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Bioorganic & Medicinal Chemistry Letters Sep 2020A novel unsymmetrical structural class of orally bioavailable hepatitis C virus (HCV) nonstructural 5A protein (NS5A) inhibitors has been generated by improving both the...
A novel unsymmetrical structural class of orally bioavailable hepatitis C virus (HCV) nonstructural 5A protein (NS5A) inhibitors has been generated by improving both the solubility and membrane permeability of the lead compound found in our previous work. The representative compound 14, with a 5-hydroxymethylpyrazine group and a 3-t-butylpropargyl group on each side of the molecule, exhibited the best oral bioavailability in this study, inhibiting not only the HCV genotype 1a, 1b, 2a, and 3a replicons with EC values in the picomolar range, but also inhibited 1a Q30 mutants induced by launched symmetrical inhibitors with EC values in the low nanomolar range.
Topics: Administration, Oral; Antiviral Agents; Genotype; Hepacivirus; Hepatitis C; Humans; Mutation; Pargyline; Pyrazines; Structure-Activity Relationship; Viral Nonstructural Proteins; Virus Replication
PubMed: 32738974
DOI: 10.1016/j.bmcl.2020.127361 -
Bioorganic Chemistry Nov 2019A series of eighteen 2-styrylchromone derivatives (see Chart 1) were synthesized and evaluated for their monoamine oxidase (MAO) A and B inhibitory activities. Many of...
A series of eighteen 2-styrylchromone derivatives (see Chart 1) were synthesized and evaluated for their monoamine oxidase (MAO) A and B inhibitory activities. Many of the derivatives inhibited MAO-B comparable to pargyline (a positive control), and most of them inhibited MAO-B selectively. Of the eighteen derivatives, compound 9 having methoxy group at R and chlorine at R showed both the best MAO-B inhibitory activity (IC = 17 ± 2.4 nM) and the best MAO-B selectivity (IC for MAO-A/IC for MAO-B = 1500). The mode of inhibition of compound 9 against MAO-B was competitive and reversible. Quantitative structure-activity relationship (QSAR) analyses of the 2-styrylchromone derivatives were conducted using their pIC values with the use of Molecular Operating Environment (MOE) and Dragon, demonstrating that the descriptors of MAO-B inhibitory activity and MAO-B selectivity were 1734 and 121, respectively, that showed significant correlations (P < 0.05). We then examined the 2-styrylchromone structures as useful scaffolds through three-dimensional-QSAR studies using AutoGPA, which is based on the molecular field analysis algorithm using MOE. The model using pIC value indexes for MAO-B exhibited a determination coefficient (R) of 0.873 as well as a Leave-One-Out cross-validated determination coefficient (Q) of 0.675. These data suggested that the 2-styrylchromone structure might be a useful scaffold for the design and development of novel MAO-B inhibitors.
Topics: Chromones; Dose-Response Relationship, Drug; Humans; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Quantitative Structure-Activity Relationship; Recombinant Proteins
PubMed: 31561103
DOI: 10.1016/j.bioorg.2019.103285 -
World Journal of Diabetes Dec 2020Benzylamine and methylamine activate glucose uptake in adipocytes. For tyramine, this effect has even been extended to cardiomyocytes.
BACKGROUND
Benzylamine and methylamine activate glucose uptake in adipocytes. For tyramine, this effect has even been extended to cardiomyocytes.
AIM
To investigate the effects of catecholamines and other amines on glucose uptake.
METHODS
A screening compared 25 biogenic amines on 2-deoxyglucose (2-DG) uptake activation in rat adipocytes. Pharmacological approaches and transgenic mouse models were then used to decipher the mode of action of several hits.
RESULTS
In rat adipocytes, insulin stimulation of 2-DG uptake was reproduced with catecholamines. 100 µmol/L or 1 mmol/L adrenaline, noradrenaline, dopamine and deoxyepinephrine, maximally activated hexose transport only when sodium orthovanadate was added at 100 µmol/L. Such activation was similar to that already reported for benzylamine, methylamine and tyramine, well-recognized substrates of semicarbazide-sensitive amine oxidase (SSAO) and monoamine oxidase (MAO). Several, but not all, tested agonists of β-adrenoreceptors (β-ARs) also activated glucose transport while α-AR agonists were inactive. Lack of blockade by α- and β-AR antagonists indicated that catecholamine-induced 2-DG uptake was not mediated by AR stimulation. Adipocytes from mice lacking β-, β- and β-ARs (triple KO) also responded to millimolar doses of adrenaline or noradrenaline by activating hexose transport in the presence of 100 µmol/L vanadate. The MAO blocker pargyline, and SSAO inhibitors did not block the effects of adrenaline or noradrenaline plus vanadate, which were blunted by antioxidants.
CONCLUSION
Catecholamines exert unexpected insulin-like actions in adipocytes when combined with vanadium. For limiting insulin resistance by activating glucose consumption at least in fat stores, we propose that catecholamine derivatives combined with vanadium can generate novel complexes that may have low toxicity and promising anti-diabetic properties.
PubMed: 33384769
DOI: 10.4239/wjd.v11.i12.622 -
Naunyn-Schmiedeberg's Archives of... Jul 2023It is unclear whether bufotenin (= N,N-dimethyl-serotonin = 5-hydroxy-N,N-dimethyl-tryptamine), a hallucinogenic drug, can act on human cardiac serotonin 5-HT...
It is unclear whether bufotenin (= N,N-dimethyl-serotonin = 5-hydroxy-N,N-dimethyl-tryptamine), a hallucinogenic drug, can act on human cardiac serotonin 5-HT receptors. Therefore, the aim of the study was to examine the cardiac effects of bufotenin and for comparison tryptamine in transgenic mice that only express the human 5-HT receptor in cardiomyocytes (5-HT-TG), in their wild-type littermates (WT) and in isolated electrically driven (1 Hz) human atrial preparations. In 5-HT-TG, we found that both bufotenin and tryptamine enhanced the force of contraction in left atrial preparations (pD2 = 6.77 or 5.5, respectively) and the beating rate in spontaneously beating right atrial preparations (pD2 = 7.04 or 5.86, respectively). Bufotenin (1 µM) increased left ventricular force of contraction and beating rate in Langendorff perfused hearts from 5-HT-TG, whereas it was inactive in hearts from WT animals, as was tryptamine. The positive inotropic and chronotropic effects of bufotenin and tryptamine were potentiated by an inhibitor of monoamine oxidases (50 µM pargyline). Furthermore, bufotenin concentration- (0.1-10 µM) and time-dependently elevated force of contraction in isolated electrically stimulated musculi pectinati from the human atrium and these effects were likewise reversed by tropisetron (10 µM). We found that bufotenin (10 µM) increased the phosphorylation state of phospholamban in the isolated perfused hearts, left and right atrial muscle strips of 5-HT-TG but not from WT and in isolated human right atrial preparations. In summary, we showed that bufotenin can increase the force of contraction via stimulation of human 5-HT receptors transgenic mouse cardiac preparations but notably also in human atrial preparations.
Topics: Mice; Animals; Humans; Serotonin; Mice, Transgenic; Bufotenin; Atrial Fibrillation; Myocardial Contraction; Receptors, Serotonin, 5-HT4; Heart Atria; Receptors, Serotonin
PubMed: 36754881
DOI: 10.1007/s00210-023-02414-8 -
Cellular Immunology Oct 2019Allergic diseases are increasing worldwide. Allergen and IgE dependent mast cell (MC) activation is the major initiator of these clinical symptoms. During this study,...
Allergic diseases are increasing worldwide. Allergen and IgE dependent mast cell (MC) activation is the major initiator of these clinical symptoms. During this study, the effect of multiple exposures to the same allergen, on MC degranulation was studied. First, MC recovery in terms of surface expression of high affinity receptor FcεRI, and granule content after a primary allergen challenge was confirmed. Overall, previous exposure of MCs to allergen challenge led to a significant reduction in pre-stored mediator release during the secondary challenge at various time points and with various doses of allergen in vitro. The dampened response was not due to any defects in very early steps in signalling involving FcεRI activation. Inhibition of dampening response during secondary challenge by various inhibitors like wortmannin, tranylcypromine and pargyline, indicated the involvement of PI3K signalling and chromatin modifications. Our study provides insight into new therapeutic avenues for treating allergic disorders targeting MCs.
Topics: Allergens; Animals; Bone Marrow Cells; Cell Degranulation; Cell Line, Tumor; Dose-Response Relationship, Immunologic; Epigenesis, Genetic; Histones; Hypersensitivity; Immune Tolerance; Mast Cells; Methylation; Mice; Mice, Inbred C57BL; Phosphatidylinositol 3-Kinase; Rats; Receptors, IgE; Signal Transduction; beta-N-Acetylhexosaminidases
PubMed: 31213284
DOI: 10.1016/j.cellimm.2019.103944 -
Molecules (Basel, Switzerland) Aug 2023Monoamine oxidase (MAO, EC 1.4.3.4) is responsible for the oxidative breakdown of both endogenous and exogenous amines and exists in MAO-A and MAO-B isomers. Eighteen...
Assembling a Cinnamyl Pharmacophore in the C3-Position of Substituted Isatins via Microwave-Assisted Synthesis: Development of a New Class of Monoamine Oxidase-B Inhibitors for the Treatment of Parkinson's Disease.
Monoamine oxidase (MAO, EC 1.4.3.4) is responsible for the oxidative breakdown of both endogenous and exogenous amines and exists in MAO-A and MAO-B isomers. Eighteen indole-based phenylallylidene derivatives were synthesized via nucleophilic addition reactions comprising three sub-series, , , and , and were developed and examined for their ability to inhibit MAO. Among them, compound showed a strong MAO-B inhibitory effect with an IC () value of 1.672 μM, followed by (IC = 16.934 μM). Additionally, showed the highest selectivity index (SI) value of >23.92. The effectiveness of was lower than the reference pargyline (0.14 μM); however, the SI value was higher than pargyline (17.16). Structurally, the (-H in the B-ring) sub-series exhibited relatively stronger MAO-B inhibition than the others. In the series, (-F in the A-ring) exhibited stronger MAO-B suppression than the other substituted derivatives in the order -F > -Br > -Cl > -OCH, -CH, and -H at the 2-position in the A-ring. In the reversibility and enzyme kinetics experiments, was a reversible inhibitor with a K value of 0.51 ± 0.15 μM for MAO-B. Further, it was observed that greatly decreased the cell death caused by rotenone in SH-SY5Y neuroblastoma cells. A molecular docking study of the lead molecule was also performed to determine hypothetical interactions in the enzyme-binding cavity. These findings suggest that is a strong, specific, and reversible MAO-B inhibitor that can be used to treat neurological diseases.
Topics: Humans; Parkinson Disease; Isatin; Microwaves; Molecular Docking Simulation; Pargyline; Pharmacophore; Neuroblastoma; Dopamine Agents; Monoamine Oxidase; Antipsychotic Agents
PubMed: 37630420
DOI: 10.3390/molecules28166167 -
Molekuliarnaia Biologiia 2021Fundamental neurophysiological processes are often studied using Danio rerio fish as a model. A selective inhibitor of striatal-enriched protein tyrosine phosphatase...
Fundamental neurophysiological processes are often studied using Danio rerio fish as a model. A selective inhibitor of striatal-enriched protein tyrosine phosphatase (STEP) reduces serotonin metabolism in the D. rerio brain. Both STEP and serotonin are involved in the development of neurodegenerative behavioral disorders. Reduction or elevation of the serotonin level in the brain of mice caused by the administration of p-chlorophenylalanine or pargyline, respectively, results in a decrease in the level of ptpn5 mRNA in the striatum, ptpn5 being the gene encoding STEP. However, it has not been established whether this occurs in other organisms. We studied the effect of inhibitors of synthesis (p-chlorophenylalanine) and degradation (pargyline) of serotonin on the expression of the ptpn5 gene and the activity of STEP in the brain of D. rerio. The fish were placed in water containing p-chlorophenylalanine (2 mg/L) or pargyline (0.5 mg/L) for 72 hours, and control subjects were kept in aquarium water. The p-chlorophenylalanine treatment decreased the serotonin level in the brain fourfold, whereas pargyline increased the level of this transmitter sixfold. Both p-chlorophenylalanine and pargyline decrease STEP activity in the D. rerio brain, without affecting the level of the ptpn5 mRNA gene. Thus, interaction between STEP and the serotonin system is observed in both mammals and fish, which indicates the similarity of the regulation processes in vertebrates.
Topics: Animals; Brain; Fenclonine; Mice; Pargyline; Protein Tyrosine Phosphatases; Zebrafish
PubMed: 34432783
DOI: 10.31857/S0026898421030113 -
Nucleic Acids Research Jan 2020One of the major hurdles in RNAi research has been the development of safe and effective delivery systems for siRNAs. Although various chemical modifications have been...
One of the major hurdles in RNAi research has been the development of safe and effective delivery systems for siRNAs. Although various chemical modifications have been proposed to improve their pharmacokinetic behaviour, their delivery to target cells and tissues presents many challenges. In this work, we implemented a receptor-targeting strategy to selectively deliver siRNAs to cancer cells using folic acid as a ligand. Folic acid is capable of binding to cell-surface folate receptors with high affinity. These receptors have become important molecular targets for cancer research as they are overexpressed in numerous cancers despite being expressed at low levels in normal tissues. Employing a post-column copper-catalyzed alkyne-azide cycloaddition (CuAAC), we report the synthesis of siRNAs bearing folic acid modifications at different positions within the sense strand. In the absence of a transfection carrier, these siRNAs were selectively taken up by cancer cells expressing folate receptors. We show that centrally modified folic acid-siRNAs display enhanced gene-silencing activity against an exogenous gene target (∼80% knockdown after 0.75 μM treatment) and low cytotoxicity. In addition, these siRNAs achieved potent dose-dependent knockdown of endogenous Bcl-2, an important anti-apoptotic gene.
Topics: Carbonates; Cell Survival; Folate Receptors, GPI-Anchored; Folic Acid; Gene Silencing; Gene Targeting; Genes, Reporter; HT29 Cells; HeLa Cells; Humans; Luciferases; Pargyline; Potassium; Protein Binding; Proto-Oncogene Proteins c-bcl-2; RNA, Small Interfering; Transfection
PubMed: 31777918
DOI: 10.1093/nar/gkz1115 -
ELife Nov 2020extensively modulates the host ubiquitin network to create the Legionella-containing vacuole (LCV) for its replication. Many of its virulence factors function as...
extensively modulates the host ubiquitin network to create the Legionella-containing vacuole (LCV) for its replication. Many of its virulence factors function as ubiquitin ligases or deubiquitinases (DUBs). Here, we identify Lem27 as a DUB that displays a preference for diubiquitin formed by K6, K11, or K48. Lem27 is associated with the LCV where it regulates Rab10 ubiquitination in concert with SidC and SdcA, two bacterial E3 ubiquitin ligases. Structural analysis of the complex formed by an active fragment of Lem27 and the substrate-based suicide inhibitor ubiquitin-propargylamide (PA) reveals that it harbors a fold resembling those in the OTU1 DUB subfamily with a Cys-His catalytic dyad and that it recognizes ubiquitin via extensive hydrogen bonding at six contact sites. Our results establish Lem27 as a DUB that functions to regulate protein ubiquitination on phagosomes by counteracting the activity of bacterial ubiquitin E3 ligases.
Topics: Amino Acid Motifs; Amino Acid Sequence; Bacterial Proteins; Deubiquitinating Enzymes; Legionella pneumophila; Pargyline; Phagosomes; Propylamines; Ubiquitin; Ubiquitin-Protein Ligases; Ubiquitination; Vacuoles
PubMed: 33136002
DOI: 10.7554/eLife.58114 -
The Journal of Organic Chemistry May 2022An efficient copper-catalyzed cascade annulation of -hydroxyphenyl propargylamines and pyrazolin-5-ones is described. This methodology leads to the rapid assembly of a...
An efficient copper-catalyzed cascade annulation of -hydroxyphenyl propargylamines and pyrazolin-5-ones is described. This methodology leads to the rapid assembly of a series of valuable pyrano[2,3-]pyrazoles with good yields across a wide range of substrates in a simple fashion. This novel reaction involves the formation of alkynyl -quinone methides, a 1,4-conjugate addition, and a subsequent 6-endo cyclization process. The mechanistic elucidation is well supported by control experiment and literature precedents.
Topics: Catalysis; Copper; Pargyline; Propylamines; Pyrazoles; Pyrazolones
PubMed: 35442039
DOI: 10.1021/acs.joc.2c00122