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Organic Letters Jul 2021We report here a three-component, Cu(I)-catalyzed hexadehydro-Diels-Alder (HDDA) benzyne 1,2-difunctionalization reaction. This protocol allowed the introduction of two...
We report here a three-component, Cu(I)-catalyzed hexadehydro-Diels-Alder (HDDA) benzyne 1,2-difunctionalization reaction. This protocol allowed the introduction of two different carbon-based substituents onto the in situ-generated benzyne. These substituents were terminal monoynes or diynes partnered with propargylic, benzylic, or allylic chlorides. An example of a sequential HDDA reaction is demonstrated using the product of a 1,3-diyne and a propargylic halide, itself a newly created HDDA precursor.
Topics: Benzene Derivatives; Catalysis; Copper; Cycloaddition Reaction; Diynes; Molecular Structure; Pargyline
PubMed: 34180676
DOI: 10.1021/acs.orglett.1c01788 -
Dalton Transactions (Cambridge, England... Mar 2024Three pargyline-phosphine copper(I) clusters, [Cu(CC-CHN)(PPh)](PF) (1) and [Cu(CC-CHN)(dppy)](X) (dppy = diphenyl-2-pyridylphosphine; X = PF for 2 and X = ClO for...
Three pargyline-phosphine copper(I) clusters, [Cu(CC-CHN)(PPh)](PF) (1) and [Cu(CC-CHN)(dppy)](X) (dppy = diphenyl-2-pyridylphosphine; X = PF for 2 and X = ClO for 3), were synthesized. Their structures were fully characterized using various spectroscopic methods and X-ray crystallography, which showed that the stoichiometry and nature of pargyline and phosphine ligands play an important role in tuning the structure and photophysical features of Cu(I) clusters. Interestingly, clusters 1, 2 and 3 exhibited red, orange and yellow phosphorescence with high quantum yields of 88.5%, 22.0% and 40.2%, respectively, at room temperature. Moreover, clusters 1-3 show distinct temperature-dependent emissions. The excellent luminescence performance of 1 and 3 was designed and employed for the construction of monochrome and white light-emitting devices (LEDs).
PubMed: 38469690
DOI: 10.1039/d4dt00022f -
PeerJ 2016Harmine is the -carboline alkaloid with the highest concentration in the psychotropic plant decoction Ayahuasca. In rodents, classical antidepressants reverse the...
Harmine is the -carboline alkaloid with the highest concentration in the psychotropic plant decoction Ayahuasca. In rodents, classical antidepressants reverse the symptoms of depression by stimulating neuronal proliferation. It has been shown that Ayahuasca presents antidepressant effects in patients with depressive disorder. In the present study, we investigated the effects of harmine in cell cultures containing human neural progenitor cells (hNPCs, 97% nestin-positive) derived from pluripotent stem cells. After 4 days of treatment, the pool of proliferating hNPCs increased by 71.5%. Harmine has been reported as a potent inhibitor of the dual specificity tyrosine-phosphorylation-regulated kinase (DYRK1A), which regulates cell proliferation and brain development. We tested the effect of analogs of harmine, an inhibitor of DYRK1A (INDY), and an irreversible selective inhibitor of monoamine oxidase (MAO) but not DYRK1A (pargyline). INDY but not pargyline induced proliferation of hNPCs similarly to harmine, suggesting that inhibition of DYRK1A is a possible mechanism to explain harmine effects upon the proliferation of hNPCs. Our findings show that harmine enhances proliferation of hNPCs and suggest that inhibition of DYRK1A may explain its effects upon proliferation and antidepressant effects .
PubMed: 27957390
DOI: 10.7717/peerj.2727 -
Bioorganic & Medicinal Chemistry Letters Aug 2021Twenty six propargylamine mycophenolate analogues were designed and synthesized from mycophenolic acid 1 employing a key step A-coupling reaction. Their cytotoxic...
Twenty six propargylamine mycophenolate analogues were designed and synthesized from mycophenolic acid 1 employing a key step A-coupling reaction. Their cytotoxic activity was examined against six cancer cell lines. Compounds 6a, 6j, 6t, 6u, and 6z exhibited selective cytotoxicity towards neuroblastoma (SH-SY5Y) cancer cells and were less toxic to normal cells in comparison to the lead compound, MPA 1 and a standard drug, ellipticine. Molecular docking results suggested that compound 6a is fit well in the key amino acid of three proteins (CDK9, EGFR, and VEGFR-2) as targets in cancer therapy. The propargylamine mycophenolate scaffold might be a valuable starting point for development of new neuroblastoma anticancer drugs.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Molecular Structure; Mycophenolic Acid; Neuroblastoma; Pargyline; Propylamines; Structure-Activity Relationship
PubMed: 34044119
DOI: 10.1016/j.bmcl.2021.128135 -
Frontiers in Pharmacology 2021Monoamine oxidases (MAO) are a valuable class of mitochondrial enzymes with a critical role in neuromodulation. In this study, we investigated the effect of natural MAO...
Monoamine oxidases (MAO) are a valuable class of mitochondrial enzymes with a critical role in neuromodulation. In this study, we investigated the effect of natural MAO inhibitors on novel environment-induced anxiety by using the zebrafish novel tank test (NTT). Because zebrafish spend more time at the bottom of the tank when they are anxious, anxiolytic compounds increase the time zebrafish spend at the top of the tank and vice versa. Using this paradigm, we found that harmane, norharmane, and 1,2,3,4-tetrahydroisoquinoline (TIQ) induce anxiolytic-like effects in zebrafish, causing them to spend more time at the top of the test tank and less time at the bottom. 2,3,6-trimethyl-1,4-naphtoquinone (TMN) induced an interesting mix of both anxiolytic- and anxiogenic-like effects during the first and second halves of the test, respectively. TIQ was unique in having no observable effect on general movement. Similarly, a reference MAO inhibitor clorgyline-but not pargyline-increased the time spent at the top in a concentration-dependent manner. We also demonstrated that the brain bioavailability of these compounds are high based on the bioavailability assay and in silico prediction models, which support the notion that the observed effects on anxiety-like behavior in zebrafish were most likely due to the direct effect of these compounds in the brain. This study is the first investigation to demonstrate the anxiolytic-like effects of MAO inhibitors on novel environment-induced anxiety in zebrafish.
PubMed: 34079463
DOI: 10.3389/fphar.2021.669370 -
Environmental Science and Pollution... Feb 2021Urban particulate matter (PM), a great danger to public health, is associated with increasing risk of pulmonary diseases. However, the involved key genes and signaling...
Urban particulate matter (PM), a great danger to public health, is associated with increasing risk of pulmonary diseases. However, the involved key genes and signaling pathways mediating the cellular responses to urban PM are largely unknown. In this study, human bronchial epithelial cells BEAS-2B was exposed to Standard reference material (SRM) 1649b, followed by RNA-sequencing (RNA-seq) and a combination of different bioinformatics analysis. A total of 201 genes (111 upregulated and 90 downregulated) were identified as the differentially expressed genes (DEGs). Moreover, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) unveiled several significant genes and pathways involved in PM-induced lung toxicity. Protein-protein interaction (PPI) network was performed with the Search Tool for the Retrieval of Interacting Genes (STRING), and the hub gene modules were recognized by Molecular Complex Detection (MCODE), a plug-in of Cytoscape. Moreover, Connectivity Map (CMap) analysis found six candidate small molecular compounds to reverse PM-altered gene expression, including aminohippuric acid, captopril, cinoxacin, fasudil, pargyline, and altizide. Finally, the expressions of part vital genes related to inflammation (IL-1β, CXCL2, CXCL5, CXCL8), ferroptosis (HMOX1, GCLM), and autophagy (BECN1, MAPK1LC3B) were in accordance with the RNA-seq data, with a concentration-dependent manner. This study may be helpful in revealing the complex molecular mechanisms underlying PM-induced lung toxicity and provide some new therapeutic targets for PM-related pulmonary diseases.
Topics: Epithelial Cells; Gene Expression Profiling; Gene Ontology; Humans; Particulate Matter; Transcriptome
PubMed: 33150508
DOI: 10.1007/s11356-020-11347-1 -
Neuropharmacology May 2018Methamphetamine and mephedrone are designer drugs with high abuse liability and they share extensive similarities in their chemical structures and neuropharmacological...
Methamphetamine and mephedrone are designer drugs with high abuse liability and they share extensive similarities in their chemical structures and neuropharmacological effects. However, these drugs differ in one significant regard: methamphetamine elicits dopamine neurotoxicity and mephedrone does not. From a structural perspective, mephedrone has a β-keto group and a 4-methyl ring addition, both of which are lacking in methamphetamine. Our previous studies found that methcathinone, which contains only the β-keto substituent, is neurotoxic, while 4-methylmethamphetamine, which contains only the 4-methyl ring substituent, elicits minimal neurotoxicity. In the present study, it was hypothesized that the varying neurotoxic potential associated with these compounds is mediated by the drug-releasable pool of dopamine, which may be accessed by methamphetamine more readily than mephedrone, methcathinone, and 4-methylmethamphetamine. To test this hypothesis, l-DOPA and pargyline, compounds known to increase both the releasable pool of dopamine and methamphetamine neurotoxicity, were combined with mephedrone, 4-methylmethamphetamine and methcathinone. Methamphetamine was also tested because of its ability to increase releasable dopamine. All three regimens significantly enhanced striatal neurotoxicity and glial reactivity for 4-methylmethamphetamine. Methcathinone neurotoxicity and glial reactivity were enhanced only by l-DOPA. Mephedrone remained non-neurotoxic when combined with either l-DOPA or pargyline. Body temperature effects of each designer drug were not altered by the combined treatments. These results support the conclusion that the neurotoxicity of 4-methylmethamphetamine, methcathinone and methamphetamine may be differentially regulated by the drug-releasable pool of dopamine due to β-keto and 4-methyl substituents, but that mephedrone remains non-neurotoxic despite large increases in this pool of dopamine. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'
Topics: Analysis of Variance; Animals; Body Temperature; Brain; Designer Drugs; Disease Models, Animal; Dopamine; Dopamine Plasma Membrane Transport Proteins; Drug Synergism; Female; Methamphetamine; Mice; Mice, Inbred C57BL; Neuroglia; Neurotoxicity Syndromes; Propiophenones; Tyrosine 3-Monooxygenase
PubMed: 28851615
DOI: 10.1016/j.neuropharm.2017.08.033 -
American Journal of Physiology. Heart... Jan 2017The aim of this study was to examine the accumulation of serotonin (5-HT) and degradation of 5-HT taken up into cells in the ischemic region during myocardial...
UNLABELLED
The aim of this study was to examine the accumulation of serotonin (5-HT) and degradation of 5-HT taken up into cells in the ischemic region during myocardial ischemia-reperfusion. Using microdialysis technique in anesthetized rats, we monitored myocardial interstitial levels of 5-HT and its metabolite produced by monoamine oxidase (MAO), 5-hydroxyindole acetic acid (5-HIAA), during 30-min coronary occlusion followed by 45-min reperfusion, and investigated the effects of local administration of the MAO inhibitor pargyline and the 5-HT uptake inhibitor fluoxetine. In the vehicle group, the dialysate 5-HT concentration increased from 1.3 ± 0.2 nM at baseline to 29.6 ± 2.8 nM at 22.5-30 min of occlusion, but the dialysate 5-HIAA concentration did not change from baseline (9.9 ± 1.1 nM). Upon reperfusion, the dialysate 5-HT concentration increased further to a peak (34.2 ± 4.2 nM) at 0-7.5 min and then declined. The dialysate 5-HIAA concentration increased to 31.9 ± 5.2 nM at 7.5-15 min of reperfusion and maintained this high level until 45 min. Pargyline markedly suppressed the increase in dialysate 5-HIAA concentration after reperfusion and increased the averaged dialysate 5-HT concentration during the reperfusion period. Fluoxetine suppressed the increase in dialysate 5-HT concentration during occlusion but did not change dialysate 5-HT or 5-HIAA concentration after reperfusion. During ischemia, 5-HT secreted from ischemic tissues accumulates but 5-HT degradation by MAO is suppressed. After reperfusion, degradation of 5-HT taken up into cells is enhanced and contributes to the clearance of accumulated 5-HT. This degradation following cellular uptake is dependent on MAO activity but not the fluoxetine-sensitive uptake transporter.
NEW & NOTEWORTHY
By monitoring myocardial interstitial levels of 5-HT and its metabolite, 5-hydroxyindole acetic acid, we investigated 5-HT kinetics during myocardial ischemia-reperfusion. 5-HT accumulates but 5-HT degradation is suppressed during ischemia. After reperfusion, 5-HT degradation is enhanced and this degradation is dependent on monoamine oxidase activity but not fluoxetine-sensitive uptake transporter.
Topics: Animals; Coronary Occlusion; Fluoxetine; Hydroxyindoleacetic Acid; Male; Microdialysis; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Myocardial Reperfusion Injury; Myocardium; Pargyline; Rats; Rats, Wistar; Serotonin; Selective Serotonin Reuptake Inhibitors
PubMed: 27793854
DOI: 10.1152/ajpheart.00471.2016 -
Carbohydrate Research Oct 2019This work combined three classes of compounds in the same molecule "amino triazole-glycoside" and developed a convenient method for the synthesis of this type of...
This work combined three classes of compounds in the same molecule "amino triazole-glycoside" and developed a convenient method for the synthesis of this type of compound via a one-pot two step reaction. Alkylation of amine derivatives with propargyl bromide to give propargylamine was performed in the first step subsequently followed by a 'click' reaction with various β-azido-glycosides in the presence of CuI in aqueous solution to provide β-amino triazole-glycosides. Thirty-two examples of glycosides were obtained in moderate to good yield using this one-pot procedure.
Topics: Alkylation; Amines; Carbohydrate Sequence; Click Chemistry; Glycosides; Pargyline; Propylamines; Triazoles
PubMed: 31479870
DOI: 10.1016/j.carres.2019.107780 -
ACS Chemical Biology Sep 2021Ubiquitin activity-based probes have proven invaluable in elucidating structural mechanisms in the ubiquitin system by stabilizing transient macromolecular complexes of...
Ubiquitin activity-based probes have proven invaluable in elucidating structural mechanisms in the ubiquitin system by stabilizing transient macromolecular complexes of deubiquitinases, ubiquitin-activating enzymes, and the assemblies of ubiquitin-conjugating enzymes with ubiquitin ligases of the RING-Between-RING and RING-Cysteine-Relay families. Here, we demonstrate that an activity-based probe, ubiquitin-propargylamine, allows for the preparative reconstitution and structural analysis of the interactions between ubiquitin and certain HECT ligases. We present a crystal structure of the ubiquitin-linked HECT domain of HUWE1 that defines a catalytically critical conformation of the C-terminal tail of the ligase for the transfer of ubiquitin to an acceptor protein. Moreover, we observe that ubiquitin-propargylamine displays selectivity among HECT domains, thus corroborating the notion that activity-based probes may provide entry points for the development of specific, active site-directed inhibitors and reporters of HECT ligase activities.
Topics: Amino Acid Sequence; Catalysis; Catalytic Domain; Cysteine; Humans; Models, Molecular; Pargyline; Propylamines; Protein Conformation; Structure-Activity Relationship; Substrate Specificity; Ubiquitin; Ubiquitin-Conjugating Enzymes; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 34403242
DOI: 10.1021/acschembio.1c00433