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[This corrects the article DOI: 10.1039/D3CB00126A.].
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Chiral oxygen-containing heterocyclic compounds are of great interest for the development of pharmaceuticals. Monoterpenes and their derivatives are naturally abundant precursors of novel synthetic chiral oxygen-containing heterocyclic compounds. In this study, acid catalyzed reactions of salicylic aldehydes with (-)-8-acetoxy-6-hydroxymethyllimonene, readily accessible from α-pinene, leads to the formation of chiral polycyclic products of various structural types. Three of the six isolated chiral heterocyclic products obtained from salicylic aldehyde contain previously unknown polycyclic ring types. Having carried out the reaction in the presence of Brønsted or Lewis acids (Amberlyst 15, trifluoromethanesulfonic acid, trifluoroacetic acid and boron trifluoride etherate) or aluminosilicates (montmorillonite K10, halloysite nanotubes), we found that the nature of products depends on the catalyst as well as the reaction conditions (reaction time, reactant ratio, presence or absence of solvent). Detailed mechanistic insight on the complex cascade reactions for product formation is provided with extensive experimental and quantum mechanical computational studies.
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At the Institute of Cytology and Genetics (Novosibirsk, Russia) for over 85 generations, gray rats have been selected for high aggression toward humans (aggressive rats) or its complete absence (tame rats). Aggressive rats are an interesting model for studying fear-induced aggression. Benzopentathiepin TC-2153 exerts an antiaggressive effect on aggressive rats and affects the serotonergic system: an important regulator of aggression. The aim of this study was to investigate effects of TC-2153 on key serotonergic-system enzymes - tryptophan hydroxylase 2 (TPH2) and monoamine oxidase A (MAOA) - in the brain of aggressive and tame rats. Either TC-2153 (10 or 20 mg/kg) or vehicle was administered once intraperitoneally to aggressive and tame male rats. TPH2 and MAOA enzymatic activities and mRNA and protein levels were assessed. The selection for high aggression resulted in upregulation of Tph2 mRNA in the midbrain, of the TPH2 protein in the hippocampus, and of proteins TPH2 and MAOA in the hypothalamus, as compared to tame rats. MAO enzymatic activity was higher in the midbrain and hippocampus of aggressive rats while TPH2 activity did not differ between the strains. The single TC-2153 administration decreased TPH2 and MAO activity in the hypothalamus and midbrain, respectively. The drug affected MAOA protein levels in the hypothalamus: upregulated them in aggressive rats and downregulated them in tame ones. Thus, this study shows profound differences in the expression and activity of key serotonergic system enzymes in the brain of rats selectively bred for either highly aggressive behavior toward humans or its absence, and the effects of benzopentathiepin TC-2153 on these enzymes may point to mechanisms of its antiaggressive action.
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Agresión , Encéfalo , Monoaminooxidasa , Triptófano Hidroxilasa , Animales , Triptófano Hidroxilasa/metabolismo , Triptófano Hidroxilasa/genética , Monoaminooxidasa/metabolismo , Monoaminooxidasa/genética , Ratas , Masculino , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Agresión/efectos de los fármacos , Humanos , Serotonina/metabolismoRESUMEN
Deoxycholic acid derivatives containing various heterocyclic functional groups at C-3 on the steroid scaffold were designed and synthesized as promising dual tyrosyl-DNA phosphodiesterase 1 and 2 (TDP1 and TDP2) inhibitors, which are potential targets to potentiate topoisomerase poison antitumor therapy. The methyl esters of DCA derivatives with benzothiazole or benzimidazole moieties at C-3 demonstrated promising inhibitory activity in vitro against TDP1 with IC50 values in the submicromolar range. Furthermore, methyl esters 4d-e, as well as their acid counterparts 3d-e, inhibited the phosphodiesterase activity of both TDP1 and TDP2. The combinations of compounds 3d-e and 4d-e with low-toxic concentrations of antitumor drugs topotecan and etoposide showed significantly greater cytotoxicity than the compounds alone. The docking of the derivatives into the binding sites of TDP1 and TDP2 predicted plausible binding modes of the DCA derivatives.
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Inhibidores de Fosfodiesterasa , Hidrolasas Diéster Fosfóricas , Inhibidores de Fosfodiesterasa/química , Hidrolasas Diéster Fosfóricas/metabolismo , Modelos Moleculares , Ácido Desoxicólico/farmacología , Relación Estructura-ActividadRESUMEN
Upon undergoing mucoid conversion within the lungs of cystic fibrosis patients, the pathogenic bacterium Pseudomonas aeruginosa synthesises copious quantities of the virulence factor and exopolysaccharide alginate. The enzyme guanosine diphosphate mannose dehydrogenase (GMD) catalyses the rate-limiting step and irreversible formation of the alginate sugar nucleotide building block, guanosine diphosphate mannuronic acid. Since there is no corresponding enzyme in humans, strategies that could prevent its mechanism of action could open a pathway for new and selective inhibitors to disrupt bacterial alginate production. Using virtual screening, a library of 1447 compounds within the Known Drug Space parameters were evaluated against the GMD active site using the Glide, FRED and GOLD algorithms. Compound hit evaluation with recombinant GMD refined the panel of 40 potential hits to 6 compounds which reduced NADH production in a time-dependent manner; of which, an usnic acid derivative demonstrated inhibition six-fold stronger than a previously established sugar nucleotide inhibitor, with an IC50 value of 17 µM. Further analysis by covalent docking and mass spectrometry confirm a single site of GMD alkylation.
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Two approaches to the synthesis of para-menthene epoxide ((1S,5S,6R)-4) are developed. The first approach includes a reaction between chlorohydrin 7 and NaH in THF. The second involves the formation of epoxide in the reaction of corresponding diacetate 6 with sodium tert-butoxide. One possible mechanism of this reaction is proposed to explain unexpected outcomes in the regio- and stereospecificity of epoxide (1S,5S,6R)-4 formation. The epoxide ring in (1S,5S,6R)-4 is then opened by various S- and O-nucleophiles. This series of reactions allows for the stereoselective synthesis of diverse derivatives of the monoterpenoid Prottremine 1, a compound known for its antiparkinsonian activity, including promising antiparkinsonian properties.
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Respiratory syncytial virus (RSV) is known to cause annual epidemics of respiratory infections; however, the lack of specific treatment options for this disease poses a challenge. In light of this, there has been a concerted effort to identify small molecules that can effectively combat RSV. This article focuses on the mechanism of action of compound K142, which was identified as a primary screening leader in the earlier stages of the project. The research conducted demonstrates that K142 significantly reduces the intensity of virus penetration into the cells, as well as the formation of syncytia from infected cells. These findings show that the compound's interaction with the surface proteins of RSV is a key factor in its antiviral activity. Furthermore, pharmacological modeling supports that K142 effectively interacts with the F-protein. However, in vivo studies have shown only weak antiviral activity against RSV infection, with a slight decrease in viral load observed in lung tissues. As a result, there is a need to enhance the bioavailability or antiviral properties of this compound. Based on these findings, we hypothesize that further modifications of the compound under study could potentially increase its antiviral activity.
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Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Infecciones del Sistema Respiratorio , Humanos , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Antivirales/farmacología , Disponibilidad BiológicaRESUMEN
Tyrosyl-DNA-phosphodiesterase 1 (TDP1) is an important enzyme in the DNA repair system. The ability of the enzyme to repair DNA damage induced by a topoisomerase 1 poison such as the anticancer drug topotecan makes TDP1 a promising target for complex antitumor therapy. In this work, a set of new 5-hydroxycoumarin derivatives containing monoterpene moieties was synthesized. It was shown that most of the conjugates synthesized demonstrated high inhibitory properties against TDP1 with an IC50 in low micromolar or nanomolar ranges. Geraniol derivative 33a was the most potent inhibitor with IC50 130 nM. Docking the ligands to TDP1 predicted a good fit with the catalytic pocket blocking access to it. The conjugates used in non-toxic concentration increased cytotoxicity of topotecan against HeLa cancer cell line but not against conditionally normal HEK 293A cells. Thus, a new structural series of TDP1 inhibitors, which are able to sensitize cancer cells to the topotecan cytotoxic effect has been discovered.
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Antineoplásicos , Topotecan , Humanos , Topotecan/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Inhibidores de Fosfodiesterasa/química , Relación Estructura-Actividad , Hidrolasas Diéster Fosfóricas/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Línea Celular TumoralRESUMEN
Azole antifungals, including fluconazole, have long been the first-line antifungal agents in the fight against fungal infections. The emergence of drug-resistant strains and the associated increase in mortality from systemic mycoses has prompted the development of new agents based on azoles. We reported a synthesis of novel monoterpene-containing azoles with high antifungal activity and low cytotoxicity. These hybrids demonstrated broad-spectrum activity against all tested fungal strains, with excellent minimum inhibitory concentration (MIC) values against both fluconazole-susceptible and fluconazole-resistant strains of Candida spp. Compounds 10a and 10c with cuminyl and pinenyl fragments demonstrated up to 100 times lower MICs than fluconazole against clinical isolates. The results indicated that the monoterpene-containing azoles had much lower MICs against fluconazole-resistant clinical isolates of Candida parapsilosis than their phenyl-containing counterpart. In addition, the compounds did not exhibit cytotoxicity at active concentrations in the MTT assay, indicating potential for further development as antifungal agents.
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The DNA repair system plays a crucial role in maintaining the integrity of the genome [...].
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Enzimas Reparadoras del ADN , Reparación del ADN , Enzimas Reparadoras del ADN/metabolismo , Genoma , Preparaciones Farmacéuticas , Daño del ADNRESUMEN
Respiratory syncytial virus (RSV) causes annual epidemics of respiratory infection. Usually harmless to adults, the RSV infection can be dangerous to children under 3 years of age and elderly people over 65 years of age, often causing serious problems, even death. At present, there are no vaccines and specific chemotherapeutic agents for the treatment of this disease, so the search for low-molecular weight compounds to combat RSV is a challenge. In this work, we have shown, for the first time, that monoterpene-substituted arylcoumarins are efficient RSV replication inhibitors at low micromolar concentrations. The most active compound has a selectivity index of about 200 and acts most effectively at the early stages of infection. The F protein of RSV is a potential target for these compounds, which is also confirmed by molecular docking and molecular dynamics simulation data.
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Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Niño , Humanos , Preescolar , Anciano , Simulación del Acoplamiento Molecular , Anticuerpos Antivirales , Proteínas Virales de Fusión , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Replicación ViralRESUMEN
Tyrosyl-DNA-phosphodiesterase 1 (TDP1) is a promising target for antitumor therapy; the use of TDP1 inhibitors with a topoisomerase 1 poison such as topotecan is a potential combination therapy. In this work, a novel series of 3,5-disubstituted thiazolidine-2,4-diones was synthesized and tested against TDP1. The screening revealed some active compounds with IC50 values less than 5 µM. Interestingly, compounds 20d and 21d were the most active, with IC50 values in the submicromolar concentration range. None of the compounds showed cytotoxicity against HCT-116 (colon carcinoma) and MRC-5 (human lung fibroblasts) cell lines in the 1-100 µM concentration range. Finally, this class of compounds did not sensitize cancer cells to the cytotoxic effect of topotecan.
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Inhibidores de Fosfodiesterasa , Hidrolasas Diéster Fosfóricas , Tiazolidinedionas , Humanos , Modelos Moleculares , Monoterpenos/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Topotecan/farmacología , Tiazolidinedionas/farmacologíaRESUMEN
The Bdnf (brain-derived neurotrophic factor) gene contains eight regulatory exons (I-VIII) alternatively spliced to the protein-coding exon IX. Only exons I, II, IV, and VI are relatively well studied. The BDNF system and brain serotonergic system are tightly interconnected and associated with aggression. The benzopentathiepine TC-2153 affects both systems and exerts antiaggressive action. Our aim was to evaluate the effects of TC-2153 on the Bdnf exons I-IX's expressions and serotonin receptors' mRNA levels in the brain of rats featuring high aggression toward humans (aggressive) or its absence (tame). Aggressive and tame adult male rats were treated once with vehicle or 10 or 20 mg/kg of TC-2153. mRNA was quantified in the cortex, hippocampus, hypothalamus, and midbrain with real-time PCR. Selective breeding for high aggression or its absence affected the serotonin receptors' and Bdnf exons' transcripts differentially, depending on the genotype (strain) and brain region. TC-2153 had comprehensive effects on the Bdnf exons' expressions. The main trend was downregulation in the hypothalamus and midbrain. TC-2153 increased 5-HT1B receptor hypothalamusc mRNA expression. For the first time, an influence of TC-2153 on the expressions of Bdnf regulatory exons and the 5-HT1B receptor was shown, as was an association between Bdnf regulatory exons and fear-induced aggression involving genetic predisposition.
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Factor Neurotrófico Derivado del Encéfalo , Receptor de Serotonina 5-HT1B , Humanos , Ratas , Animales , Masculino , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Receptor de Serotonina 5-HT1B/genética , Receptor de Serotonina 5-HT1B/metabolismo , Encéfalo/metabolismo , Miedo/fisiología , ARN Mensajero/análisis , Hipocampo/metabolismo , Agresión/fisiologíaRESUMEN
Parkinson's disease (PD) is the most common age-related movement disorder characterized by the progressive loss of nigrostriatal dopaminergic neurons. To date, PD treatment strategies are mostly based on dopamine replacement medicines, which can alleviate motor symptoms but do not slow down the progression of neurodegeneration. Thus, there is a need for disease-modifying PD therapies. The aim of this work was to evaluate the neuroprotective effects of the novel compound PA96 on dopamine neurons in vivo and in vitro, assess its ability to alleviate motor deficits in MPTP- and haloperidol-based PD models, as well as PK profile and BBB penetration. PA96 was synthesized from (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl) cyclohex-3-ene-1,2-diol (Prottremin) using the original three-step stereoselective procedure. We found that PA96: (1) supported the survival of cultured näive dopamine neurons; (2) supported the survival of MPP+-challenged dopamine neurons in vitro and in vivo; (3) had chemically appropriate properties (synthesis, solubility, etc.); (4) alleviated motor deficits in MPTP- and haloperidol-based models of PD; (5) penetrated the blood-brain barrier in vivo; and (6) was eliminated from the bloodstream relative rapidly. In conclusion, the present article demonstrates the identification of PA96 as a lead compound for the future development of this compound into a clinically used drug.
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Intoxicación por MPTP , Fármacos Neuroprotectores , Enfermedad de Parkinson , Animales , Ratones , Humanos , Neuronas Dopaminérgicas , Intoxicación por MPTP/tratamiento farmacológico , Monoterpenos/farmacología , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Haloperidol/farmacología , Sustancia NegraRESUMEN
The stability of a new coumarin derivative, agent K-142, bearing α-pinene residue and possessing antiviral activity against respiratory syncytial virus (RSV) was studied in whole mice blood in vitro, and a method for its quantification in this matrix was developed and validated. The sample preparation method was precipitation of whole blood with a mixture of 0.2 M ZnSO4 with MeOH (2:8 v/v) containing 2-adamantylamine hydrochloride as an internal standard (IS). Analysis was carried out by HPLC-MS/MS using reversed phase chromatography and a triple quadrupole mass spectrometer 6500 QTRAP (SCIEX) in multiple reaction monitoring (MRM) mode. The transitions 351.2 â 217.1 Da and 152.2 â 93.1/107.2 Da were monitored for K-142 and the IS, respectively. The method was validated in terms of selectivity, calibration curve, LLOQ, accuracy and precision, stability, recovery and carry over. The developed method was used for a pharmacokinetics study of the compound after its oral administration to mice at a dose of 20 mg/kg.
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The ability of actinobacteria of the genus Rhodococcus to biotransform the monoterpenoid (-)-isopulegol has been established for the first time. R. rhodochrous strain IEGM 1362 was selected as a bacterium capable of metabolizing (-)-isopulegol to form new, previously unknown, 10-hydroxy (2) and 10-carboxy (3) derivatives, which may presumably have antitumor activity and act as respiratory stimulants and cancer prevention agents. In the experiments, optimal conditions were selected to provide the maximum target catalytic activity of rhodococci. Using up-to-date (TEM, AFM-CLSM, and EDX) and traditional (cell size, roughness, and zeta potential measurements) biophysical and microbiological methods, it was shown that (-)-isopulegol and halloysite nanotubes did not negatively affect the bacterial cells. The data obtained expand our knowledge of the biocatalytic potential of rhodococci and their possible involvement in the synthesis of pharmacologically active compounds from plant derivatives.
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Tyrosyl-DNA phosphodiesterase 1(TDP1) is a promising target for a new therapy in oncological disease as an adjunct to topoisomerase 1 (TOP1) drugs. In this paper, novel thiazolidin-4-one derivatives with a benzyl and monoterpene substituents were synthesized. Compounds with a monoterpene fragment attached via a phenyloxy linker were active against TDP1 with IC50 values in the 1 ÷ 3 µM range, while direct attachment of monoterpene moiety to the thiazolidin-4-one fragment had no activity. Molecular modelling predicted two plausible binding modes of the active compounds both effectively blocking access to the catalytic site of TDP. At non-toxic concentrations the active ligands potentiated the efficacy of the TOP1 poison topotecan in human cervical cancer HeLa cells, but not in non-cancerous HEK293A cells.
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Inhibidores de Fosfodiesterasa , Hidrolasas Diéster Fosfóricas , Esterasas/metabolismo , Células HeLa , Humanos , Monoterpenos/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Relación Estructura-ActividadRESUMEN
Inhibiting tyrosyl-DNA phosphodiesterase 1 (TDP1) is a promising strategy for increasing the effectiveness of existing antitumor therapy since it can remove the DNA lesions caused by anticancer drugs, which form covalent complexes with topoisomerase 1 (TOP1). Here, new adamantane-monoterpene conjugates with a 1,2,4-triazole or 1,3,4-thiadiazole linker core were synthesized, where (+)-and (-)-campholenic and (+)-camphor derivatives were used as monoterpene fragments. The campholenic derivatives 14a-14b and 15a-b showed activity against TDP1 at a low micromolar range with IC50 ~5-6 µM, whereas camphor-containing compounds 16 and 17 were ineffective. Surprisingly, all the compounds synthesized demonstrated a clear synergy with topotecan, a TOP1 poison, regardless of their ability to inhibit TDP1. These findings imply that different pathways of enhancing topotecan toxicity other than the inhibition of TDP1 can be realized.
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Adamantano , Antineoplásicos , Adamantano/farmacología , Antineoplásicos/farmacología , Alcanfor , Monoterpenos/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Topotecan/farmacologíaRESUMEN
The zebrafish is a promising model species in biomedical research, including neurotoxicology and neuroactive drug screening. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) evokes degeneration of dopaminergic neurons and is commonly used to model Parkinson's disease (PD) in laboratory animals, including zebrafish. However, cognitive phenotypes in MPTP-evoked experimental PD models remain poorly understood. Here, we established an LD50 (292 mg/kg) for intraperitoneal MPTP administration in adult zebrafish, and report impaired spatial working memory (poorer spontaneous alternation in the Y-maze) in a PD model utilizing fish treated with 200 µg of this agent. In addition to conventional behavioral analyses, we also employed artificial intelligence (AI)-based approaches to independently and without bias characterize MPTP effects on zebrafish behavior during the Y-maze test. These analyses yielded a distinct cluster for 200-µg MPTP (vs. other) groups, suggesting that high-dose MPTP produced distinct, computationally detectable patterns of zebrafish swimming. Collectively, these findings support MPTP treatment in adult zebrafish as a late-stage experimental PD model with overt cognitive phenotypes.
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Striatal-enriched protein tyrosine phosphatase (STEP) is a signal transduction protein involved in the pathogenesis of neuropathologies. A STEP inhibitor (TC-2153) has antipsychotic and antidepressant effects. Here, we evaluated the role of STEP in fear-induced aggression using Norway rats selectively bred for 90 generations for either high aggression toward humans (aggressive rats) or its absence (tame rats). We studied the effects of acute administration of TC-2153 on behavior and STEP expression in the brain of these animals and the influence of chronic treatment with TC-2153 on the behavior and STEP expression in aggressive rats in comparison with classic antidepressant fluoxetine, which is known to exert antiaggressive action. Acute TC-2153 administration decreased the aggressive reaction to humans in aggressive rats, while having no impact on the friendly behavior of tame rats. Moreover, in the elevated plus-maze test, the drug had an anxiolytic effect on both aggressive and tame rats. Aggressive rats demonstrated elevated levels of a STEP isoform (STEP46) as compared to tame animals, whereas acute TC-2153 administration significantly reduced STEP46 protein concentration in the brain of aggressive rats. Chronic treatment of aggressive rats with either TC-2153 or fluoxetine attenuated fear-induced aggression. Chronic administration of fluoxetine enhanced the exploratory activity in the elevated plus-maze test and decreased the STEP46 protein level in aggressive rats' hippocampus, whereas chronic TC-2153 administration did not affect these parameters. Thus, STEP46 can play an important role in the mechanisms of aggression and may mediate antiaggressive effects of TC-2153 and fluoxetine.