Vol 68, No 12 (2019)

We describe the current version of the PASS program for prediction of biological activity spectra of organic compounds based on analysis of structure—activity relationships (SAR) for a training set containing information on more than 1000 000 biologically active organic compounds. The average accuracy of prediction for more than 5 000 types of biological activity exceeds a value of 0.96. To analyze quantitative SAR, the GUSAR program was developed. The advantages of GUSAR were demonstrated in a number of computational experiments. The local versions of the PASS and GUSAR programs, as well as 19 freely available web services were developed. The latter are freely accessible via the Internet at http://way2drug.com/dr. The web services at the Way2Drug portal are used by more than 24 000 researchers working in about 100 countries. Currently, more than 830 000 predictions were made, the most promising compounds were selected for chemical synthesis, and priorities for testing their biological activity were established. The PharmaExpert software was developed to analyze the results of the PASS- and GUSAR-based predictions and to search for chemical compounds with necessary biological activity spectra. Combined use of the PASS, GUSAR, and PharmaExpert programs enables an assessment of the pharmacotherapeutic, adverse, and toxic effects of new compounds based on the systems pharmacology.

The review considers methods for the synthesis of stoichiometric and nonstoichiometric nanostructured titanium dioxide for medicinal chemistry. The influence of the synthesis method on the amorphous atomic and crystal structures, specific surface area, morphology, and photooptical properties of the material is analyzed. The review compares the results of using stoichiometric and nonstoichiometric titanium dioxide in the synthesis of new organic molecules by cross-coupling of heteroarenes, which can be utilized in drugs.

The UV spectra of four binuclear sulfur-containing iron nitrosyl clusters, namely, cationic Fe₂{[S(CH₂)₂NH₃]₂(NO)₄}SO₄·2.5H₂0 and Fe₂[(SC₅H₁₁NO₂)₂(NO)₄]SO₄·5H₂O, anionic Na₂[Fe₂(S₂O₃)₂(NO)₄]·4H₂O, and neutral [Fe₂(SC₅H₆)₂(NO)₄], were modeled using time-dependent density functional theory (TDDFT) and compared with experimental results. It was determined that the strong bands at 310 and 360 nm in the experimental spectra correspond to electronic transitions (Fe—NO) → π*(Fe—NO), but the unshared electron pairs of sulfur atoms also contribute. The presence of an aromatic ring in the sulfur-containing ligand changes the form of the UV spectrum, as was observed in the experiment. Strong characteristic bands are absent from the theoretical spectra of possible products.

New allocolchicine derivatives bearing 2,3-dihydrobenzo[b]oxepine moiety were synthesized via gold-catalyzed cyclization as a key synthetic step. The obtained 2,3-dihydrobenzo[b]oxepine-containing allocolchicinoids possess cytotoxic activity against HEK293, PANC-1, COL0357, HeLa, and Colon26 cancer cell lines at low micromolar range of concentrations.

A new binuclear μ-NSC-type nitrosyl iron complex [Fe₂(SR)₂(NO)₄] (R is 5-phenyl-1H-1,2,4-triazole-3-thiolyl) was synthesized. The composition and structure of the newly synthesized complex were determined by atomic absorption, IR, EPR, and Mössbauer spectroscopy and SQUID magnetometry. Amperometric analysis showed that the new complex is an effective nitric oxide (NO) donor in a 1% aqueous DMSO solution. The amounts of NO generated by the complex [Fe₂(SR)₂(NO)₄] in aqueous solutions at physiological pH values were determined. The new complex was shown to have higher antibacterial activity against the gram-positive bacteria Micrococcus luteus compared to kanamycin and streptomycin. According to assays, sulfur-containing ligands of the 1,2,4-triazole-3-thiol series are promising for the design of new antibacterial agents containing the {Fe(NO)₂} structural moiety.

A synthetic approach to the modification of the drug “riluzole” with pharmacologically active fragments such as carbazole, tetrahydrocarbazole, phenothiazine, and aminothiophene, based on the copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition of azide-containing pharmacophores with “riluzole” decorated with 5-trifluoromethylhydantoin, has been suggested.

2,3-Secooleanane hydroxynitriles undergo dehydration and anionotropic 1,2-migration of the methyl group C(24)H₃ under the action of the SOCl_2-CH₂Cl₂ system to form a mixture of isomeric Δ⁴-alkenes. A similar E1-elimination process in the presence of the H₂SO₄—AcOH system is accompanied by hydrolysis of the CN group giving A-ring unsaturated C(2)-ketones and diastereomeric ε-lactones. Epimeric 4,23-epoxides and isopropyl ketone were synthesized by oxidative transformations of 4,23-alkene, which was selectively formed from 2,3-secooleanane hydroxynitrile under the action of the POCl_3-Py system. The in vitro cytotoxic evaluation by the MTT assay showed that the synthesized compounds are not toxic (IC₅₀ > 100 μmol L⁻¹) against the human cancer cell lines HEp-2, HCT116, MS, RD TE32, MCF-7, A549, and PC-3.

A new simple, technological, and environmentally friendly method for the catalyst-free synthesis in water of a promising antituberculosis drug, 6-ethoxycarbonyl-5-methyl-7-(thien-2-yl)-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine, was developed. The amount of the solvent in the reaction mixture has a decisive effect on the yield and purity of the target product.

A series of eight novel 5-N,N-disubstituted-5-amino-3-(2-oxopropyl)-1,2,4-thiadiazoles with diverse lipophilic groups was obtained by reaction of 3-isothiocyanato-5-methylisoxazole with secondary amines. All the compounds of the series (independently on the type of the substituents) were found to be ineffective as inhibitors of calcium ions uptake in synaptosomes of rat cerebral cortex. Screening of the cytotoxicity to four cell lines (breast adenocarcinoma MCF-7, conditionnally normal breast epithelial cells MCF-10A, lung carcinoma A549, non-cancer lung fibroblasts VA13) revealed three compounds with good selectivity to cancer cells MCF-7 in comparison with non-cancer cell line MCF- 10A. These 1,2,4-thiadiazoles can serve as new leads for further study of their antitumor properties.

New potentially bioactive derivatives comprising spatially hindered pyrocatechol linked to hydrazine, acid hydrazides (including isoniazid), and acetylcysteine by a covalent bridge, have been obtained. The structure of the obtained compounds was studied by X-ray diffraction analysis.

A salt-like conjugate of xymedone with para-aminobenzoic acid in a series of pyrimidine derivatives was synthesized, and its hepatoprotective properties were studied. The compound studied exhibits a cytoprotective effect at a concentration of 25 μmol L^-1 enhancing the viability of normal human hepatocyte cells of the Chang Liver line by 2.1 times against the background of the impact of the d-galactosamine toxicant, which was shown by experiments in vitro. The cytotoxicity of the compound (IC₅₀) is 20.7 mmol L^-1. The data indicating the hepatoprotective effect most pronounced at the early stages of therapy were obtained in experiments in vivo performed according to the therapeutic scheme on the model of CCl₄-induced toxic hepatitis. The ability of the conjugate to exert reparative and protective effects was found, since the surface area of destructive-degenerative and necrotic injuries revealed in hematoxylin- and eosin-stained sections on the third day of intraperitoneal administration of the studied compound in a dose of 0.7 mg kg^-1 decreased by 1.5 times. The areas of detection of lipid inclusions in frozen sections stained with Sudan black decreased by four times on the third day at a dose of 1.7 mg kg^-1, whereas the decrease was 3.2 times on the seventh day at a dose of 0.7 mg kg^-1 compared to the control group of animals administrated with saline. According to the biochemical parameters, positive effects on the secretory and synthetic functions of the liver, bilirubin metabolism, and metabolism of iron and magnesium were observed during the treatment of animals with the conjugate.

The results on amperometric determination of antioxidant activity of a large group of iso-bornylphenols are present. The antioxidant activity is dependent on a degree of sterical hindering of hydroxy groups. The obtained data can be used for employing these antioxidants to decrease the oxidation of plastics, rubbers, and fuels.

Daunorubicin was conjugated with spacered N-glycosides of di- and trisaccharides containing terminal α-l-fucopyranose residues. The synthesis was carried out by N-monoalkylation of daunorubicin hydrochloride (1) in aqueous DMF in the presence of NaHCO₃ using N-β-glycoside N-bromoacetylglycyl derivatives, namely, α-l-Fucp-(1→2)-β-d-Galp-(1→4)-β-d-Glcp-NHCOCH₂NHCOCH₂Br (2a), α-l-Fucp-(1→4)-[β-d-Galp-(1→3)]-β-d-GlcpNAc-NHCOCH₂NHCOCH₂Br (3a), α-l-Fucp-(1→3)-β-d-GlcpNAc-NHCOCH₂NHCOCH₂Br (4a), and α-l-Fucp-(1→6)-β-d-GlcpNAc-NHCOCH₂NHCOCH₂Br (5a). The conjugates of daunorubicin were obtained as hydrochlorides (2b-5b) in 40% yield. Their oligosaccharide components are fragments of H type 5, Le^a, Le^x antigens and N-fucolglycan, respectively. 0(I) Erythrocytes hemagglutination inhibition assay was performed with conjugates 2b–5b and Ulex europaeus (UEA 1), Lotus tetragonolobus (LTA), and Laburnum anagyroides (LAA) plant fucolectins.

A convenient preparative synthesis of 3-methoxyestra-1,3,5(10),16-tetraene-17-carb-aldehyde and its epimeric 13α-analog, the key structures in the synthesis of steroid estrogen receptor modulators and potential antitumor agents, was developed starting from estrone and including the generation of intermediate 16-dehydro-17-carbonitriles and their reaction with diisobutylaluminum hydride. The influence of conformational dif erences in the steroid molecules with the natural 13β- and epimeric 13α-configurations on the reactivity of intermediate compounds and the stereoselectivity of the trimethylsilyl cyanide addition to the carbonyl group of methyl ethers of epimeric estrones was considered.

It was shown by immunoblotting that the introduction of an antitumor antioxidant, sodium 2-carboxy-2-(N-acetylamino)-3-(3,5-di-tert-butyl-4-hydrophenyl)propanoate (anphen sodium), into a suspension of Lewis carcinoma cells induces a sharp decrease in the contents of the monomer and homodimer of the anti-apoptotic Bcl-2 protein. According to fluorescence analysis, the number of apoptotic cells sharply increased 1 h after exposure to anphen sodium; preliminary addition of 5 μmol L^-1 of hydrogen peroxide increased the cell membrane permeability of anphen sodium and the number of apoptotic cells. The onset of apoptosis detected using fluorophores is comparable in time with the start of the decline of the Bcl-2 level. It was assumed that the mechanism of action of anphen sodium may include the interaction of the agent with the hydrophobic (BH3) domain of Bcl-2 family proteins.

New ditopic organic ligands with (pyridylmethylidene)imidazolone and pyridylbenzothi-azole moieties were synthesized by Cu-catalyzed azide-alkyne cycloaddition of 6-(prop-2-yn-1yloxy)-2-(pyridin-2-yl)benzothiazoleto3-azidoalkyl-5-[(Z-(pyridin-2-yl)methylidene]-2-(methylthio)dihydro-4H-imidazol-4-ones. The synthesized ligands (L) react with copper(ii) chloride to give coordination compounds of general formula LCuCl₂ with coordination of the copper ion on the pyridylbenzothiazole fragment.

The cytostatic effects of 5-fluorouracil, oxaliplatin, and 4-(5-methyl-5H-[1,3]dioxolo[4,5-f]-indol-7-yl)-3-(5-fluoro-1-benzofuran-3-yl)-1 H-pyrrole-2,5-dione (9-ING-41), a new glycogen synthase kinase-3 inhibitor, were evaluated in 2D and 3D models of HT-29 colorectal adenocarcinoma cells. The HT-29 cells cultured in 3D were resistant to the test drugs, while in the case of the 2D model, not only cytostatic but also cytotoxic effect was observed. The highest cytotoxic effect was detected upon the addition of 9-ING-41, at high concentrations of which the cell viability decreased to 50% after 3 h of incubation. The results indicate that 3D cultures reproduce the tumor structure and drug resistance more accurately.

To the article “Glycosylation in flow: effect of the flow rate and type of the mixer,” by I. V. Myachin, A. V. Orlova, and L. O. Kononov, Vol. 68, No. 11, pp. 2126–2129, November, 2019.

In the original international version of the article, one phrase was omitted.

To be added:

This work was financially supported by the Russian Science Foundation (Project No. 16-13-10244-P).