Study of the Pharmacological Activity Spectrum of the New Original NT-3 Mimetic Dipeptide GTS-302.

Unlabelled: The association of the pathogenesis of neurodegenerative diseases, depression, anxiety, and cognitive disorders with neurotrophin-3 deficiency determines the prospect of creating drugs with a similar mechanism of action. Since the use of full-length NT-3 is limited by unsatisfactory pharmacokinetic properties, the creation of low-molecular mimetics of neurotrophin-3 that are active when administered systemically is relevant. The Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies has created a dimeric dipeptide mimetic of the 4th loop of NT-3, hexamethylenediamide bis-(N-γ-oxybutyryl-L-glutamyl-L-asparagine) with the laboratory code GTS-302, which activates TrkC and TrkB receptors.

Synthesis and comparative analysis of the cytotoxicity and mitochondrial effects of triphenylphosphonium and F16 maslinic and corosolic acid hybrid derivatives.

The cytotoxic profile and antiproliferative and mitochondrial effects of triterpene acid conjugates with mitochondriotropic lipophilic triphenylphosphonium (TPP) and F16 cations were evaluated. Maslinic and corosolic acids chosen as the investigation objects were synthesized from commercially available oleanolic and ursolic acids. Study of the cytotoxic activity of TPP and F16 triterpenoid derivatives against six tumor cell lines demonstrated a comparable synergistic effect in the anticancer activity, which was most pronounced in the case of MCF-7 mammary adenocarcinoma cells and Jurkat and THP-1 leukemia cells.

Novel binuclear copper(II) complexes with sulfanylpyrazole ligands: synthesis, crystal structure, fungicidal, cytostatic, and cytotoxic activity.

New binuclear copper(II) [Cu(II)] tetraligand complexes (six examples) with sulfanylpyrazole ligands were synthesized. Electron spin resonance (ESR) studies have shown that in solution the complexes are transformed to the mononuclear one. Fungicidal properties against Candida albicans were found for the Cu complexes with benzyl and phenyl substituents.

Synthesis and cytotoxic activity of some (+)-salsolidine derivatives.

On the basis of typical for secondary amino group reactions a number of derivatives of alkaloid (+)-salsolidine was synthesised. Cytotoxic properties of obtained compounds towards the HEK293, A549, MCF-7 and SH-SY5Y cell lines have been evaluated. As a result of the screening, the hit compound - 2-(chloroacetyl)-6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline () was identified, that inhibited the metabolic activity of A-549, MCF-7 and SH-SY5Y tumour cell lines with the IC values of 3.

Pharmacogenetic Analysis of the Interaction of the Low-Molecular-Weight BDNF Mimetic Dipeptide GSB-106 with TRK Receptors.

Using TrkA or TrkB receptor gene knockout HT-22 cells, the selectivity of the interaction of the low-molecular-weight dipeptide BDNF mimetic GSB-106 (hexamethylenediamide bis(N-monosuccinyl-L-seryl-L-lysine)) with TrkB receptors was shown.

Pharmacological Analysis of GABA Receptor and Sigma1R Chaperone Interaction: Research Report I-Investigation of the Anxiolytic, Anticonvulsant and Hypnotic Effects of Allosteric GABA Receptors' Ligands.

Two groups of facts have been established in previous drug development studies of the non-benzodiazepine anxiolytic fabomotizole. First, fabomotizole prevents stress-induced decrease in binding ability of the GABA receptor's benzodiazepine site. Second, fabomotizole is a Sigma1R chaperone agonist, and exposure to Sigma1R antagonists blocks its anxiolytic effect.

Chaperone-Dependent Mechanisms as a Pharmacological Target for Neuroprotection.

Modern pharmacotherapy of neurodegenerative diseases is predominantly symptomatic and does not allow vicious circles causing disease development to break. Protein misfolding is considered the most important pathogenetic factor of neurodegenerative diseases. Physiological mechanisms related to the function of chaperones, which contribute to the restoration of native conformation of functionally important proteins, evolved evolutionarily.

Synthesis of fusidane triterpenoid Mannich bases as potential antibacterial and antitumor agents.

Mannich bases (8 examples) were synthesized aminomethylation of fusidane propargyl esters. antimicrobial screening against key ESKAPE pathogens showed that the fusidic acid based Mannich products exhibit a high antimicrobial effect against Gram-positive bacteria and the fungus . Moreover, the cytotoxic effect of fusidic acid and its analogs, which showed high antibacterial activity, was determined by MTT assay on cancer HepG2, HCT-116, SH-SY5Y, MCF-7, A549 and conditionally normal cells HEK293.

Comparative Study of Cytotoxic and Membranotropic Properties of Betulinic Acid-F16 Conjugate on Breast Adenocarcinoma Cells (MCF-7) and Primary Human Fibroblasts.

The present study evaluates the cytotoxicity of a previously synthesized conjugate of betulinic acid (BA) with the penetrating cation F16 on breast adenocarcinoma (MCF-7) and human fibroblast (HF) cell lines, and also shows the mechanism underlying its membranotropic action. It was confirmed that the conjugate exhibits higher cytotoxicity compared to native BA at low doses also blocking the proliferation of both cell lines and causing cell cycle arrest in the G/G phase. We show that the conjugate indeed has a high potential for accumulation in mitochondria, being visualized in these organelles, which is most pronounced in cancer cells.

Analysis of Antidepressant-like Effects and Action Mechanisms of GSB-106, a Small Molecule, Affecting the TrkB Signaling.

Induction of BDNF-TrkB signaling is associated with the action mechanisms of conventional and fast-acting antidepressants. GSB-106, developed as a small dimeric dipeptide mimetic of BDNF, was previously shown to produce antidepressant-like effects in the mouse Porsolt test, tail suspension test, Nomura water wheel test, in the chronic social defeat stress model and in the inflammation-induced model of depression. In the present study, we evaluated the effect of chronic per os administration of GSB-106 to Balb/c mice under unpredictable chronic mild stress (UCMS).

Neuroprotective Properties of Quinone Reductase 2 Inhibitor M-11, a 2-Mercaptobenzimidazole Derivative.

The ability of NQO2 to increase the production of free radicals under enhanced generation of quinone derivatives of catecholamines is considered to be a component of neurodegenerative disease pathogenesis. The present study aimed to investigate the neuroprotective mechanisms of original NQO2 inhibitor M-11 (2-[2-(3-oxomorpholin-4-il)-ethylthio]-5-ethoxybenzimidazole hydrochloride) in a cellular damage model using NQO2 endogenous substrate adrenochrome (125 µM) and co-substrate BNAH (100 µM). The effects of M-11 (10-100 µM) on the reactive oxygen species (ROS) generation, apoptosis and lesion of nuclear DNA were evaluated using flow cytometry and single-cell gel electrophoresis assay (comet assay).

Novel A-Ring Chalcone Derivatives of Oleanolic and Ursolic Amides with Anti-Proliferative Effect Mediated through ROS-Triggered Apoptosis.

A series of A-ring modified oleanolic and ursolic acid derivatives including C28 amides (3-oxo-C2-nicotinoylidene/furfurylidene, 3β-hydroxy-C2-nicotinoylidene, 3β-nicotinoyloxy-, 2-cyano-3,4-seco-4(23)-ene, indolo-, lactame and azepane) were synthesized and screened for their cytotoxic activity against the NCI-60 cancer cell line panel. The results of the first assay of thirty-two tested compounds showed that eleven derivatives exhibited cytotoxicity against cancer cells, and six of them were selected for complete dose-response studies. A systematic study of local SARs has been carried out by comparative analysis of potency distributions and similarity relationships among the synthesized compounds using network-like similarity graphs.

Involvement of Chaperone Sigma1R in the Anxiolytic Effect of Fabomotizole.

Sigma-1 receptor (chaperone Sigma1R) is an intracellular protein with chaperone functions, which is expressed in various organs, including the brain. Sigma1R participates in the regulation of physiological mechanisms of anxiety (Su, T. P.

Dimeric mimetic of BDNF loop 4 promotes survival of serum-deprived cell through TrkB-dependent apoptosis suppression.

Brain-derived neurotrophic factor (BDNF) is involved in the regulation of neuronal cell growth, differentiation, neuroprotection and synaptic plasticity. Although aberrant BDNF/TrkB signaling is implicated in several neurological, neurodegenerative and psychiatric disorders, neurotrophin-based therapy is challenging and is limited by improper pharmacokinetic properties of BDNF. Dimeric dipeptide compound GSB-106 (bis-(N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide) has earlier been designed to mimic the TrkB-interaction 4 loop of BDNF.

Cognitive Enhancer Noopept Activates Transcription Factor HIF-1.

The effect of noopept (N-phenylacetyl-L-prolyl-glycine ethyl ester) on the DNA-binding activity of HIF-1 in SH-SH5Y cells and the mechanisms of stabilization of this transcription factor were studied in vitro. Noopept was shown to increase both the basal DNA-binding activity of HIF-1 and the activity induced by various hypoxia mimetics. The mechanism of stabilization of the oxygen-sensitive HIF1α subunit by noopept involves the inhibition of HIF-1 prolyl hydroxylase, which is indirectly indicated by the data obtained using the ODD-Luc reporter, and the positive effect on the level of the HIF1α protein.

Chaperone Sigma1R and Antidepressant Effect.

This review analyzes the current scientific literature on the role of the Sigma1R chaperone in the pathogenesis of depressive disorders and pharmacodynamics of antidepressants. As a result of ligand activation, Sigma1R is capable of intracellular translocation from the endoplasmic reticulum (ER) into the region of nuclear and cellular membranes, where it interacts with resident proteins. This unique property of Sigma1R provides regulation of various receptors, ion channels, enzymes, and transcriptional factors.

Effect of Neuropeptide Cyclo-L-Prolylglycine on Cell Proliferative Activity.

Endogenous neuropeptide cyclo-L-prolylglycine possesses mnemotropic and neuroprotective properties, which can result from its positive effect on the level of brain-derived neurotrophic factor and modulation of activity of insulin-like growth factor-1 and AMPA receptors. For detection of possible mitogenic action of cyclo-L-prolylglycine, we analyzed its effect on proliferative activity of HEK293 and SH-SY5Y cells assessed by expression of Ki-67 proliferation marker, cell cycle examination, and incorporation of modified nucleotide analog EdU into DNA. Cyclo-L-prolylglycine did not affect the level of Ki-67 in examined cell lines and distribution of the cells over G1 and G2 phases of the cell cycle, although it insignificantly reduced the percentage of S phase cells, which attested to the absence of intrinsic mitogenic activity of the peptide.

Low-Molecular-Weight Compound GSB-106 Mimics the Cellular Effects of BDNF after Serum Deprivation.

The in vitro model of serum deprivation shows that the survival of SH-SY5Y neuronal cells is ensured by the intrinsic trophic activity of BDNF loop 4 mimetic GSB-106 (10 М), which is comparable to that of endogenous neurotrophin (10 М). The analysis of the cell cycle and S-phase showed that GSB-106, similarly to BDNF, induces the cell-cycle arrest in the G phase, diminishes the number of cells in the S-phase, reduces the number of apoptotic cells, and does not stimulate proliferation.

Effect of Fabomotizole on Brain Gene Expression in MR Rats in the Open Field Test.

Selective anxiolytic fabomotizole (Afobazol®) has affinity for the Sigma-1 chaperone receptor site, quinone reductase 2 (NQO2) and MAO-A regulatory sites, and melatonin receptor type 1 (MT receptor). The analysis of the effect of fabomotizole on the gene expression profile in the brain of MR (Maudsley Reactive) rats was carried out when modeling emotional stress in the open field test. A change in the expression of 14 genes was found, the results of the functional annotation of which showed that the mechanisms of action of fabomotizole may be associated with the regulation of translation of proteins (Rpl5, Rpl15, Ncl, and Ybx1), synaptic functions (Cplx2, Dlg4, Syngap1, Add1, Rab8b, Klc1, and Chn1), and cellular metabolism (Akr1d1, Bcat1, and Pkm).

[The role of glutamate in the pathogenesis of multiple sclerosis].

The results of recent studies indicate that the hyperactivation of the glutamatergic system plays an important role in the pathophysiology of multiple sclerosis (MS). In addition to the well-known direct toxic effect of the excessive extracellular level of the glutamate neurotransmitter on neurons, additional mechanisms of glutamate-induced cell damage have been described in the literature, including effects on oligodendrocytes, astrocytes, endothelial cells and immune cells. The study of these toxic effects will reveal the possible link between various pathological hallmarks of MS, such as axonal damage, oligodendrocyte death, demyelination, neurodegeneration, autoimmune reactions and dysfunction of blood-brain barrier.

Substituted Furanocoumarins as Novel Class of Antibacterial Translation Inhibitors.

Introduction: A variety of organic compounds has been reported to have antibacterial activity. However, antimicrobial resistance is one of the main problems of current anti-infective therapy, and the development of novel antibacterials is one of the main challenges of current drug discovery.

Methods: Using our previously developed dual-reporter High-Throughput Screening (HTS) platform, we identified a series of furanocoumarins as having high antibacterial activity.

Synthesis of new 1,3-thiazol derivatives of maleopimaric acid as anticancer, antibacterial and antifungal agents.

A series of new 1,3-thiazole derivatives of maleopimaric acid , were synthesized and evaluated for anticancer, antibacterial and antifungal activities. Evaluation of cytotoxic activity against human embryonic kidney 293 cells (HEK293), human neuroblastoma cell line (SH-SY5Y), hepatocellular carcinoma cell line (HepG2) and human T-cell lymphoblast-like line (Jurkat), showed that introduction of the aminothiazole fragment at position 6 of the diterpenoid molecule leads to decrease of cell viability. Substance 3 was found to be the most active against all tested cell lines, inhibiting cell viability with IC values in the range of 2-24 μM.

Large-scale High-throughput Screening Revealed 5'-(carbonylamino)-2,3'- bithiophene-4'-carboxylate as Novel Template for Antibacterial Agents.

Background: The key issue in the development of novel antimicrobials is a rapid expansion of new bacterial strains resistant to current antibiotics. Indeed, World Health Organization has reported that bacteria commonly causing infections in hospitals and in the community, e.g.

Identification of N-Substituted Triazolo-azetidines as Novel Antibacterials using pDualrep2 HTS Platform.

Aim And Objective: Antibiotic resistance is a serious constraint to the development of new effective antibacterials. Therefore, the discovery of the new antibacterials remains one of the main challenges in modern medicinal chemistry. This study was undertaken to identify novel molecules with antibacterial activity.

Identification of pyrrolo-pyridine derivatives as novel class of antibacterials.

A series of 5-oxo-4H-pyrrolo[3,2-b]pyridine derivatives was identified as novel class of highly potent antibacterial agents during an extensive large-scale high-throughput screening (HTS) program utilizing a unique double-reporter system-pDualrep2. The construction of the reporter system allows us to perform visual inspection of the underlying mechanism of action due to two genes-Katushka2S and RFP-which encode the proteins with different imaging signatures. Antibacterial activity of the compounds was evaluated during the initial HTS round and subsequent rescreen procedure.