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In Russia some companies didn’t have a marketing strategy yet, but marketing is very important part of company management. In the case of the absence of the marketing strategy, a director risks to fill the storage by goods with no demand, or to try to do some useless services, to encounter with unknown competing goods, or to reduce some successful operations. In the article was developed methodic techniques and economic-mathematical models for creating the marketing strategy for companies providing special equipment service in Novosibirsk region. Using the proposed models and methods was created marketing strategy for «TC Athena» with regard to the sphere of activity of the company.

In the present work, we report a new series of potent SARS-CoV-2 Main Protease (Mpro) inhibitors based on maleimide derivatives. The inhibitory activities were tested in an enzymatic assay using recombinant Mpro (3CL Protease from coronavirus SARS-CoV-2). Within the set of new Mpro inhibitors, 6e demonstrated the highest activity in the enzymatic assay with an IC 50 value of 8.52 ± 0.44 µM. The IC 50 value for Nirmatrelvir (PF-07321332, used as a reference) was 0.84 ± 0.37 µM. The cytotoxic properties were determined in the MTT assay using MRC-5 and HEK-293 cell lines. In the course of the investigation, we found that the newly obtained maleimide derivatives are not substantially cytotoxic (IC 50 values for most compounds were above 200 µM).

Several molecular cobalt(ii) complexes, one Co(ii) coordination polymer and one ionic cobalt(iii) complex with imine hemisalen ligands were synthesized. The hemisalen ligands were synthesized from o -vanillin ( o VP) and diverse aminopyridines (compounds HL1-HL4) or aminophenol (compound HL5). It was observed that cobalt(ii) chloride in dry acetonitrile catalyzes a transformation of HL1 and HL3 instead of complex formation. The conversion of these imines proceeded via self-cyclization to N -2''-pyridyl-2,6-dioxo-9-aza-[ c , g ]di-2'-methoxybenzo nonan or its methyl derivative as the major product. The remaining reactions were performed using imines HL1-HL5 and cobalt(ii) acetate Co(Ac) 2 in methanol or DMSO/acetonitrile resulting in forming a series of cobalt complexes. The following series of compounds was obtained: two similar tetrahedral molecular Co(ii) complexes [Co(L1) 2 ] and [Co(L3) 2 ], one trinuclear, mixed-ligand Co 3 (Ac) 2 (L4) 2 ( o VP) 2 , one coordination polymer {Co(L2) 2 } ∞ and finally one octahedral anionic Co(iii) complex [HNEt 3 ][Co(L5) 3 ]. The latter complex formed in a cobalt(ii) acetate reaction with a hemisalen HL5 derived from o VP and 2-aminophenol. The molecular structures of all compounds were confirmed by X-ray diffraction, and the cytotoxicity of Co(ii) and Co(iii) complexes towards cancer cell lines HCT116, HL-60 and normal cell line MRC-5 was studied., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The group of 18 new amide derivatives of mycophenolic acid (MPA) and selected heterocyclic amines was synthesised as potential immunosuppressive agents functioning as inosine-5'-monophosphate dehydrogenase (IMPDH) uncompetitive inhibitors. The synthesis of 14 of them employed uronium-type activating system (TBTU/HOBt/DIPEA) while 4 of them concerned phosphonic acid anhydride method (T3P/Py) facilitating amides to be obtained in moderate to excellent yields without the need of phenolic group protection. Most of optimised protocols did not require complicated reaction work-ups, including chromatographic, solvent-consuming methods. The biological activity assay was performed on the T-Jurkat cell line and peripheral mononuclear blood cells (PBMCs) which are both dedicated for antiproliferative activity determination. Each of designed derivatives was characterised by reduced cytotoxicity and benzoxazole analogue ( A2 ) revealed the most promising activity. Subsequently, an observed structure-activity relationship was discussed.

In this work, we designed, synthesised and biologically investigated a novel series of 14  N - and O -phosphorylated tacrine derivatives as potential anti-Alzheimer's disease agents. In the reaction of 9-chlorotacrine and corresponding diamines/aminoalkylalcohol we obtained diamino and aminoalkylhydroxy tacrine derivatives. Next, the compounds were acid to give final products 6 - 13 and 16 - 21 that were characterised by 1 H, 13  C, 31  P NMR and MS. The results of the docking studies revealed that the designed phosphorus hybrids, in theory can bind to AChE and BChE. All compounds exhibited significantly lower AutoDock Vina scores compared to tacrine. The inhibitory potency evaluation was performed using the Ellman's method. The most inhibitory activity against AChE exhibited compound 8 with an IC 50 value of 6.11 nM and against BChE 13 with an IC 50 value of 1.97 nM and they were 6- and 12-fold potent than tacrine. Compound 19 showed the lack of hepatocytotoxicity in MTT assay.

In this study, we evaluated the antiproliferative potential, DNA damage, crystal structures, and docking calculation of two spiropyrazoline derivatives. The main focus of the research was to evaluate the antiproliferative potential of synthesized compounds towards eight cancer cell lines. Compound I demonstrated promising antiproliferative properties, especially toward the HL60 cell line, for which IC 50 was equal to 9.4 µM/L. The analysis of DNA damage by the comet assay showed that compound II caused DNA damage to tumor lineage cells to a greater extent than compound I . The level of damage to tumor cells of the HEC-1-A lineage was 23%. The determination of apoptotic and necrotic cell fractions by fluorescence microscopy indicated that cells treated with spiropyrazoline-based analogues were entering the early phase of programmed cell death. Compounds I and II depolarized the mitochondrial membranes of cancer cells. Furthermore, we performed simple docking calculations, which indicated that the obtained compounds are able to bind to the PARP1 active site, at least theoretically (the free energy of binding values for compound I and II were -9.7 and 8.7 kcal mol -1 , respectively). In silico studies of the influence of the studied compounds on PARP1 were confirmed in vitro with the use of eight cancer cell lines. The degradation of the PARP1 enzyme was observed, with compound I characterized by a higher protein degradation activity.

We present here the advances achieved in the development of new sulfamoylated 4-(1-phenyl-1 H -1,2,3-triazol-4-yl)phenol derivatives as potent steroid sulfatase (STS) inhibitors for the treatment of breast cancer. Prompted by promising biological results and in silico analysis, the initial series of similar compounds were extended, appending a variety of m-substituents at the outer phenyl ring. The inhibition profiles of the newly synthesized compounds were evaluated using a radioisotope enzymatic assay and, together with the preceding reported derivatives, using a radioisotope assay in MCF-7 cells. The most active compound, 5l , demonstrated an extraordinary STS inhibitory potency in MCF-7 cells with an IC 50 value improved 5-fold compared to that of the reference Irosustat (0.21 vs 1.06 nM). The five most potent compounds were assessed in vivo in a 67NR mouse mammary gland cancer model, with 4b measured to induce up to 51% tumor growth inhibition at 50 mg/kg with no evidence of side effects and toxicity.

Histone deacetylases (HDACs) are a large family of epigenetic metalloenzymes that are involved in gene transcription and regulation, cell proliferation, differentiation, migration, and death, as well as angiogenesis. Particularly, disorders of the HDACs expression are linked to the development of many types of cancer and neurodegenerative diseases, making them interesting molecular targets for the design of new efficient drugs and imaging agents that facilitate an early diagnosis of these diseases. Thus, their selective inhibition or degradation are the basis for new therapies. This is supported by the fact that many HDAC inhibitors (HDACis) are currently under clinical research for cancer therapy, and the Food and Drug Administration (FDA) has already approved some of them. In this review, we will focus on the recent advances and latest discoveries of innovative strategies in the development and applications of compounds that demonstrate inhibitory or degradation activity against HDACs, such as PROteolysis-TArgeting Chimeras (PROTACs), tumor-targeted HDACis (e.g., folate conjugates and nanoparticles), and imaging probes (positron emission tomography (PET) and fluorescent ligands).

In the present work, we report a new class of potent steroid sulphatase (STS) inhibitors based on 6-(1-phenyl-1 H -1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate derivatives. Within the set of new STS inhibitors, 6-(1-(1,2,3-trifluorophenyl)-1 H -1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate 3L demonstrated the highest activity in the enzymatic assay inhibiting the STS activity to 7.98% at 0.5 µM concentration. Furthermore, to verify whether the obtained STS inhibitors are able to pass through the cellular membrane effectively, cell line experiments have been carried out. We found that the lowest STS activities were measured in the presence of compound 3L (remaining STS activity of 5.22%, 27.48% and 99.0% at 100, 10 and 1 nM concentrations, respectively). The measured STS activities for Irosustat (used as a reference) were 5.72%, 12.93% and 16.83% in the same concentration range. Moreover, a determined IC 50 value of 15.97 nM for 3L showed that this compound is a very promising candidate for further preclinical investigations.

The interaction between sertraline hydrochloride (SRT) and randomly methylated β-cyclodextrin (RMβCD) molecules have been investigated at 298.15 K under atmospheric pressure. The method used-Isothermal Titration Calorimetry (ITC) enabled to determine values of the thermodynamic functions like the enthalpy (ΔH), the entropy (ΔS) and the Gibbs free energy (ΔG) of binding for the examined system. Moreover, the stoichiometry coefficient of binding (n) and binding/association constant (K) value have been calculated from the experimental results. The obtained outcome was compared with the data from the literature for other non-ionic βCD derivatives interacting with SRT and the enthalpy-entropy compensation were observed and interpreted. Furthermore, the connection of RMβCD with SRT was characterized by circular dichroism spectroscopy (CD) and complexes of βCD derivatives with SRT were characterized through the computational studies with the use of molecular docking (MD).

One tetracyclic antidepressant, mianserin hydrochloride (MIA), has quite significant side effects on a patients' health. Cyclodextrins, which are most commonly used to reduce the undesirable features of contained drugs within their hydrophobic interior, also have the potential to alter the toxic behavior of the drug. The present paper contains investigations and the characteristics of interaction mechanisms for MIA and the heptakis (2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD) system, and evaluated the effects of the complexation on MIA cytotoxicity. In order to assess whether there was an interaction between MIA and DM-β-CD molecules, isothermal titration calorimetry (ITC) have been chosen. Electrospray ionization mass spectrometry (ESI-MS) helped to establish the complex stoichiometry, and circular dichroism spectroscopy was used to describe the process of complex formation. In order to make a wider interpretative perspective, the molecular docking results have been performed. The viability of Chinese hamster cells were investigated in the presence of DM-β-CD and its complexes with MIA in order to estimate the cytotoxicity of the drug and the conjugate with the chosen cyclodextrin. The viability of B14 cells treated with MIA+DM-β-CD is lower (the toxicity is higher) than with MIA alone, and no protective effects have been observed for complexes of MIA with DM-β-CD in any ratio.

Herein, we present the synthesis and crystal structures determination of five 4-(1-phenyl-1 H -1,2,3-triazol-4-yl)phenol derivatives containing halogen atoms, 6a - e , which may be used as an excellent mimic of steroids in the drug development process. Good quality crystals obtained for all of the synthesized compounds allowed the analysis of their molecular structures. Subsequently, the determined crystal structures were used to calculate the Hirshfeld surfaces for each of the synthesized compounds. Furthermore, results of our docking studies indicated that synthesized derivatives are able to bind effectively to the active sites of selected enzymes and receptors involved in the hormone biosynthesis and signaling pathways, analogously to the native steroids.

The purpose of this review article is to provide an overview of recent achievements in the synthesis of novel steroid sulphatase (STS) inhibitors. STS is a crucial enzyme in the biosynthesis of active hormones (including oestrogens and androgens) and, therefore, represents an extremely attractive molecular target for the development of hormone-dependent cancer therapies. The inhibition of STS may effectively reduce the availability of active hormones for cancer cells, causing a positive therapeutic effect. Herein, we report examples of novel STS inhibitors based on steroidal and nonsteroidal cores that contain various functional groups (e.g. sulphamate and phosphorus moieties) and halogen atoms, which may potentially be used in therapies for hormone-dependent cancers. The presented work also includes examples of multitargeting agents with STS inhibitory activities. Furthermore, the fundamental discoveries in the development of the most promising drug candidates exhibiting STS inhibitory activities are highlighted.

A series of fluorinated analogs based on the frameworks of 4-(1-phenyl-1 H -[1,2,3]triazol-4-yl)-phenyl sulfamates have been synthesized as steroid sulfatase (STS) inhibitors. The design of chemical structures of new potential STS inhibitors was supported by molecular docking techniques to identify potential interactions between inhibitors and amino acid residues located in the STS active site. The STS inhibitory potency was evaluated on STS isolated from human placenta. We found that compounds substituted with fluorine atom at the meta position demonstrated the highest inhibitory effects in enzymatic STS assay. The most active analog 12e - inhibited STS enzyme with the IC 50 value of 36 nM.

Five-membered 1,2,4-oxadiazole heterocyclic ring has received considerable attentionbecause of its unique bioisosteric properties and an unusually wide spectrum of biological activities.Thus, it is a perfect framework for the novel drug development. After a century since the1,2,4-oxadiazole have been discovered, the uncommon potential attracted medicinal chemists'attention, leading to the discovery of a few presently accessible drugs containing 1,2,4-oxadiazoleunit. It is worth noting that the interest in a 1,2,4-oxadiazoles' biological application has been doubledin the last fifteen years. Herein, after a concise historical introduction, we present a comprehensiveoverview of the recent achievements in the synthesis of 1,2,4-oxadiazole-based compounds and themajor advances in their biological applications in the period of the last five years as well as briefremarks on prospects for further development.

Background: Alzheimer's disease (AD) is progressive and irreversible neurodegenerative disorder. Current pharmacotherapy is not able to stop progression of the disease and can only improve cognitive functions. Therefore, new drugs are being sought that will slow down the development of the disease., Objective: Novel phosphorus and thiophosphorus tacrine derivatives 7-14 were designed, synthesized and their biological activity and molecular modeling was investigated as a new potential anti- Alzheimer's disease (AD) agents., Methods: 9-Chlorotacrine was treated with propane-1,3-diamine in the presence of sodium iodide to yield N1-(1,2,3,4-tetrahydroacridin-9-yl)propane-1,3-diamine 6. Finally, it was treated with corresponding acid ester or thioester to give phosphorus or thiophosphorus tacrine derivative 7-14. All of the obtained final structures were characterized by 1H NMR, 13C NMR, 31P NMR and MS., Results: The results of the docking studies showed that the newly designed phosphorus and thiophosphorus tacrine analogs, theoretically possess AChE and BChE-binding ability. Kinetic study showed that 8 and 12 in the series proved to be more potent electric eel AChE (eeAChE) and human (hAChE) inhibitors than tacrine, where 8 inhibited eeAChE three times more than the referenced drug. The highest BChE inhibition revealed 11 and 13. The most active compounds against eeAChE, hAChE and BChE showed mixed type of inhibition., Conclusion: All new synthesized compound exhibited lower toxicity against neuroblastoma.cell line (SH-SY5Y) in comparison with tacrine. Two analogues in the series, 7 and 9, demonstrated lack of cytotoxicity against hepatocellular cells (hepG2)., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In the present work, we described convenient methods for the synthesis of N-thiophosphorylated 3-(4-aminophenyl)-coumarin-7-O-sulfamates as steroid sulfatase (STS) inhibitors. To design the structures of the potential STS inhibitors, molecular modeling techniques were used. A computational docking method was used to determine the binding modes of the synthesized inhibitors as well as to identify potential interactions between specified functional groups on the inhibitors and the amino acid residues present in the active site of the enzyme. The inhibitory activities of the synthesized compounds were tested in an enzymatic assay with STS isolated from a human placenta. Within the set of newly synthesized compounds, 9e demonstrated the highest inhibitory activity in the enzymatic assay with an IC 50 value of 0.201 μM (the IC 50 value of 667-COUMATE in the same test was 0.062 μM). Furthermore, we tried to verify if the obtained STS inhibitors are able to pass through the cellular membrane effectively in cell line experiments. In the course of our study, we determined the STS activity in the MCF-7 cell line after incubation in the presence of the inhibitors (at 100 nM concentration). For this evaluation, we included newly synthesized compounds 9a-g and their N-phosphorylated analogs 6a-h, whose synthesis has been previously described. We found that the lowest STS activities were measured in the presence of N-phosphorylated derivatives 6e (0.1% of STS activity) and 6f (0.2% of STS activity). The measured STS activity in the presence of 667-COUMATE (used as a reference) was 0.1%. Moreover, at concentrations up to 1 μM, the most active compounds (6e, 6f, 9b, and 9e) did not exert any toxic effects on zebrafish embryos., (© 2019 Wiley Periodicals, Inc.)

In the present work, we report convenient methods for the synthesis of 3-(4-aminophenyl)-coumarin-7-O-sulfamate derivatives N-acylated with fluorinated analogues of benzoic or phenylacetic acid as steroid sulfatase (STS) inhibitors. The design of these potential STS inhibitors was supported by molecular modeling techniques. Additionally, computational docking methods were used to determine the binding modes of the synthesized inhibitors and to identify potential interactions between inhibitors and amino acid residues located in the active site of STS. The inhibitory effects of the synthesized compounds were tested on STS isolated from human placenta and against estrogen receptor-(ER)-positive MCF-7 and T47D cells, as well as ER-negative MDA-MB-231 and SkBr3 cancer cell lines. In the course of our investigation, compounds 6c and 6j demonstrated the highest inhibitory effect in enzymatic STS assays, both with IC 50 values of 0.18 μM (the IC 50 value of coumarin-7-O-sulfamate is 1.38 μM, used as a reference). Compound 6j exhibited the highest potency against the MCF-7 and T47D cell lines (15.9 μM and 8.7 μM, respectively). The GI 50 values of tamoxifen (used as a reference) were 6.8; 10.6; 15.1; 12.5 μM against MCF-7, T47D, MDA-MB-231 and SkBr3 cancer cell lines, respectively. Despite the slightly lower activity of compounds 1 and 2 (both in enzymatic and cell-based experiments) compared to 6g and 6j, analogues 1 and 2 proved to selectively inhibit the growth of ER- and PR-positive cell lines., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

The present mini-review highlights recent developments on antitumor activity of metal-based therapeutics which have been a subject of researches for the last few decades. In 1965, Rosenberg found that during an electrolysis on platinum electrodes a complex of Pt is generated which inhibited to a great extent a binary fission in Escherichia coli bacteria. This discovery started a new chapter in medicinal chemistry and the interesting properties of cisplatin were soon applied in cancer therapy especially in curing genitourinary tumors. However, various side effects limited its use in medical treatment. Since then a great number of other metal-organic complexes based on platinum, palladium, ruthenium, gold, copper, silver, rhodium, osmium, rhenium, iridium and others have been synthesized. Among them, NAMI-A and KP1019 have recently undergone clinical trials. In this review paper we report a detailed account of metal complexes with phosphorus-based ligands which are of particular interest in therapeutics.

A series of phosphate and thiophosphate flavone derivatives were synthesized and biologically evaluated in vitro for inhibition of steroid sulfatase (STS) activity. The described synthesis includes the straightforward preparation of 7-hydroxy-2-phenyl-4H-chromen-4-one 3a, 2-(4-fluorophenyl)-7-hydroxy-4H-chromen-4-one 3b, 7-hydroxy-2-(4-(trifluoromethyl)phenyl)-4H-chromen-4-one 3c, 7-hydroxy-2-(p-tolyl)-4H-chromen-4-one 3d modified with different phosphate or thiophosphate moieties. The inhibitory properties of the synthesized compounds were tested against human placenta STS. Some of the novel STS inhibitors had good activities against STS. In particular, the bis-(4-oxo-2-(p-tolyl)-4H-chromen-7-yl) hydrogenthiophosphate, 6i had the most potent inhibitory effect with an IC50 value of 3.25 µM as compared to an IC50 value of 8.50 µM for the 2-(4-trifluoromethylphenyl)-chromen-4-one-7-O-sulfamate used as a reference., (© 2015 Wiley Periodicals, Inc.)

Based on the frameworks of 7-hydroxy-2,3-dihydro-1H-cyclopenta[c]chromen-4-one, 3-hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one and 3-hydroxy-8,9,10,11-tetrahydro-7H-cyclohepta[c]chromen-6-one, a series of bicoumarin thiophosphate analogs have been synthesized and biologically evaluated. Additionally, their binding modes have been modeled using docking techniques. The inhibitory properties of the synthesized compounds were tested against the STS isolated from human placenta. Most of the new STS inhibitors possessed good activities against STS. In particular, we found that the bis-(6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-3-yl) hydrogenthiophosphate (10b) produced the largest inhibitory effect, with an IC50 value of 860 nM (an IC50 value of 1 μM for the 665-COUMATE used as a reference). The structure-activity relationships of the synthesized bicoumarin thiophosphate derivatives toward the STS enzyme have been discussed previously., (Copyright © 2015. Published by Elsevier Masson SAS.)

In the present work, we report convenient methods for the synthesis and biological evaluation of phosphate and thiophosphate biphenyl derivatives exhibiting steroid sulfatase (STS) activity. The described synthesis is based on straightforward preparation of biphenyl-4-ol and 4'-hydroxy-biphenyl-4-carboxylic acid ethyl ester modified with various phosphate or thiophosphate moieties. The inhibitory effects of these compounds were tested on STS isolated from human placenta and led to two compounds of interest, 5a and 5d with IC50 values of 28.0 and 22.1 µM, respectively and that had interesting new binding modes in the STS active site., (© 2015 Wiley Periodicals, Inc.)

Steroid sulfatase (STS) enzyme inhibition is an important approach to the management of hormone-dependent breast cancer. In this paper, we report convenient methods for the synthesis and biological evaluation of thiophosphate tricyclic coumarin analogs exhibiting STS activity. The described methods are based on the straightforward preparation of 7-hydroxy-2,3-dihydro-1H-cyclopenta[c]chromen-2-one, 3-hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one, and 3-hydroxy-8,9,10,11-tetrahydro-7H-cyclohepta[c]chromen-6-one and their further modification by the introduction of various thiophosphate moieties. The inhibition properties of the synthesized compounds were tested toward STS isolated from human placenta. Most of the new STS inhibitors possessed good to moderate activity toward STS. During the course of our investigation, the largest inhibitory effects in the STS enzyme assays were observed for the two compounds 3f and 4r, with IC50 values of 13.3 and 30.3 μM, respectively (the IC50 value of 1 μM for the 665-COUMATE was used as a reference). The structure-activity relationships of the synthesized coumarin derivatives toward STS enzymes are discussed.