relevant in this industry, undoubtedly contributing to its rapid development. As a result of this development, there is a huge number of services and applications. Internet resources, not only for health tracking (more than 3,500 applications are available by the end of 2023), but also the development of diagnostic resources, telemedicine, etc.

[Analysis of the demand for medical services using digital programs in the Russian healthcare system: an overview of trends].

The research conducted in this article has determined that among Russians, preference for private medical services, including through online technologies, is given for the following reasons: the speed of service provision - 45.1%; lack of queues (44%); quality of medical procedure (39.8%); ease of making an appointment (32.

Depolymerisation of the Capsular Polysaccharide K21 by Klebsiella Phage K5.

is a pathogen associated with various infection types, which often exhibits multiple antibiotic resistance. Phages, or bacterial viruses, have an ability to specifically target and destroy , offering a potential means of combatting multidrug-resistant infections. Phage enzymes are another promising therapeutic agent that can break down bacterial capsular polysaccharide, which shields from the immune response and external factors.

Sn and Ge Complexes with Redox-Active Ligands as Efficient Interfacial Membrane-like Buffer Layers for p-i-n Perovskite Solar Cells.

Inverted perovskite solar cells with a p-i-n configuration have attracted considerable attention from the research community because of their simple design, insignificant hysteresis, improved operational stability, and low-temperature fabrication technology. However, this type of device is still lagging behind the classical n-i-p perovskite solar cells in terms of its power conversion efficiency. The performance of p-i-n perovskite solar cells can be increased using appropriate charge transport and buffer interlayers inserted between the main electron transport layer and top metal electrode.

Mitochondrion-targeted antioxidant SkQ1 prevents rapid animal death caused by highly diverse shocks.

The response to stress involves the activation of pathways leading either to protection from the stress origin, eventually resulting in development of stress resistance, or activation of the rapid death of the organism. Here we hypothesize that mitochondrial reactive oxygen species (mtROS) play a key role in stress-induced programmed death of the organism, which we called "phenoptosis" in 1997. We demonstrate that the synthetic mitochondria-targeted antioxidant SkQ1 (which specifically abolishes mtROS) prevents rapid death of mice caused by four mechanistically very different shocks: (a) bacterial lipopolysaccharide (LPS) shock, (b) shock in response to intravenous mitochondrial injection, (c) cold shock, and (d) toxic shock caused by the penetrating cation CTPP.

Gallium (III) Complexes Based on Aminobisphenolate Ligands: Extremely High Active ROP-Initiators from Well-Known and Easily Accessible Compounds.

We report herein the synthesis and full characterizations of the first examples of gallium complexes based on "privileged" aminobisphenolate ligands which are easily available. These complexes turned out to be extremely active in the ring-opening polymerization of ε-caprolactone even at room temperature and highly active in the ROP of L-lactide. The combination of factors such as the easy availability of these compounds and the supposedly low toxicity, together with the extremely high activity in ROP, allows us to consider these compounds as suitable for use on an industrial scale for the synthesis of biodegradable polymers for biomedical applications.

The Novel Gallium Aminobisphenolate Initiator of the Ring-Opening Copolymerization of L-Lactide and ε-Caprolactone: A Computational Study.

Density functional theory (DFT) simulations of ring-opening copolymerization of ε-caprolactone (CL) and L-lactide (LA) in presence of novel gallium complex on aminobis (phenolate) ligand are conducted. The initial steps of polymerization of CL and LA as well as the first steps of propagation which led to LGa-LA-LA-OMe, LGa-LA-CL-OMe, LGa-CL-LA-OMe, or LGa-CL-CL-OMe derivatives have been analyzed in detail. According to these data, the studied catalyst is a rare example of a catalyst in which, during copolymerization, the polymerization of CL should proceed faster than LA.

2-Imidazoline Nitroxide Derivatives of Cymantrene.

The 2-imidazoline nitroxide derivatives of cymantrene-2-(-cyclopentadienyl)tricarbonylmanganese(I)-4,4,5,5-tetramethyl-4,5-dihydro-1-imidazole-3-oxide-1-oxyl (NNMn) and 2-(-cyclopentadienyl)tricarbonylmanganese(I)-4,4,5,5-tetramethyl-4,5-dihydro-1-imidazole-1-oxyl (INMn) were synthesized. It was shown that NNMn and INMn exhibit a sufficiently high kinetic stability both in solids and in solutions under normal conditions. Their structural characteristics, magnetic properties and electrochemical behavior are close to Re(I) analogs.

Re(i)-nitroxide complexes.

Spin-labeled cyrhetrenes [(NNCp)Re(CO)] and [(INCp)Re(CO)], where NNCp is nitronyl nitroxide 2-(η-cyclopentadienyl)-4,4,5,5-tetramethyl-4,5-dihydro-1-imidazole-3-oxide-1-oxyl and INCp is the corresponding imino nitroxide, were synthesized and characterized by EPR, CV, XRD, magnetochemistry and quantum chemistry methods. The correlations between different arrangements of paramagnetic centers and the magnetic exchange interactions for three polymorphs of [(NNCp)Re(CO)] were studied. It was concluded that high kinetic stability of nitroxide-substituted cyrhetrenes is a promising feature of compounds for the creation of multifunctional contrast agents.

Supramolecular D⋯A-layered structures based on germanium complexes with 2,3-dihydroxynaphthalene and ,'-bidentate ligands.

The concept of using redox-active ligands, which has become extremely widespread in organometallic chemistry, is often considered from 'their effect on the metal center properties' point of view and 'how to modify the ligands'. In this paper, we present the reverse side of this effective approach - a dramatic change of redox properties of ligands under the influence of a redox-inert metal. Germanium derivatives based on 2,3-dihydroxynaphthalene (1) and ,'-bidentate ligands, namely 2,2'-bipyridine (2) and 1,10-phenanthroline (3), were obtained and characterized by CV, UV-vis spectroscopy, DFT calculations and in the case of 3 X-ray diffraction.

Remote Stereoelectronic Effects in Pyrrolidone- and Caprolactam-Substituted Phenols: Discrepancies in Antioxidant Properties Evaluated by Electrochemical Oxidation and H-Atom Transfer Reactivity.

New antioxidants are commonly evaluated via two main approaches, i.e., the ability to donate an electron and the ability to intercept free radicals.

Automatic Extraction and Decryption of Abbreviations from Domain-Specific Texts.

This paper explores the problems of extraction and decryption of abbreviations from domain-specific texts in Russian. The main focus are unstructured electronic medical records which pose specific preprocessing problems. The major challenge is that there is no uniform way to write medical histories.

Investigations into the structure-activity relationship in gemini QACs based on biphenyl and oxydiphenyl linker.

Eighteen novel gemini quaternary ammonium compounds were synthesized to examine the effect of linker nature, aliphatic chain length and their relative position on antibacterial and antifungal activity. The synthesized compounds showed strong bacteriostatic activity against a panel of both Gram-positive and Gram-negative bacteria, including methicillin-resistant (MRSA) and two fungi. Some of these compounds exhibited a wider and more potent antimicrobial spectrum than commonly-used antiseptics, such as benzalkonium chloride (BAC), cetylpyridinium chloride (CPC), chlorhexidine digluconate (CHG) and octenidine dihydrochloride (OCT).

Phase I dose escalation study of 12b80 (hydroxybisphosphonate linked doxorubicin) in naturally occurring osteosarcoma.

Purpose: 12b80 combines doxorubicin bound to a bone targeting hydroxybisphosphonate vector using a pH-sensitive linker, designed to specifically trigger doxorubicin release in an acidic bone tumor microenvironment. This phase I study aimed to determine the safety and toxicity profiles of 12b80 in dogs with naturally occurring osteosarcoma, with the objective to translate findings from dogs to humans.

Experimental Design: Ten client-owned dogs with osteosarcoma were enrolled in an accelerated dose-titration design followed by 3 + 3 design.

Catalyst-Solvent System for PASE Approach to Hydroxyquinolinone-Substituted Chromeno[2,3-]pyridines Its Quantum Chemical Study and Investigation of Reaction Mechanism.

The Pot, Atom, and Step Economy (PASE) approach is based on the Pot economy principle and unites it with the Atom and Step Economy strategies; it ensures high efficiency, simplicity and low waste formation. The PASE approach is widely used in multicomponent chemistry. This approach was adopted for the synthesis of previously unknown hydroxyquinolinone substituted chromeno[2,3-]pyridines via reaction of salicylaldehydes, malononitrile dimer and hydroxyquinolinone.

2-Carboxyethylgermanium Sesquioxide as A Promising Anode Material for Li-Ion Batteries.

Various forms of germanium and germanium-containing compounds and materials are actively investigated as energy-intensive alternatives to graphite as the anode of lithium-ion batteries. The most accessible form-germanium dioxide-has the structure of a 3D polymer, which accounts for its rapid destruction during cycling, and requires the development of further approaches to the production of nanomaterials and various composites based on it. For the first time, we propose here the strategy of using 2-carboxyethylgermanium sesquioxide ([O GeCH CH CO H] , 2-CEGS), in lieu of GeO , as a promising, energy-intensive, and stable new source system for building lithium-ion anodes.

One-pot five-component high diastereoselective synthesis of polysubstituted 2-piperidinones from aromatic aldehydes, nitriles, dialkyl malonates and ammonium acetate.

A novel five-component diastereoselective synthesis of polysubstituted 2-piperidinones is reported. The Knoevenagel condensation-Michael addition-Mannich cascade of two equivalents of aromatic aldehydes, nitriles, dialkyl malonates and ammonium acetate or aqueous ammonia in alcohols provides convenient access to alkyl (3SR,4RS,6SR)-5,5-dicyano-2-oxo-4,6-diarylpiperidine-3-carboxylates with three stereocenters in 52-90% or dialkyl (2SR,3RS,4RS,5SR)-2,4-diaryl-3-cyano-6-oxopiperidine-3,5-dicarboxylates with four stereocenters in 38-88%. The formation of products was highly stereoselective, with only one diastereomer formed.

Infrared-Spectroscopic Study of (4-Methylpent-3-en-1-ynyl)methylthiocarbene, Its Photochemical Transformations, and Reactions in an Argon Matrix.

The first representative of singlet carbenes bearing both ethynyl and methylthio groups at the carbene center, (4-methylpent-3-en-1-ynyl)methylthiocarbene, has been generated in a low-temperature Ar matrix upon UV photolysis of 3,3-dimethyl-5-methylthioethynyl-3-pyrazole and detected by FTIR spectroscopy. The generation of the carbene proceeds via intermediate (3-diazo-5-methylhex-4-en-1-ynyl)methylsulfane. The comparison of FTIR spectroscopy data with the results of quantum chemical calculations (B3LYP/aug-cc-pVTZ) and NRT analysis shows that (4-methylpent-3-en-1-ynyl)methylthiocarbene has a singlet ground state with the localization of the unpaired spins on the carbon atom in the α-position to methylthio moiety.

Novel non-toxic high efficient antibacterial azido chitosan derivatives with potential application in food coatings.

In this work, we developed a simple method for the preparation of N-(3-azido-2-hydroxypropyl)chitosan. We compared the antibacterial activity of N-(3-azido-2-hydroxypropyl)chitosans and previously synthesized N-(2-azidoethyl)chitosans. N-(3-azido-2-hydroxypropyl)chitosans possess higher antibacterial effect which is comparable with that of ampicillin and gentamicin.

Pot, atom and step economic (PASE) assembly of salicylaldehydes, malononitrile dimer and 4-hydroxypyridine-2(1H)-ones into medicinally relevant 5H-chromeno[2,3-b]pyridine scaffold.

The new multicomponent reaction (MCR) has been found: one-pot selective and efficient formation of the new 5-(4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl)-substituted 5H-chromeno[2,3-b]pyridines in 61-97% yields directly from simple and easily available salicylaldehydes, malononitrile dimer and 4-hydroxypyridine-2(1H)-ones in small amount of pyridine-ethanol catalyst/solvent system. This complex "domino" transformation includes Knoevenagel condensation of salicylaldehyde with malononitrile dimer, Michael addition of 4-hydroxypyridine-2(1H)-one, double Pinner-type reaction cyclization and isomerization with following protonation. This facile multicomponent process opens a new way to 5-(4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl)-substituted 5H-chromeno[2,3-b]pyridine systems, which are promising compounds for the treatment for human inflammatory TNFα-mediated diseases and different biomedical applications.

12b80 - Hydroxybisphosphonate Linked Doxorubicin: Bone Targeted Strategy for Treatment of Osteosarcoma.

To reply to as yet unmet medical needs to treat osteosarcoma, a form of primary bone cancer, we conceived the 12b80 compound by covalently conjugating antineoplastic compound doxorubicin to a bone targeting hydroxybisphosphonate vector and turned it into a prodrug through a custom linker designed to specifically trigger doxorubicin release in acidic bone tumor microenvironment. Synthesis of 12b80 was thoroughly optimized to be produced at gram scale. 12b80 was evaluated in vitro for high bone support affinity, specific release of doxorubicin in acidic condition, lower cytotoxicity, and cellular uptake of the prodrug.

Identification of CDC42 Effectors Operating in FGD1-Dependent Trafficking at the Golgi.

Loss of function mutations in the gene cause a rare X-linked disease, faciogenital dysplasia (FGDY, also known as Aarskog-Skott syndrome), which is associated with bone and urogenital abnormalities. The gene encodes à CDC42-specific guanine nucleotide exchange factor. The mutations are frequently located in the DH module of FGD1 preventing its transformation to the active form.

Halogen-free GeO conversion: electrochemical reduction vs. complexation in (DTBC)Ge[Py(CN)] (n = 0…2) complexes.

3,5-di-tert-Butylcatecholate (DTBC) germanium complexes (DTBC)2Ge[Py(CN)n]2 (n = 0…2) have been synthesized from GeO2, 3,5-di-tert-butylcatechol and cyano-substituted pyridines Py(CN)n and characterized by elemental analysis, NMR, IR and UV-VIS spectroscopy. The structure of 1 (with 4-cyanopyridine) has been determined by X-ray single crystal analysis. UV-VIS spectra have shown that these complexes are stable in CH3CN, toluene and CH2Cl2 solutions; in contrast, they are rapidly decomposed by dimethylformamide and tetrahydrofuran.

Upconversion of Reductants.

The many applications of photon upconversion-conversion of low-energy photons into high-energy photons-raises the question of the possibility of "electron upconversion". In this Review, we illustrate how the reduction potential can be increased by using the free energy of exergonic chemical reactions. Electron (reductant) upconversion can produce up to 20-25 kcal mol of additional redox potential, thus creating powerful reductants under mild conditions.