New Chemicals Suppressing SARS-CoV-2 Replication in Cell Culture

Candidates to being inhibitors of the main protease (Mpro) of SARS-CoV-2 were selected from the database of Voronezh State University using molecular modeling. The database contained approximately 19,000 compounds represented by more than 41,000 ligand conformers. These ligands were docked into Mpro using the SOL docking program. For one thousand ligands with best values of the SOL score, the protein–ligand binding enthalpy was calculated by the PM7 quantum-chemical method with the COSMO solvent model. Using the SOL score and the calculated protein–ligand binding enthalpies, eighteen compounds were selected for the experiments. Several of these inhibitors suppressed the replication of the coronavirus in cell culture, and we used the best three among them in the search for chemical analogs. Selection among analogs using the same procedure followed by experiments led to identification of seven inhibitors of the SARS-CoV-2 replication in cell culture with EC50 values at the micromolar level. The identified inhibitors belong to three chemical classes. The three inhibitors, 4,4-dimethyldithioquinoline derivatives, inhibit SARS-CoV-2 replication in Vero E6 cell culture just as effectively as the best published non-covalent inhibitors, and show low cytotoxicity. These results open up a possibility to develop antiviral drugs against the SARS-CoV-2 coronavirus.     

Structural Diversity and Carbon Dioxide Sorption Selectivity of Zinc(II) Metal-Organic Frameworks Based on Bis(1,2,4-triazol-1-yl)methane and Terephthalic Acid

A three-component reaction between the 1,4-benzenedicarboxylic (terephthalic) acid (H₂bdc), bis(1,2,4-triazol-1-yl)methane (btrm) and zinc nitrate was studied, and three new coordination polymers were isolated by a careful selection of the reaction conditions. Coordination polymers {[Zn₃(DMF)(btrm)(bdc)₃]·nDMF}_∞ and {[Zn₃(btrm)(bdc)₃]·nDMF}_∞ containing trinuclear {Zn₃(bdc)₃} secondary building units are joined by btrm auxiliary linkers into three-dimensional metal–organic frameworks. The coordination polymer {[Zn(bdc)(btrm)]∙nDMF}_∞ consists of Zn²⁺ cations joined by bdc²⁻ and btrm linkers into a two-fold interpenetrated network. Upon activation, MOF [Zn₃(btrm)(bdc)₃]_∞ demonstrated CO₂/N₂ adsorption selectivity with an ideal adsorbed solution theory (IAST) factor of 21. All three MOF demonstrated photoluminescence with a maximum near 435–440 nm upon excitation at 330 nm.     

Variable Dimensionality of Europium(III) and Terbium(III) Coordination Compounds with a Flexible Hexacarboxylate Ligand

A reaction between 4,4′,4″-(benzene-1,3,5-triyltris(oxy))triphthalic acid (H₆L) and lanthanide(III) nitrates (Ln = Eu³⁺, Tb³⁺) in water under the same conditions gave a molecular coordination compound [Tb(H_4.5L)₂(H₂O)₅]∙6H₂O in the case of terbium(III) and a one-dimensional linear coordination polymer {[Eu₂(H₃L)₂(H₂O)₆]∙8H₂O}_n in the case of europium(III). The crystal structures of both compounds were established by single-crystal X-ray diffraction, and they were further characterized by powder X-ray diffraction, thermogravimetric analysis and infrared spectroscopy. The compounds demonstrated characteristic lanthanide-centered photoluminescence. The lanthanide-dependent dimensionality of the synthesized compounds, which are the first examples of the coordination compounds of hexacarboxylic acid H₆L demonstrates its potential as a linker for new coordination polymers.     

Pyridine Carboxamides Based on Sulfobetaines: Design,Reactivity, and Biological Activity

The synthesis of the products of the 1,3-propanesultone ring opening during its interaction with amides of pyridinecarboxylic acids has been carried out. The dependence of the yield of the reaction products on the position (ortho-, meta-, para-) of the substituent in the heteroaromatic fragment and temperature condition was revealed. In contrast to the meta- and para-substituted substrates, the reaction involving ortho-derivatives at the boiling point of methanol unexpectedly led to the formation of a salt. On the basis of spectroscopic, X-Ray, and quantum-chemical calculation data, a model of the transition-state, as well as a mechanism for this alkylation reaction of pyridine carboxamides with sultone were proposed in order to explain the higher yields obtained with the nicotinamide and its N-methyl analog compared to ortho or meta parents. Based on the analysis of ESP maps, the positions of the binding sites of reagents with a potential complexing agent in space were determined. The in silico evaluation of possible biological activity showed that the synthetized compounds revealed some promising pharmacological effects and low acute toxicity.     

α-Diimine Cisplatin Derivatives: Synthesis,Structure, Cyclic Voltammetry and Cytotoxicity

Three new Pt(II) complexes [(dpp-DAD)PtCl₂] (I), [(Mes-DAD(Me)₂)PtCl₂] (II) and [(dpp-DAD(Me)₂)PtCl₂] (III) were synthesized by the direct reaction of [(CH₃CN)₂PtCl₂] and corresponding redox-active 1,4-diaza-1,3-butadienes (DAD). The compounds were isolated in a single crystal form and their molecular structures were determined by X-ray diffraction. The purity of the complexes and their stability in solution was confirmed by NMR analysis. The Pt(II) ions in all compounds are in a square planar environment. The electrochemical reduction of complexes I–III proceeds in two successive cathodic stages. The first quasi-reversible reduction leads to the relatively stable monoanionic complexes; the second cathodic stage is irreversible. The coordination of 1,4-diaza-1,3-butadienes ligands with PtCl₂ increases the reduction potential and the electron acceptor ability of the DAD ligands. The synthesized compounds were tested in relation to an adenocarcinoma of the ovary (SKOV3).     

Hybrid Silsesquioxane/Benzoate Cu7-Complexes: Synthesis,Unique Cage Structure,and Catalytic Activity

A series of phenylsilsesquioxane-benzoate heptacopper complexes 1–3 were synthesized and characterized by X-ray crystallography. Two parallel routes of toluene spontaneous oxidation (into benzyl alcohol and benzoate) assisted the formation of the cagelike structure 1. A unique multi-ligation of copper ions (from (i) silsesquioxane, (ii) benzoate, (iii) benzyl alcohol, (iv) pyridine, (v) dimethyl-formamide and (vi) water ligands) was found in 1. Directed self-assembly using benzoic acid as a reactant afforded complexes 2–3 with the same main structural features as for 1, namely heptanuclear core coordinated by (i) two distorted pentameric cyclic silsesquioxane and (ii) four benzoate ligands, but featuring other solvate surroundings. Complex 3 was evaluated as a catalyst for the oxidation of alkanes to alkyl hydroperoxides and alcohols to ketones with hydrogen peroxide and tert-butyl hydroperoxide, respectively, at 50 °C in acetonitrile. The maximum yield of cyclohexane oxidation products as high as 32% was attained. The oxidation reaction results in a mixture of cyclohexyl hydroperoxide, cyclohexanol, and cyclohexanone. Upon the addition of triphenylphosphine, the cyclohexyl hydroperoxide is completely converted to cyclohexanol. The specific regio- and chemoselectivity in the oxidation of n-heptane and methylcyclohexane, respectively, indicate the involvement of of hydroxyl radicals. Complex 3 exhibits a high activity in the oxidation of alcohols.     

Radiochemical Synthesis of 4-[18F]FluorobenzylAzide and Its Conjugation with EGFR-Specific Aptamers

Central nervous system tumors related to gliomas are of neuroectodermal origin and cover about 30% of all primary brain tumors. Glioma is not susceptible to any therapy and surgical attack remains one of the main approaches to its treatment. Preoperative tumor imaging methods, such as positron emission tomography (PET), are currently used to distinguish malignant tissue to increase the accuracy of glioma removal. However, PET is lacking a specific visualization of cells possessing certain molecular markers. Here, we report an application of aptamers to enhancing specificity in imaging tumor cells bearing the epidermal growth factor receptor (EGFR). Glioblastoma is characterized by increased EGFR expression, as well as mutations of this receptor associated with active division, migration, and adhesion of tumor cells. Since 2021, EGFR has been included into the WHO classification of gliomas as a molecular genetic marker. To obtain conjugates of aptamers GR20 and GOL1-specific to EGFR, a 4-[¹⁸F]fluorobenzylazide radiotracer was used as a synthon. For the production of the synthon, a method of automatic synthesis on an Eckert & Ziegler research module was adapted and modified using spirocyclic iodonium ylide as a precursor. Conjugation of 4-[¹⁸F]fluorobenzylazide and alkyne-modified aptamers was carried out using Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) with/without the TBTA ligand. As a result, it was possible to obtain ¹⁸F-labelled conjugates with 97% radiochemical purity for [¹⁸F]FB-GR20 and 98% for [¹⁸F]FB-GOL1. The obtained conjugates can be used for further studies in PET analysis on model animals with grafted glioblastoma.     

Exploration of the Crystal Structure and Thermal and Spectroscopic Properties of Monoclinic Praseodymium Sulfate Pr2(SO4)3

Praseodymium sulfate was obtained by the precipitation method and the crystal structure was determined by Rietveld analysis. Pr₂(SO₄)₃ is crystallized in the monoclinic structure, space group C2/c, with cell parameters a = 21.6052 (4), b = 6.7237 (1) and c = 6.9777 (1) Å, β = 107.9148 (7)°, Z = 4, V = 964.48 (3) ų (T = 150 °C). The thermal expansion of Pr₂(SO₄)₃ is strongly anisotropic. As was obtained by XRD measurements, all cell parameters are increased on heating. However, due to a strong increase of the monoclinic angle β, there is a direction of negative thermal expansion. In the argon atmosphere, Pr₂(SO₄)₃ is stable in the temperature range of T = 30–870 °C. The kinetics of the thermal decomposition process of praseodymium sulfate octahydrate Pr₂(SO₄)₃·8H₂O was studied as well. The vibrational properties of Pr₂(SO₄)₃ were examined by Raman and Fourier-transform infrared absorption spectroscopy methods. The band gap structure of Pr₂(SO₄)₃ was evaluated by ab initio calculations, and it was found that the valence band top is dominated by the p electrons of oxygen ions, while the conduction band bottom is formed by the d electrons of Pr³⁺ ions. The exact position of ZPL is determined via PL and PLE spectra at 77 K to be at 481 nm, and that enabled a correct assignment of luminescent bands. The maximum luminescent band in Pr₂(SO₄)₃ belongs to the ³P₀ → ³F₂ transition at 640 nm.     

Exploring the Interplay between Drug Release and Targeting of Lipid-Like Polymer Nanoparticles Loaded with Doxorubicin

Targeted delivery of doxorubicin still poses a challenge with regards to the quantities reaching the target site as well as the specificity of the uptake. In the present approach, two colloidal nanocarrier systems, NanoCore-6.4 and NanoCore-7.4, loaded with doxorubicin and characterized by different drug release behaviors were evaluated in vitro and in vivo. The nanoparticles utilize a specific surface design to modulate the lipid corona by attracting blood-borne apolipoproteins involved in the endogenous transport of chylomicrons across the blood–brain barrier. When applying this strategy, the fine balance between drug release and carrier accumulation is responsible for targeted delivery. Drug release experiments in an aqueous medium resulted in a difference in drug release of approximately 20%, while a 10% difference was found in human serum. This difference affected the partitioning of doxorubicin in human blood and was reflected by the outcome of the pharmacokinetic study in rats. For the fast-releasing formulation NanoCore-6.4, the AUC_0→1h was significantly lower (2999.1 ng × h/mL) than the one of NanoCore-7.4 (3589.5 ng × h/mL). A compartmental analysis using the physiologically-based nanocarrier biopharmaceutics model indicated a significant difference in the release behavior and targeting capability. A fraction of approximately 7.310–7.615% of NanoCore-7.4 was available for drug targeting, while for NanoCore-6.4 only 5.740–6.057% of the injected doxorubicin was accumulated. Although the targeting capabilities indicate bioequivalent behavior, they provide evidence for the quality-by-design approach followed in formulation development.     

Electrodeposited polyaniline/Cu2ZnSnSe4 heterojunction

Journal of Solid State Electrochemistry - One-step method for the electrodeposition of thin Cu2ZnSnSe4 (CZTSe) film onto a polyaniline/FTO/glass substrate was developed. Polyaniline film was...