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Organic & Biomolecular Chemistry May 2021An Ag(i)-catalyzed tandem addition-cyclization of isothiocyanate and propargylamine was successfully applied to the synthesis of 2-amino-4-methylenethiazolines. This...
An Ag(i)-catalyzed tandem addition-cyclization of isothiocyanate and propargylamine was successfully applied to the synthesis of 2-amino-4-methylenethiazolines. This route features an unprecedented fast reaction rate with full conversion reached within 10 min at room temperature for aromatic isothiocyanates and excellent chemoselectivity for exocyclic products. The application of this strategy is further highlighted by the accelerated bioconjugation of propargylamine with fluorescein isothiocyanate (FITC) under Ag(i)-catalysis.
Topics: Pargyline; Propylamines
PubMed: 33978054
DOI: 10.1039/d1ob00464f -
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 -
Neurochemistry International May 2021Monoamine oxidase (MAO) enzymes, type A and B metabolise the amine neurotransmitters of the body. Selective inhibition of either enzyme is an approach for treating...
Monoamine oxidase (MAO) enzymes, type A and B metabolise the amine neurotransmitters of the body. Selective inhibition of either enzyme is an approach for treating neurodegenerative and stress-induced disorders, and inhibition of an enzyme is proportional to the binding of the MAO inhibitor. Conventionally, the binding of test compounds to enzymes is assessed by radiolabelled ligands in ex vivo and in vivo occupancy assays. Regulatory restrictions and turnaround time are the limitations of the methods that use radiolabelled ligands. But the use of non-radiolabelled tracers and sensitive mass spectrometry (LC-MS/MS) based assays accelerated the determination of target occupancy in pre-clinical species. A report on use of non-radiolabelled ligand in in vivo MAO occupancy assay is not available. The objectives of the present study were to optimise non-radiolabelled harmine and deprenyl as selective tracers in MAO-A and MAO-B occupancy assays and evaluate MAO occupancy of test compounds in rat brain. Tracer optimisation resulted in a detectable, stable, and low ratio (<3.0) of tracer concentrations between any two brain tissues. In occupancy assay, tracer was intravenously administered (10 μg/kg, harmine or 60 μg/kg, L-deprenyl) after the treatment with test compound (clorgyline or tranylcypromine or pargyline or phenelzine or thioperamide). Specific brain tissues were isolated at a defined interval and tracer concentrations were quantified using LC-MS/MS method. Pre-treatment with MAO inhibitors resulted in a decrease (maximum, 80-85%) in harmine or an increase (maximum, 85-300%) in L-deprenyl concentrations. But we considered the change in tracer concentration, relative to the vehicle and positive control groups to calculate MAO occupancy. The observed selectivity and ratio of occupancies (ED) of test compound towards MAO-A and MAO-B are comparable with the results from in vitro radiolabelled ligand-based inhibition assay. The results demonstrated the application of these non-radiolabelled tracers as suitable pre-clinical tools to determine MAO occupancy.
Topics: Administration, Intravenous; Animals; Brain; Dose-Response Relationship, Drug; Harmine; Male; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Protein Binding; Rats; Rats, Sprague-Dawley; Selegiline
PubMed: 33636211
DOI: 10.1016/j.neuint.2021.105006 -
The Journal of Organic Chemistry Mar 2021A novel and versatile approach to construct 12-phenacyl-11-benzo[]xanthene-6,11(12)-dione derivatives through copper-catalyzed cascade reaction of propargylamines with...
A novel and versatile approach to construct 12-phenacyl-11-benzo[]xanthene-6,11(12)-dione derivatives through copper-catalyzed cascade reaction of propargylamines with 2-hydroxynaphthalene-1,4-diones has been developed. The procedure is proposed to go through a sequence of 1,4-conjugate addition, intramolecular nucleophilic addition/dehydration, and hydrolysis of alkyne followed by an enol-ketone tautomerization. The reaction provides a new and highly efficient method for the synthesis of 12-phenacyl-11-benzo[]xanthene-6,11(12)-diones by formation of three new bonds and one heterocycle from readily available starting materials in good to high yields (70-88%) with broad functional group compatibility in a single step.
Topics: Catalysis; Copper; Hydrolysis; Naphthols; Pargyline; Propylamines; Xanthenes
PubMed: 33625853
DOI: 10.1021/acs.joc.0c03029 -
Organic & Biomolecular Chemistry Mar 2021Described herein is the first example of glycosidation of thioglycosides in the presence of palladium(ii) bromide. While the activation with PdBr2 alone was proven...
Described herein is the first example of glycosidation of thioglycosides in the presence of palladium(ii) bromide. While the activation with PdBr2 alone was proven feasible, higher yields and cleaner reactions were achieved when these glycosylations were performed in the presence of propargyl bromide as an additive. Preliminary mechanistic studies suggest that propargyl bromide assists the reaction by creating an ionizing complex, which accelerates the leaving group departure. A variety of thioglycoside donors in reactions with different glycosyl acceptors were investigated to determine the initial scope of this new reaction. Selective and chemoselective activation of thioglycosides over other leaving groups has also been explored.
Topics: Catalysis; Disaccharides; Glycosylation; Palladium; Pargyline; Thioglycosides
PubMed: 33599667
DOI: 10.1039/d1ob00004g -
The Journal of Organic Chemistry Feb 2021The stereoselective synthesis of terminal bromo-substituted propargylamines via generation of lithium bromoacetylide from 1,2-dibromoethene and addition to Ellman...
The stereoselective synthesis of terminal bromo-substituted propargylamines via generation of lithium bromoacetylide from 1,2-dibromoethene and addition to Ellman chiral --butanesulfinyl aldimines is reported. Modest to good yields (43-85%) and diastereoselectivity (dr = 3:1 to >20:1) were achieved for a range of aryl, heteroaryl, alkyl, and α,β-unsaturated substrates. Terminal bromo-substituted propargylamines prepared via this method can be directly used in the frequently employed Cadiot-Chodkiewicz coupling to produce functionalized diynes. The method reported here increases the structural diversity of chiral terminal bromo-substituted propargylamines that can be readily synthesized as previous methods for the stereoselective synthesis of these compounds rely on amino acid precursors from the chiral pool.
Topics: Imines; Lithium; Pargyline; Propylamines; Stereoisomerism
PubMed: 33448846
DOI: 10.1021/acs.joc.0c02697 -
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 -
Bioorganic Chemistry Mar 2021A series of active hybrids combining 3-hydroxypyridin-4(1H)-one and coumarin pharmacophores were designed and synthesized as potential agents for the treatment of...
A series of active hybrids combining 3-hydroxypyridin-4(1H)-one and coumarin pharmacophores were designed and synthesized as potential agents for the treatment of Alzheimer's disease (AD). All the compounds exhibited excellent iron-chelating activities (pFe = 14.8-19.2) and showed favorable monoamine oxidase B (MAO-B) inhibitory effects compared to the reference drug Pargyline (IC = 86.9 nM). Among them, compound 11 g displayed the best MAO-B inhibitory activity with an IC value of 99.3 nM. Molecular docking analysis showed that compound 11 g could enter the entrance cavity and substrate cavity of MAO-B. Furthermore, the compound 11 g had an excellent antioxidant effect and was capable of protecting from the amyloid-β (Aβ) induced PC12 cell damage. In silico tools were applied for predicting the blood-brain barrier (BBB) penetration and compound 11 g was proved to overcome the brain exposure challenge. In the mice behavioral study, compound 11 g significantly ameliorated cognitive impairment induced by Scopolamine. More importantly, compound 11 g displayed favorable pharmacokinetic profiles in a rat model. In summary, compound 11 g, with both anti-MAO-B and iron-chelating ability, was proved to be a promising potential anti-AD agent for further optimization.
Topics: Alzheimer Disease; Animals; Dose-Response Relationship, Drug; Drug Design; Humans; Iron Chelating Agents; Maze Learning; Mice; Mice, Inbred ICR; Models, Molecular; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; PC12 Cells; Rats; Structure-Activity Relationship
PubMed: 33353806
DOI: 10.1016/j.bioorg.2020.104564 -
Macromolecular Rapid Communications Mar 2021Multicomponent polymerizations (MCPs) are a group of fascinating polymer synthesis approaches that are developed rapidly in the recent decade. As a popular alkyne-based...
Multicomponent polymerizations (MCPs) are a group of fascinating polymer synthesis approaches that are developed rapidly in the recent decade. As a popular alkyne-based MCP, the A -polycouplings of alkynes, aldehydes, and amines are developed for the synthesis of poly(propargylamine)s under the catalysis of metal catalysts. In this work, through the design of carboxylic acid group-activated alkyne monomers, a catalyst-free, four-component polymerization of propiolic acids, benzylamines, organoboronic acids, and formaldehyde is reported under mild condition at 45 °C in dichloroethane. This four-component polymerization is applicable to different monomer structures, which can afford seven poly(propargylamine)s with up to 94% yields and molecular weights of up to 13 900 g mol . Moreover, the poly(propargylamine)s demonstrate good solubility and processibility, high thermal stability and light refractivity, unique photophysical property, and so on. The simple monomers, mild condition, low cost, high efficiency, and procedure simplicity of this catalyst-free four-component polymerization demonstrates an elegant example of functional polymer synthesis.
Topics: Alkynes; Benzylamines; Catalysis; Formaldehyde; Pargyline; Polymerization; Propylamines
PubMed: 33314555
DOI: 10.1002/marc.202000633 -
ACS Medicinal Chemistry Letters Nov 2020The radiotracers [C]COU and [C]PHXY are potential PET imaging agents for in vivo studies of monoamine oxidases (MAOs), as previously shown in rodent and primate brain....
The radiotracers [C]COU and [C]PHXY are potential PET imaging agents for in vivo studies of monoamine oxidases (MAOs), as previously shown in rodent and primate brain. One-pot, automated methods for the radiosynthesis of [C]PHXY and [C]COU were developed to provide reliable and improved radiochemical yields. Although derived from the structure of the neurotoxin MPTP, COU did not exhibit in vivo neurotoxicity to dopaminergic nerve terminals in the mouse brain as assayed by losses of VMAT2 radioligand binding. PET imaging studies in rats demonstrated that both [C]COU and [C]PHXY exhibit retention in cardiac tissues that can be blocked by pretreatment with the MAO inhibitors deprenyl (MAO-B) and pargyline (MAO-A and -B). In addition to prior neuroimaging applications, [C]COU and [C]PHXY are thus also of interest for studies of MAO enzymatic activity and imaging of sympathetic nerve density in heart.
PubMed: 33214844
DOI: 10.1021/acsmedchemlett.0c00419