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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 -
Organic Letters Jun 2023Base-mediated rearrangement of 1,3-dithianyl-substituted propargylamines in DMF via expansion of the dithiane ring has been reported. The rearrangement provided...
Base-mediated rearrangement of 1,3-dithianyl-substituted propargylamines in DMF via expansion of the dithiane ring has been reported. The rearrangement provided 9-membered amino-functionalized sulfur-containing heterocycles (dithionine derivatives) in good yields under mild conditions. Propargylamines bearing 5-membered 1,3-dithiolane and 7-membered 1,3-dithiepane rings rearranged in a similar manner yielding 8- and 10-membered -heterocycles, respectively.
Topics: Sulfur; Propylamines; Pargyline; Culture Media
PubMed: 37232086
DOI: 10.1021/acs.orglett.3c01118 -
Pharmaceuticals (Basel, Switzerland) Mar 2020Treatment with several antipsychotic drugs exhibits a tendency to induce weight gain and diabetic complications. The proposed mechanisms by which the atypical...
Opipramol Inhibits Lipolysis in Human Adipocytes without Altering Glucose Uptake and Differently from Antipsychotic and Antidepressant Drugs with Adverse Effects on Body Weight Control.
Treatment with several antipsychotic drugs exhibits a tendency to induce weight gain and diabetic complications. The proposed mechanisms by which the atypical antipsychotic drug olanzapine increases body weight include central dysregulations leading to hyperphagia and direct peripheral impairment of fat cell lipolysis. Several investigations have reproduced in vitro direct actions of antipsychotics on rodent adipocytes, cultured preadipocytes, or human adipose tissue-derived stem cells. However, to our knowledge, no such direct action has been described in human mature adipocytes. The aim of the present study was to compare in human adipocytes the putative direct alterations of lipolysis by antipsychotics (haloperidol, olanzapine, ziprazidone, risperidone), antidepressants (pargyline, phenelzine), or anxiolytics (opipramol). Lipolytic responses to the tested drugs, and to recognized lipolytic (e.g., isoprenaline) or antilipolytic agents (e.g., insulin) were determined, together with glucose transport and amine oxidase activities in abdominal subcutaneous adipocytes from individuals undergoing plastic surgery. None of the tested drugs were lipolytic. Surprisingly, only opipramol exhibited substantial antilipolytic properties in the micromolar to millimolar range. An opipramol antilipolytic effect was evident against isoprenaline-, forskolin-, or atrial natriuretic peptide-stimulated lipolysis. Opipramol did not impair insulin activation of glucose transport but inhibited monoamine oxidase (MAO) activity to the same extent as antidepressants recognized as MAO inhibitors (pargyline, harmine, or phenelzine), whereas antipsychotics were inefficient. Considering its unique properties, opipramol, which is not associated with weight gain in treated patients, is a good candidate for drug repurposing because it limits exaggerated lipolysis, prevents hydrogen peroxide release by amine oxidases in adipocytes, and is thereby of potential use to limit lipotoxicity and oxidative stress, two deleterious complications of diabetes and obesity.
PubMed: 32151075
DOI: 10.3390/ph13030041 -
Journal of the American Chemical Society May 2021Terminal unactivated alkynes are nowadays considered the golden standard for cysteine-reactive warheads in activity-based probes (ABPs) targeting cysteine...
Terminal unactivated alkynes are nowadays considered the golden standard for cysteine-reactive warheads in activity-based probes (ABPs) targeting cysteine deubiquitinating enzymes (DUBs). In this work, we study the versatility of the thiol-alkyne addition reaction in more depth. Contrary to previous findings with UCHL3, we now show that covalent adduct formation can progress with substituents on the terminal or internal alkyne position. Strikingly, acceptance of alkyne substituents is strictly DUB-specific as this is not conserved among members of the same subfamily. Covalent adduct formation with the catalytic cysteine residue was validated by gel analysis and mass spectrometry of intact ABP-treated USP16CD and catalytically inactive mutant USP16CD. Bottom-up mass spectrometric analysis of the covalent adduct with a deuterated propargyl ABP provides mechanistic understanding of the thiol-alkyne reaction, identifying the alkyne rather than an allenic intermediate as the reactive species. Furthermore, kinetic analysis revealed that introduction of (bulky/electron-donating) methyl substituents on the propargyl moiety decreases the rate of covalent adduct formation, thus providing a rational explanation for the commonly lower level of observed covalent adduct compared to unmodified alkynes. Altogether, our work extends the scope of possible propargyl derivatives in cysteine targeting ABPs from unmodified terminal alkynes to internal and substituted alkynes, which we anticipate will have great value in the development of ABPs with improved selectivity profiles.
Topics: Alkynes; Cysteine Proteases; Deubiquitinating Enzymes; HEK293 Cells; Humans; Pargyline; Propylamines; Sulfhydryl Compounds; Ubiquitin Thiolesterase
PubMed: 33885283
DOI: 10.1021/jacs.0c10513 -
Molecules (Basel, Switzerland) May 2024A versatile family of quaternary propargylamines was synthesized employing the KA multicomponent reaction, through the single-step coupling of a number of amines,...
A versatile family of quaternary propargylamines was synthesized employing the KA multicomponent reaction, through the single-step coupling of a number of amines, ketones, and terminal alkynes. Sustainable synthetic procedures using transition metal catalysts were employed in all cases. The inhibitory activity of these molecules was evaluated against human monoaminoxidase (hMAO)-A and hMAO-B enzymes and was found to be significant. The IC values for hMAO-B range from 152.1 to 164.7 nM while the IC values for hMAO-A range from 765.6 to 861.6 nM. Furthermore, these compounds comply with Lipinski's rule of five and exhibit no predicted toxicity. To understand their binding properties with the two target enzymes, key interactions were studied using molecular docking, all-atom molecular dynamics (MD) simulations, and MM/GBSA binding free energy calculations. Overall, herein, the reported family of propargylamines exhibits promise as potential treatments for neurodegenerative disorders, such as Parkinson's disease. Interestingly, this is the first time a propargylamine scaffold bearing an internal alkyne has been reported to show activity against monoaminoxidases.
Topics: Alkynes; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Pargyline; Propylamines; Structure-Activity Relationship; Molecular Structure
PubMed: 38893361
DOI: 10.3390/molecules29112486 -
Journal of the American Chemical Society Sep 2020An efficient catalytic method to convert an α-C-H bond of -alkylamines into an α-C-alkynyl bond was developed. In the past, such transformations were carried out under...
Direct Conversion of -Alkylamines to -Propargylamines through C-H Activation Promoted by Lewis Acid/Organocopper Catalysis: Application to Late-Stage Functionalization of Bioactive Molecules.
An efficient catalytic method to convert an α-C-H bond of -alkylamines into an α-C-alkynyl bond was developed. In the past, such transformations were carried out under oxidative conditions, and the enantioselective variants were confined to tetrahydroisoquinoline derivatives. Here, we disclose a method for the union of -alkylamines and trimethylsilyl alkynes, without the presence of an external oxidant and promoted through cooperative actions of two Lewis acids, B(CF) and a Cu-based complex. A variety of propargylamines can be synthesized in high diastereo- and enantioselectivity. The utility of the approach is demonstrated by the late-stage site-selective modification of bioactive amines. Kinetic investigations that shed light on various mechanistic nuances of the catalytic process are presented.
Topics: Amines; Catalysis; Copper; Lewis Acids; Molecular Structure; Organometallic Compounds; Pargyline; Propylamines; Stereoisomerism
PubMed: 32830966
DOI: 10.1021/jacs.0c08599